https://hemonc.org/w/api.php?action=feedcontributions&user=Rozinachowdhery&feedformat=atomHemOnc.org - A Hematology Oncology Wiki - User contributions [en]2024-03-29T13:02:44ZUser contributionsMediaWiki 1.35.14https://hemonc.org/w/index.php?title=Pancreatic_NET&diff=36583Pancreatic NET2019-04-25T19:57:22Z<p>Rozinachowdhery: /* Regimen */</p>
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<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Chowdhery.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Rozinachowdhery|Rozina Chowdhery, MD]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br />
| style="background-color:#F0F0F0; width: 15%" |[[File:Jeenavarghese.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Jvarghese|Jeena M. Varghese, MBBS]]<br>MD Anderson Cancer Center<br>Houston, TX</big><br>[https://www.linkedin.com/in/jeena-varghese-b2b45b9b/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
<big>Note: for more general neuroendocrine regimens, please visit the '''[[neuroendocrine tumors]]''' page.</big><br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2012:''' Öberg et al. [https://www.esmo.org/Guidelines/Endocrine-and-Neuroendocrine-Cancers/Neuroendocrine-Gastroenteropancreatic-Tumours Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf NCCN Guidelines - Neuroendocrine Tumors]<br />
<br />
=All lines of therapy=<br />
==Capecitabine & Temozolomide {{#subobject:738284|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:fc2dd9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665634/ Strosberg et al. 2011]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day at bedtime on days 10 to 14<br />
<br />
====Supportive medications====<br />
*[[Ondansetron (Zofran)]] 8 mg (route not specified) prior to each dose of [[Temozolomide (Temodar)]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, Helm J, Kvols L. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011 Jan 15;117(2):268-75. Epub 2010 Sep 7. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.25425/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665634/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20824724 PubMed]<br />
<br />
==Doxorubicin & Streptozocin {{#subobject:5c625d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:a9c7ed|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199202203260804 Moertel et al. 1992]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Chlorozotocin<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. [[#Fluorouracil_.26_Streptozocin_.26|5-FU & Streptozocin]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 22<br />
*[[Streptozocin (Zanosar)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. [https://www.nejm.org/doi/full/10.1056/NEJM199202203260804 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1310159 PubMed]<br />
<br />
==Everolimus monotherapy {{#subobject:78dff1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:5ea369|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ Yao et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208619/ Yao et al. 2011 (RADIANT-3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Everolimus (Afinitor)]] 10 mg PO once per day<br />
<br />
'''Given until progression of disease, unacceptable toxicity, drug interruption of 3 weeks or longer, or withdrawal of consent'''<br />
<br />
===References===<br />
# Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. Epub 2009 Nov 23. [http://jco.ascopubs.org/content/28/1/69.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19933912 PubMed]<br />
# '''RADIANT-3:''' Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Öberg K; RAD001 in Advanced Neuroendocrine Tumors Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1009290 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208619/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21306238 PubMed]<br />
# '''Review:''' Yao JC, Phan AT, Jehl V, Shah G, Meric-Bernstam F. Everolimus in advanced pancreatic neuroendocrine tumors: the clinical experience. Cancer Res. 2013 Mar 1;73(5):1449-53. Epub 2013 Feb 22. [http://cancerres.aacrjournals.org/content/73/5/1449.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23436795 PubMed]<br />
<br />
==Everolimus & Octreotide {{#subobject:d6b3eb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:b0f62f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ Yao et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Patients in Yao et al. 2010 who received this regimen had already been receiving octreotide LAR for at least 3 months before participating in the study.''<br />
====Endocrine & Chemotherapy====<br />
*[[Everolimus (Afinitor)]] 10 mg PO once per day<br />
*[[Octreotide LAR (Sandostatin LAR)]] up to 30 mg (whatever their prestudy dose was) IM once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:f82bb5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: Everolimus "dose of 10 mg was associated with superior PFS...however, the study was not prospectively powered for these comparisons. These analyses should be considered exploratory."''<br />
====Endocrine & Chemotherapy====<br />
*[[Everolimus (Afinitor)]] 5 or 10 mg PO once per day on days 1 to 28<br />
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1<br />
<br />
'''28-day cycle for up to 12 cycles or until progression of disease, though treatment could be continued beyond this period if thought by the treating physician to be beneficial'''<br />
<br />
===References===<br />
# Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008 Sep 10;26(26):4311-8. [http://jco.ascopubs.org/content/26/26/4311.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18779618 PubMed]<br />
# Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. Epub 2009 Nov 23. [http://jco.ascopubs.org/content/28/1/69.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19933912 PubMed]<br />
<br />
==FAS {{#subobject:66b05e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FAS: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>S</u>'''treptozocin<br />
<br />
===Regimen {{#subobject:de76a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/22/23/4762.long Kouvaraki et al. 2004]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Streptozocin (Zanosar)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
<br />
'''28-day cycles, given until progression of disease, unacceptable toxicity, or patient intolerance'''<br />
<br />
===References===<br />
# '''Retrospective:''' Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, Yao JC. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004 Dec 1;22(23):4762-71. [http://jco.ascopubs.org/content/22/23/4762.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15570077 PubMed]<br />
<br />
==Fluorouracil & Streptozocin {{#subobject:6f7b84|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e45011|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM198011203032101 Moertel et al. 1980]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Fluorouracil<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199202203260804 Moertel et al. 1992]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Chlorozotocin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. [[#Doxorubicin_.26_Streptozocin|Doxorubicin & Streptozocin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Note: treatment details are from Moertel et al. 1992.''<br />
====Chemotherapy====<br />
*[[Streptozocin (Zanosar)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# Moertel CG, Hanley JA, Johnson LA. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1980 Nov 20;303(21):1189-94. [https://www.nejm.org/doi/full/10.1056/NEJM198011203032101 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6252466 PubMed]<br />
# Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. [https://www.nejm.org/doi/full/10.1056/NEJM199202203260804 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1310159 PubMed]<br />
<br />
==Lanreotide Depot/Autogel monotherapy {{#subobject:8bca3a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:a9ee08|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1316158 Caplin et al. 2014 (CLARINET)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740728/ Caplin et al. 2016 (CLARINET extension)]<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
====Hormonotherapy====<br />
*[[Lanreotide (Somatuline) | Lanreotide (Somatuline) Depot/Autogel]] 120 mg SC once on day 1<br />
<br />
'''28-day cycle for 96 weeks (CLARINET) or up to 8 years (CLARINET extension)'''<br />
<br />
===References===<br />
# '''CLARINET:''' Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33. [https://www.nejm.org/doi/full/10.1056/NEJMoa1316158 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25014687 PubMed]<br />
# '''CLARINET Extension:''' Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Gomez-Panzani E, Ruszniewski P; CLARINET Investigators. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. Endocr Relat Cancer. 2016 Mar;23(3):191-9. Epub 2016 Jan 7. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740728/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26743120 PubMed]<br />
<br />
==Lanreotide & Interferon alfa-2b {{#subobject:9c5a59|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:652f4d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 Fjällskog et al. 2002]<br />
| style="background-color:#ffffbe" |Pilot, <20 pts<br />
|-<br />
|}<br />
''Fjällskog et al. 2002 contained case reports of several patients treated with lanreotide & interferon alfa. Each patient received individualized therapy rather than a standard regimen.''<br />
====Endocrine & Immunotherapy====<br />
*[[Lanreotide (Somatuline)]] 3 mg SC twice per day<br />
*[[Interferon alfa-2b (Intron-A)]] 3 to 5 million units SC given once per day, 3 to 7 days per week (total of 9 to 25 million units per week)<br />
<br />
===References===<br />
# Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. [http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12025889 PubMed]<br />
<br />
==Octreotide monotherapy {{#subobject:665a8b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cd8cf6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://annonc.oxfordjournals.org/content/15/6/966.long Oberg et al. 2004]<br />
| style="background-color:#ffffbe" |Consensus guideline<br />
|-<br />
|}<br />
====Hormonotherapy====<br />
*[[Octreotide (Sandostatin)]] 0.1 to 0.5 mg SC given 2 to 4 times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms<br />
**"A reasonable starting dose is" 0.15 mg SC TID<br />
<br />
'''Treatment continued indefinitely unless patients have unmanageable side-effects or insufficient control of symptoms'''<br />
<br />
===References===<br />
# '''Review:''' Brentjens R, Saltz L. Islet cell tumors of the pancreas: the medical oncologist's perspective. Surg Clin North Am. 2001 Jun;81(3):527-42. [http://www.sciencedirect.com/science/article/pii/S0039610905701419 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/11459269 PubMed]<br />
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [http://annonc.oxfordjournals.org/content/15/6/966.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15151956 PubMed]<br />
<br />
==Octreotide LAR monotherapy {{#subobject:e356ea|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f0bc1b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/28/4656.long Rinke et al. 2009 (PROMID)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior TTP<br />
|-<br />
|}<br />
====Hormonotherapy====<br />
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1, with potentially higher doses if needed for symptom control<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [http://annonc.oxfordjournals.org/content/15/6/966.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15151956 PubMed]<br />
# '''PROMID:''' Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. [http://jco.ascopubs.org/content/27/28/4656.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19704057 PubMed]<br />
<br />
==Octreotide & Interferon alfa {{#subobject:1cf4c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:cbf5c4|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 Fjällskog et al. 2002]<br />
| style="background-color:#ffffbe" |Pilot, <20 pts<br />
|-<br />
|}<br />
''Fjällskog et al. 2002 contained case reports of several patients treated with octreotide & interferon alfa. Each patient received individualized therapy rather than a standard regimen.''<br />
====Endocrine & Immunotherapy====<br />
*[[Octreotide (Sandostatin)]] 0.05 to 0.5 mg SC given 2 to 3 times per day<br />
*[[Interferon alfa-2b (Intron-A)]] 3 to 5 million units SC given once per day, 3 to 7 days per week (total of 9 to 25 million units per week)<br />
<br />
===References===<br />
# Janson ET, Oberg K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. [https://www.tandfonline.com/doi/full/10.3109/02841869309083916 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7686765 PubMed]<br />
# Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. [http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12025889 PubMed]<br />
<br />
==Placebo==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/28/4656.long Rinke et al. 2009 (PROMID)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Octreotide_LAR_monotherapy|Octreotide LAR]]<br />
| style="background-color:#d73027" |Inferior TTP<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1003825 Raymond et al. 2011 (A6181111)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
| rowspan="2" |[[#Sunitinib_monotherapy|Sunitinib]]<br />
| rowspan="2" style="background-color:#d73027" |Inferior PFS<br />
| style="background-color:#1a9850" |Less diarrhea<br />
|-<br />
| style="background-color:#91cf60" |Seems to have better insomnia<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208619/ Yao et al. 2011 (RADIANT-3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Everolimus_monotherapy|Everolimus]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1316158 Caplin et al. 2014 (CLARINET)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lanreotide_Depot.2FAutogel_monotherapy|Lanreotide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only. Note: while the initial A6181111 publication seemed to have a significant survival disadvantage for this arm (p=0.02), this finding was no longer significant at the final update (p=0.094). The primary endpoint (PFS) remains significant.''<br />
<br />
===References===<br />
# '''PROMID:''' Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. [http://jco.ascopubs.org/content/27/28/4656.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19704057 PubMed]<br />
# '''A6181111:''' Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):501-13. Erratum in: N Engl J Med. 2011 Mar 17;364(11):1082. [https://www.nejm.org/doi/full/10.1056/NEJMoa1003825 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306237 PubMed]<br />
## '''HRQoL analysis:''' Vinik A, Bottomley A, Korytowsky B, Bang YJ, Raoul JL, Valle JW, Metrakos P, Hörsch D, Mundayat R, Reisman A, Wang Z, Chao RC, Raymond E. Patient-reported outcomes and quality of life with sunitinib versus placebo for pancreatic neuroendocrine tumors: results from an international phase III trial. Target Oncol. 2016 Dec;11(6):815-824. [https://link.springer.com/article/10.1007%2Fs11523-016-0462-5 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27924459 PubMed]<br />
## '''Update:''' Faivre S, Niccoli P, Castellano D, Valle JW, Hammel P, Raoul JL, Vinik A, Van Cutsem E, Bang YJ, Lee SH, Borbath I, Lombard-Bohas C, Metrakos P, Smith D, Chen JS, Ruszniewski P, Seitz JF, Patyna S, Lu DR, Ishak KJ, Raymond E. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol. 2017 Feb 1;28(2):339-343. [https://academic.oup.com/annonc/article/28/2/339/2676883 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27836885 PubMed]<br />
# '''RADIANT-3:''' Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Öberg K; RAD001 in Advanced Neuroendocrine Tumors Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1009290 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208619/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21306238 PubMed]<br />
# '''CLARINET:''' Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33. [https://www.nejm.org/doi/full/10.1056/NEJMoa1316158 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25014687 PubMed]<br />
<br />
==Lutetium Lu 177 dotatate & Octreotide LAR {{#subobject:ee13c4|Regimen=1}} ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:33d0ef|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ Strosberg et al. 2017 (NETTER-1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
| High-dose Octreotide LAR<br />
| style="background-color:#1a9850" |Superior PFS<br />
| style="background-color:#d73027" |More cytopenias (neutropenia, thrombocytopenia and lymphopenia)<br />
|-<br />
|}<br />
''Note: patients had well-differentiated (Ki67 less than 20%) midgut neuroendocrine tumors with somatostatin receptors present in all target lesions''<br />
<br />
==== Chemotherapy ====<br />
* [[Lutetium Lu 177 dotatate (Lutathera)]] 7.4 GBq (200 mCi) IV once every 8 weeks for 4 cycles* <br />
* [[Octreotide LAR (Sandostatin LAR)]] 30mg SC once every 4 weeks <br />
**Octreotide was given 2 hours after each infusion and then continued monthly <br />
<br />
<nowiki>*</nowiki>For renal protection, an IV amino acid solution was administered concomitantly for at least 4 hours, starting 30 minutes before drug infusion.<br />
<br />
=== References ===<br />
# '''NETTER-1:''' Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. [https://www.nejm.org/doi/full/10.1056/NEJMoa1607427 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28076709 PubMed]<br />
<br />
==Sunitinib monotherapy {{#subobject:ee13d2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:80d0ef|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1003825 Raymond et al. 2011 (A6181111)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
| rowspan="2" |[[#Placebo|Placebo]]<br />
| rowspan="2" style="background-color:#1a9850" |Superior PFS<br />
| style="background-color:#d73027" |More diarrhea<br />
|-<br />
| style="background-color:#fc8d59" |Seems to have worse insomnia<br />
|-<br />
|}<br />
''Note: while the initial publication seemed to have a significant survival advantage for this arm (p=0.02), this finding was no longer significant at the final update (p=0.094). The primary endpoint (PFS) remains significant.''<br />
====Chemotherapy====<br />
*[[Sunitinib (Sutent)]] 37.5 mg PO once per day<br />
<br />
'''Given indefinitely'''<br />
<br />
===References===<br />
# '''A6181111:''' Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):501-13. Erratum in: N Engl J Med. 2011 Mar 17;364(11):1082. [https://www.nejm.org/doi/full/10.1056/NEJMoa1003825 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306237 PubMed]<br />
## '''HRQoL analysis:''' Vinik A, Bottomley A, Korytowsky B, Bang YJ, Raoul JL, Valle JW, Metrakos P, Hörsch D, Mundayat R, Reisman A, Wang Z, Chao RC, Raymond E. Patient-reported outcomes and quality of life with sunitinib versus placebo for pancreatic neuroendocrine tumors: results from an international phase III trial. Target Oncol. 2016 Dec;11(6):815-824. [https://link.springer.com/article/10.1007%2Fs11523-016-0462-5 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27924459 PubMed]<br />
## '''Update:''' Faivre S, Niccoli P, Castellano D, Valle JW, Hammel P, Raoul JL, Vinik A, Van Cutsem E, Bang YJ, Lee SH, Borbath I, Lombard-Bohas C, Metrakos P, Smith D, Chen JS, Ruszniewski P, Seitz JF, Patyna S, Lu DR, Ishak KJ, Raymond E. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol. 2017 Feb 1;28(2):339-343. [https://academic.oup.com/annonc/article/28/2/339/2676883 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27836885 PubMed]<br />
<br />
==Temozolomide monotherapy {{#subobject:69ae1c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:6aac4c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://clincancerres.aacrjournals.org/content/13/10/2986.long Ekeblad et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Temozolomide (Temodar)]] as follows:<br />
**Cycle 1: 100 or 150 mg/m<sup>2</sup> PO once per day on days 1 to 5<br />
**Cycle 2 onwards: increased as tolerated up to 200 mg/m<sup>2</sup> PO once per day on days 1 to 5<br />
<br />
====Supportive medications====<br />
*[[Tropisetron (Navoban)]] (dose/route/schedule not specified) routinely used as an antiemetic<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007 May 15;13(10):2986-91. [http://clincancerres.aacrjournals.org/content/13/10/2986.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17505000 PubMed]<br />
<br />
==Temozolomide & Bevacizumab {{#subobject:ce7fe6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:be3718|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874232/ Chan et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Temozolomide (Temodar)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 7, 15 to 21<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1 & 15<br />
<br />
====Supportive medications====<br />
*[[Trimethoprim/Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO once every Monday, Wednesday, and Friday; allergic patients received alternate Pneumocystis carinii (PCP) prophylaxis<br />
*[[Acyclovir (Zovirax)]] 400 mg PO three times per day as prophylaxis against varicella zoster<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Chan JA, Stuart K, Earle CC, Clark JW, Bhargava P, Miksad R, Blaszkowsky L, Enzinger PC, Meyerhardt JA, Zheng H, Fuchs CS, Kulke MH. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol. 2012 Aug 20;30(24):2963-8. Epub 2012 Jul 9. [http://jco.ascopubs.org/content/30/24/2963.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874232/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22778320 PubMed]<br />
<br />
==Temozolomide & Thalidomide {{#subobject:16afb7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:ceca5a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/3/401.long Kulke et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Temozolomide (Temodar)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 7, 15 to 21<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, Vincitore M, Michelini A, Fuchs CS. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006 Jan 20;24(3):401-6. [http://jco.ascopubs.org/content/24/3/401.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16421420 PubMed]<br />
<br />
[[Category:Pancreatic NET regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Endocrine cancers]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdheryhttps://hemonc.org/w/index.php?title=Pancreatic_cancer&diff=36476Pancreatic cancer2019-03-28T20:22:16Z<p>Rozinachowdhery: Updated OS for 5-FU liposomal irinotecan</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Chowdhery.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Rozinachowdhery|Rozina Chowdhery, MD]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br />
| style="background-color:#F0F0F0; width:15%" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2018:''' Sohal et al. [http://ascopubs.org/doi/full/10.1200/JCO.2018.78.9636 Metastatic pancreatic cancer: ASCO Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/29791286 PubMed]<br />
*'''2017:''' Khorana et al. [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.4948 Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/28398845 PubMed]<br />
===Older===<br />
*'''2016:''' Sohal et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019760/ Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2016:''' Balaban et al. [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.5561 Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/27247216 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2017:''' [https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Cancer-of-the-Pancreas/eUpdate-Treatment-Recommendations eUpdate – Cancer of the Pancreas Treatment Recommendations]<br />
*'''2015:''' Ducreux et al. [https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Cancer-of-the-Pancreas Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015)] [https://www.ncbi.nlm.nih.gov/pubmed/26314780 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf NCCN Guidelines - Pancreatic Adenocarcinoma]<br />
<br />
=Adjuvant therapy=<br />
==Capecitabine & Gemcitabine {{#subobject:17f9f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Regimen {{#subobject:e6a3e3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Treatment starts within 12 weeks of surgery.''<br />
====Preceding treatment====<br />
*[[Surgery#Pancreatic_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week on weeks 1 to 3<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# '''ESPAC-4:''' Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:29266e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:242770|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Fluorouracil.2FFluorouracil_.26_RT|5-FU/5-FU & RT]]<br> 2. 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|3. [[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3 version 2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2011.38.2960 Schmidt et al. 2012 (CapRI)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU, Cisplatin, IFN alfa-2b, RT<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: reported efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*[[Surgery#Pancreatic_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# '''ESPAC-1:''' Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [https://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# '''ESPAC-3 version 2:''' Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# '''CapRI:''' Schmidt J, Abel U, Debus J, Harig S, Hoffmann K, Herrmann T, Bartsch D, Klein J, Mansmann U, Jäger D, Capussotti L, Kunz R, Büchler MW. Open-label, multicenter, randomized phase III trial of adjuvant chemoradiation plus interferon alfa-2b versus fluorouracil and folinic acid for patients with resected pancreatic adenocarcinoma. J Clin Oncol. 2012 Nov 20;30(33):4077-83. Epub 2012 Sep 24. [http://ascopubs.org/doi/full/10.1200/JCO.2011.38.2960 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23008325 PubMed]<br />
<br />
==Fluorouracil/Fluorouracil & RT {{#subobject:331d4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Fluorouracil/Fluorouracil & RT: Fluorouracil alternating with Fluorouracil & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:89426a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br> 2. [[#Observation|Observation]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|3. 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008 (RTOG 9704)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine.2FFluorouracil_.26_RT|Gemcitabine/5-FU & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior (*)<br />
|-<br />
|}<br />
''Note: reported efficacy for ESPAC-1 is based on the 2004 update. Reported efficacy for RTOG 9704 is based on the 2011 update.''<br />
====Preceding treatment====<br />
*[[Surgery#Pancreatic_cancer_surgery|Surgery]]<br />
====Chemotherapy, part 1====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose: 5000 mg/m<sup>2</sup>)<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 7000 mg/m<sup>2</sup>)<br />
<br />
'''6-week cycle for 2 cycles'''<br />
<br />
===References===<br />
# '''ESPAC-1:''' Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [https://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# '''RTOG 9704:''' Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
## '''Update:''' Regine WF, Winter KA, Abrams R, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Rich TA, Willett CG. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the US Intergroup/RTOG 9704 phase III trial. Ann Surg Oncol. 2011 May;18(5):1319-26. Epub 2011 Mar 10. [https://link.springer.com/article/10.1245%2Fs10434-011-1630-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548408/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21499862 PubMed]<br />
<br />
==mFOLFIRINOX {{#subobject:bbb2c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
mFOLFIRINOX: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:a170cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1809775 Conroy et al. 2018 (NCIC CTG PA.6)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#d73027" |More toxic<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Surgery#Pancreatic_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given fourth'''<br />
*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given third'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.6:''' Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, Choné L, Francois E, Artru P, Biagi JJ, Lecomte T, Assenat E, Faroux R, Ychou M, Volet J, Sauvanet A, Breysacher G, Di Fiore F, Cripps C, Kavan P, Texereau P, Bouhier-Leporrier K, Khemissa-Akouz F, Legoux JL, Juzyna B, Gourgou S, O'Callaghan CJ, Jouffroy-Zeller C, Rat P, Malka D, Castan F, Bachet JB; Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med. 2018 Dec 20;379(25):2395-2406. [https://www.nejm.org/doi/full/10.1056/NEJMoa1809775 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30575490 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:34e70d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 2 out of 3 weeks {{#subobject:dc12dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Gemcitabine_.26_RT|Gemcitabine & RT]], then [[Surgery#Pancreatic_cancer_surgery|surgery]]<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 5 cycles'''<br />
<br />
===Variant #2, 3 out of 4 weeks {{#subobject:a756a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743365/ Ueno et al. 2009 (JSAP-02)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3 version 2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_.26_Folinic_acid|Fluorouracil & Leucovorin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine|Capecitabine & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.72.6463 Sinn et al. 2017 (CONKO-005)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Erlotinib & Gemcitabine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1809775 Conroy et al. 2018 (NCIC CTG PA.6)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#mFOLFIRINOX|mFOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
<br />
''Note: efficacy for CONKO-001 is based on the 2013 update.''<br />
====Preceding treatment====<br />
*[[Surgery#Pancreatic_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# '''CONKO-001:''' Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
# '''JSAP-02:''' Ueno H, Kosuge T, Matsuyama Y, Yamamoto J, Nakao A, Egawa S, Doi R, Monden M, Hatori T, Tanaka M, Shimada M, Kanemitsu K. A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer. Br J Cancer. 2009 Sep 15;101(6):908-15. Epub 2009 Aug 18. [https://www.nature.com/articles/6605256 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743365/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19690548 PubMed]<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [https://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# '''ESPAC-3 version 2:''' Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# '''JASPAC 01:''' Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
# '''ESPAC-4:''' Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
# '''CONKO-005:''' Sinn M, Bahra M, Liersch T, Gellert K, Messmann H, Bechstein W, Waldschmidt D, Jacobasch L, Wilhelm M, Rau BM, Grützmann R, Weinmann A, Maschmeyer G, Pelzer U, Stieler JM, Striefler JK, Ghadimi M, Bischoff S, Dörken B, Oettle H, Riess H. CONKO-005: Adjuvant Chemotherapy With Gemcitabine Plus Erlotinib Versus Gemcitabine Alone in Patients After R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial. J Clin Oncol. 2017 Oct 10;35(29):3330-3337. Epub 2017 Aug 17. [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.6463 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28817370 PubMed]<br />
# '''NCIC CTG PA.6:''' Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, Choné L, Francois E, Artru P, Biagi JJ, Lecomte T, Assenat E, Faroux R, Ychou M, Volet J, Sauvanet A, Breysacher G, Di Fiore F, Cripps C, Kavan P, Texereau P, Bouhier-Leporrier K, Khemissa-Akouz F, Legoux JL, Juzyna B, Gourgou S, O'Callaghan CJ, Jouffroy-Zeller C, Rat P, Malka D, Castan F, Bachet JB; Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med. 2018 Dec 20;379(25):2395-2406. [https://www.nejm.org/doi/full/10.1056/NEJMoa1809775 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30575490 PubMed]<br />
<br />
==Gemcitabine/Fluorouracil & RT {{#subobject:f8c8d9|Regimen=1}}==<br />
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Gemcitabine/Fluorouracil & RT: Gemcitabine alternating with Fluorouracil & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:3fef3f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008 (RTOG 9704)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil.2FFluorouracil_.26_RT|5-FU/5-FU & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior (*)<br />
|-<br />
|}<br />
''Note: reported efficacy is based on the 2011 update.''<br />
====Preceding treatment====<br />
*[[Surgery#Pancreatic_cancer_surgery|Surgery]]<br />
====Chemotherapy, part 1====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
# '''RTOG 9704:''' Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
## '''Update:''' Regine WF, Winter KA, Abrams R, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Rich TA, Willett CG. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the US Intergroup/RTOG 9704 phase III trial. Ann Surg Oncol. 2011 May;18(5):1319-26. Epub 2011 Mar 10. [https://link.springer.com/article/10.1245%2Fs10434-011-1630-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548408/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21499862 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1420941/ Klinkenbijl et al. 1999 (EORTC 40891)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & RT<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. [[#Fluorouracil.2FFluorouracil_.26_RT|5-FU/5-FU & RT]]<br> 3. 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Efficacy for ESPAC-1 is based on the 2004 update and efficacy for CONKO-001 is based on 2013 update.''<br />
====Preceding treatment====<br />
*[[Surgery#Pancreatic_cancer_surgery|Surgery]]<br />
===References===<br />
# '''EORTC 40891:''' Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH, Arnaud JP, Gonzalez DG, de Wit LT, Hennipman A, Wils J. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999 Dec;230(6):776-82. [https://insights.ovid.com/pubmed?pmid=10615932 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1420941/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/10615932 PubMed]<br />
## '''Update:''' Smeenk HG, van Eijck CH, Hop WC, Erdmann J, Tran KC, Debois M, van Cutsem E, van Dekken H, Klinkenbijl JH, Jeekel J. Long-term survival and metastatic pattern of pancreatic and periampullary cancer after adjuvant chemoradiation or observation: long-term results of EORTC trial 40891. Ann Surg. 2007 Nov;246(5):734-40. [https://insights.ovid.com/pubmed?pmid=17968163 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17968163 PubMed]<br />
# '''ESPAC-1:''' Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [https://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# '''CONKO-001:''' Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:252c51|Regimen=1}}==<br />
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===Regimen {{#subobject:cdcc15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
====Preceding treatment====<br />
*[[Surgery#Pancreatic_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 28<br />
<br />
'''42-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
# '''JASPAC 01:''' Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, potentially resectable=<br />
<br />
==Docetaxel, Gemcitabine, RT {{#subobject:49a407|Regimen=1}}==<br />
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RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:78b0ba|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1245%2FASO.2005.04.503 Pipas et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 65 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Gemcitabine (Gemzar)]] 4000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29<br />
<br />
'''6-week course, followed immediately (day 43) by:'''<br />
<br />
====Chemoradiation====<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy to primary target volume. Then 5.4 Gy boost to secondary target volume of 1- to 1.5-cm margin on all sides, including proven nodal involvement. Total 50.4 Gy in 28 fractions.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
# Pipas JM, Barth RJ Jr, Zaki B, Tsapakos MJ, Suriawinata AA, Bettmann MA, Cates JM, Ripple GH, Sutton JE, Gordon SR, McDonnell CE, Perez RP, Redfield N, Meyer LP, Marshall JF, Cole BF, Colacchio TA. Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2005 Dec;12(12):995-1004. Epub 2005 Nov 1. [http://link.springer.com/article/10.1245%2FASO.2005.04.503 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16252135 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:55e32d|Regimen=1}}==<br />
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RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:6ce551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract Takahashi et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy per fraction, 5 days per week, 25 fractions, total dose of 50 Gy over 5 weeks.<br />
<br />
'''28-day cycle for 3 cycles''' ''(Radiation given over weeks 1-5 only)''<br />
====Subsequent treatment====<br />
*Restaging is performed 8 weeks after radiation complete (2 weeks after chemotherapy complete). [[Surgery#Pancreatic_cancer_surgery|Resection]] immediately thereafter, if feasible<br />
<br />
===Variant #2 {{#subobject:dc32dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 500 mg/m<sup>2</sup> IV over 50 minutes once per week for 6 weeks<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 180 cGy x 22 with 3 cm margin to GTV then 180 cGy x 6 with 2 cm margin to GTV, total 50.4 Gy over 6 weeks<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
*Restaging after radiation complete. 4 to 6 week break, followed by [[Surgery#Pancreatic_cancer_surgery|surgery]], followed by 4 to 8 week break, then [[#Gemcitabine_monotherapy|adjuvant gemcitabine]]<br />
<br />
===References===<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [https://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, Ioka T, Uehara H, Yano M, Ishikawa O. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013 Dec;258(6):1040-50.[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23799421 PubMed]<br />
<br />
==Gemcitabine, Cetuximab, RT {{#subobject:aea7b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c38534|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ Pipas et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**6 to 8 days prior radiation: 400 mg/m<sup>2</sup> IV over 2 hours once<br />
**During radiation: 250 mg/m<sup>2</sup> IV over 60 minutes once per week for 6 doses<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], delivered using IMRT. Gross tumor volume (GTV) was all known disease including imaging proven nodal disease. The primary planning target volume (PTV1) included the GTV with 2- to 3-cm margins in all directions as well as potential nodal involvement. Secondary planning target volume (PTV2) included the GTV with 1- to 1.5-cm margins on all sides including proven nodal involvement. Tertiary planning treatment volume (PTV3) included the area of the GTV adjacent to the vascular structures specifically the mesenteric and portal vessels with a 0.5-cm margin. The prescription dose delivered to PTV3 was 54 Gy in 28 fractions. Synchronously, PTV1 and PTV2 received 45 and 50.4 Gy, respectively. All fields were treated daily at five fractions per week.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
''One month following therapy, patients were restaged with CT scan of chest/abdomen/pelvis. Patients deemed to be candidates for surgical resection were offered laparotomy ∼6 to 10 weeks after completion of neoadjuvant therapy.''<br />
<br />
===References===<br />
# Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, Tsongalis GJ, Colacchio TA, Gordon SR, Sutton JE, Srivastava A, Smith KD, Gardner TB, Korc M, Davis TH, Preis M, Tarczewski SM, Mackenzie TA, Barth RJ Jr. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. 2012 Nov;23(11):2820-7. Epub 2012 May 9. [http://annonc.oxfordjournals.org/content/23/11/2820.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571859 PubMed]<br />
<br />
== FOLFIRINOX/modified FOLFIRINOX +/- Chemoradiation ==<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|Murphy et al. 2018 <br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: FOLFIRINOX should be limited to those with ECOG 0-1''<br />
<br />
==== Chemotherapy ====<br />
* Folinic acid (Leucovorin) 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, given second<br />
* Fluorouracil (5-FU) 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, given fourth (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
* Irinotecan (Camptosar) 180* mg/m<sup>2</sup> IV over 90 minutes once on day 1, given third with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin<br />
* Oxaliplatin (Eloxatin) 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, given first<br />
<br />
==== Supportive medications ====<br />
* Pegfilgrastim (Neulasta) 6 mg SC once on day 4<br />
'''14-day cycle for 8* cycles''' <br />
<br />
<nowiki>*</nowiki>Amendment after first 6 patients were enrolled increased neoadjuvant cycles from 4 to 8 if no progression was detected on restaging CT<br />
<br />
Followed by restaging with CT scan. If tumor was resectable (no vascular involvement), they received short-course proton chemoradiotherapy:<br />
<br />
==== Proton Chemoradiotherapy ====<br />
* Capecitabine 825 mg/m<sup>2</sup> PO BID, Monday – Friday for 2 weeks<br />
* Proton radiotherapy of 25 GyE in 5 treatments OR Intensity modulated radiotherapy (IMRT) of 30 Gy in 10 fractions<br />
<br />
=== References ===<br />
# Murphy J.E., Wo J.Y., Ryan D.P., Jiang W., Yeap B.Y., Drapek L.C., Blaszkowsky L.S., Kwak E.L., Allen J.N., Clark J.W., et al. Total neoadjuvant therapy with folfirinox followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: A phase 2 clinical trial. JAMA Oncol. 2018; 4:963–969. doi: 10.1001/jamaoncol.2018.0329. Link to original article: <nowiki>https://jamanetwork.com/journals/jamaoncology/fullarticle/2679565</nowiki> contains verified protocol Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/29800971<br />
<br />
==mFOLFIRINOX, Gemcitabine, RT {{#subobject:b71003|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFIRINOX, Gemcitabine, RT: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin, Gemcitabine, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:d87ec0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ Blazer et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Fluorouracil (5-FU)]] 1200 mg/m<sup>2</sup>/day IV continuous infusion over 46 hours, started on day 1 (total dose per cycle: 2400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once on day 1<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 4<br />
<br />
'''14-day cycle for 4 to 8 cycles'''<br />
<br />
''Followed by complete restaging. If tumor localized but still not resectable, chemoradiotherapy was administered:''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week<br />
*[[External beam radiotherapy]] was 36 Gy in 15 daily fractions<br />
<br />
'''3-week course'''<br />
<br />
===Variant #2 {{#subobject:7bb0e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ Hosein et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles. Protocol followed "per ACCORD-11 trial." Filgrastim was given at the discretion of the treating physician.'''<br />
<br />
''Treatment stopped at maximum response or tolerability. Resectable patients by imaging criteria were offered surgery, followed by postoperative chemoradiotherapy. Unresectable patients were offered chemoradiotherapy, followed by surgery (if they became resectable):''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV once per week<br />
*[[External beam radiotherapy]] at 50.4 Gy in 28 fractions.<br />
<br />
'''6-week course'''<br />
===References===<br />
# '''Retrospective:''' Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, Narayanan G, Ribeiro A, Portelance L, Merchan JR, Levi JU, Rocha-Lima CM. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012 May 29;12:199. [http://www.biomedcentral.com/1471-2407/12/199 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22642850 PubMed]<br />
# '''Retrospective:''' Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, Wuthrick E, Williams TM, Reardon J, Christopher Ellison E, Bloomston M, Bekaii-Saab T. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015 Apr;22(4):1153-9. [http://link.springer.com/article/10.1245%2Fs10434-014-4225-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25358667 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, unresectable=<br />
<br />
==Capecitabine monotherapy {{#subobject:dbd841|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dc4779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:6d97a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, Gem 3 out of 4 weeks x 4 {{#subobject:87edde|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Erlotinib & Gemcitabine x 2 more cycles (6 total) versus Capecitabine, Erlotinib, RT<br />
<br />
===Variant #2, Gem 3 out of 4 weeks x 6 {{#subobject:5a5e14|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
''Note: it is not clear from the protocol whether erlotinib is continued beyond the end of chemotherapy.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] as follows:<br />
**Cycles 1 to 4: 100 mg PO once per day<br />
**Cycles 5 & 6: 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 100 mg/day {{#subobject:b4258e|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #4, gemcitabine lead-in, erlotinib 150 mg/day {{#subobject:b7a41f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''GERCOR LAP07:''' Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Fluorouracil & RT {{#subobject:26f1c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:29784e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19811015)48:8%3C1705::AID-CNCR2820480803%3E3.0.CO;2-4 Moertel et al. 1981]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|RT<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ Herman et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Fluorouracil & RT with TNFerade<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on Mondays (total dose per week: 1000 mg/m<sup>2</sup>)<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 50.4 Gy total: 1.80 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy, followed by 1.80 Gy x 3 fractions boost to the tumor bed.<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
*Herman et al. 2013: Gemcitabine or Erlotinib & Gemcitabine maintenance, starting four weeks after chemoradiotherapy<br />
<br />
===References===<br />
# Moertel CG, Frytak S, Hahn RG, O'Connell MJ, Reitemeier RJ, Rubin J, Schutt AJ, Weiland LH, Childs DS, Holbrook MA, Lavin PT, Livstone E, Spiro H, Knowlton A, Kalser M, Barkin J, Lessner H, Mann-Kaplan R, Ramming K, Douglas HO Jr, Thomas P, Nave H, Bateman J, Lokich J, Brooks J, Chaffey J, Corson JM, Zamcheck N, Novak JW. Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer. 1981 Oct 15;48(8):1705-10. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19811015)48:8%3C1705::AID-CNCR2820480803%3E3.0.CO;2-4 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7284971 PubMed]<br />
# Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, Donehower RC, Pawlik TM, Ziegler MA, Cai H, Savage DT, Canto MI, Klapman J, Reid T, Shah RJ, Hoffe SE, Rosemurgy A, Wolfgang CL, Laheru DA. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013 Mar 1;31(7):886-94. Epub 2013 Jan 22. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.7516 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23341531 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:4f0be9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 3 out of 4 weeks x 4 {{#subobject:c511a7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Gemcitabine x 2 more cycles (6 total) versus Capecitabine & RT<br />
<br />
===Variant #2, 3 out of 4 weeks x 6 {{#subobject:cf89f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in ("Burris regimen") {{#subobject:82f8b2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.tandfonline.com/doi/abs/10.1179/joc.2004.16.6.589 Cantore et al. 2004]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Intraarterial FLEC<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://academic.oup.com/annonc/article/19/9/1592/208785 Chauffert et al. 2008 (FFCD/SFRO 2000-01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|CF & RT, then Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011 (ECOG E4201)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_RT_2|Gemcitabine & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent 4-week cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''Continued for at least 3 months'''<br />
====Subsequent treatment====<br />
*Louvet et al. 2005: 5-FU & RT consolidation was recommended but not mandated<br />
<br />
===References===<br />
# Cantore M, Fiorentini G, Luppi G, Rosati G, Caudana R, Piazza E, Comella G, Ceravolo C, Miserocchi L, Mambrini A, Del Freo A, Zamagni D, Rabbi C, Marangolo M. Gemcitabine versus FLEC regimen given intra-arterially to patients with unresectable pancreatic cancer: a prospective, randomized phase III trial of the Italian Society for Integrated Locoregional Therapy in Oncology. J Chemother. 2004 Dec;16(6):589-94. [https://www.tandfonline.com/doi/abs/10.1179/joc.2004.16.6.589 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15700852 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# '''FFCD/SFRO 2000-01:''' Chauffert B, Mornex F, Bonnetain F, Rougier P, Mariette C, Bouché O, Bosset JF, Aparicio T, Mineur L, Azzedine A, Hammel P, Butel J, Stremsdoerfer N, Maingon P, Bedenne L. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer: definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol. 2008 Sep;19(9):1592-9. Epub 2008 May 7. [https://academic.oup.com/annonc/article/19/9/1592/208785 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18467316 PubMed]<br />
# '''ECOG E4201:''' Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
# '''GERCOR LAP07:''' Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:a6e6fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 (600 mg/m<sup>2</sup>) {{#subobject:a6de29|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract Cardenes et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011 (ECOG E4201)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV over 30 to 60 minutes once per week during radiation<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy per fraction, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks.<br />
<br />
'''One course, followed in 4 weeks by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycle for up to 5 cycles'''<br />
<br />
===Variant #2 (400 mg/m<sup>2</sup>) {{#subobject:c1ac3c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract Epelbaum et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week for 7 weeks<br />
<br />
'''Radiation planning during this phase, followed by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 400 mg/m<sup>2</sup> IV over 30 minutes once per week (days 1, 8, 15)<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks<br />
<br />
'''28 day cycle for 2 cycles, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Epelbaum R, Rosenblatt E, Nasrallah S, Faraggi D, Gaitini D, Mizrahi S, Kuten A. Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J Surg Oncol. 2002 Nov;81(3):138-43. [https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12407726 PubMed]<br />
# Cardenes HR, Moore AM, Johnson CS, Yu M, Helft P, Chiorean EG, Vinson J, Howard TJ, Stephens AW, Tai DF, Loehrer PJ Sr. A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study. Am J Clin Oncol. 2011 Oct;34(5):460-5.[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20881474 PubMed]<br />
# '''ECOG E4201:''' Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
<br />
==GemOx {{#subobject:19d87f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:5a25e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_2|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycle for at least 3 months'''<br />
<br />
''Subsequent chemoradiotherapy (45 Gy in 25 fractions for 5 weeks, associated with a daily FU 250 mg/m<sup>2</sup> continuous infusion, and a boost of 10 Gy in 8 fractions restricted to the initial tumor volume)'' ''was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
<br />
==Radiation therapy {{#subobject:5ac377|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:ce3d2d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.redjournal.org/article/S0360-3016(05)00096-9/fulltext Cohen et al. 2005 (ECOG E8282)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU, MMC, RT<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Radiotherapy====<br />
*[[External beam radiotherapy]]<br />
<br />
===References===<br />
# '''ECOG E8282:''' Cohen SJ, Dobelbower R Jr, Lipsitz S, Catalano PJ, Sischy B, Smith TJ, Haller DG; Eastern Cooperative Oncology Group. A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282. Int J Radiat Oncol Biol Phys. 2005 Aug 1;62(5):1345-50. [https://www.redjournal.org/article/S0360-3016(05)00096-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16029791 PubMed]<br />
<br />
=Metastatic disease, first-line=<br />
<br />
==Capecitabine monotherapy {{#subobject:4f5f03|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b31bbb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Capecitabine & Gemcitabine {{#subobject:2f0431|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Variant #1 {{#subobject:fcd708|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Note: this is essentially identical to the maintenance phase of variant #2, below.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:e8f0bf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO twice per day on days 1 to 21, 29 to 49<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO twice per day on days 1 to 21<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:a7e551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 650 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 24 weeks'''<br />
<br />
===References===<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:c30d8f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 25/1000, weekly dosing {{#subobject:20a0f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.10323 Colucci et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note that cisplatin is not given on day 22 of the first 8 weeks; otherwise, the schedule is identical to the schedule for gemcitabine. Treatment in Colucci et al. 2002 is given for a total of 3 cycles (16 weeks).''<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] as follows, '''given first, 60 minutes prior to gemcitabine''':<br />
**First 8 weeks: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Subsequent cycles: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 35/1000, 2 out of 3 weeks {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract Cascinu et al. 2008]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Cisplatin, Gemcitabine, Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8 (with 1500 mL NS)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #3, 50/1000, bi-weekly dosing {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Colucci G, Giuliani F, Gebbia V, Biglietto M, Rabitti P, Uomo G, Cigolari S, Testa A, Maiello E, Lopez M. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell'Italia Meridionale. Cancer. 2002 Feb 15;94(4):902-10. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.10323 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11920457 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 Jan;9(1):39-44. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18077217 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM); Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD); Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:bf797a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, no gemcitabine lead-in {{#subobject:43fe43|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext Kordes et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Erlotinib, Gemcitabine, Metformin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, gemcitabine lead-in, erlotinib 100 mg/day {{#subobject:fc43f2|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2008.20.0238 Van Cutsem et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Erlotinib, Gemcitabine, Bevacizumab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 150 mg/day {{#subobject:d49fb0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[https://gut.bmj.com/content/62/5/751.long Heinemann et al. 2012 (AIO-PK0104)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Capecitabine & Erlotinib<br />
| style="background-color:#1a9850" |Superior TTF1<br />
|-<br />
|}<br />
''Note: due to low accrual in NCIC CTG PA.3, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, Verslype C, Scheithauer W, Shang A, Cosaert J, Moore MJ. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009 May 1;27(13):2231-7. Epub 2009 Mar 23. [http://ascopubs.org/doi/full/10.1200/JCO.2008.20.0238 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19307500 PubMed]<br />
# '''AIO-PK0104:''' Heinemann V, Vehling-Kaiser U, Waldschmidt D, Kettner E, Märten A, Winkelmann C, Klein S, Kojouharoff G, Gauler TC, von Weikersthal LF, Clemens MR, Geissler M, Greten TF, Hegewisch-Becker S, Rubanov O, Baake G, Höhler T, Ko YD, Jung A, Neugebauer S, Boeck S. Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the 'Arbeitsgemeinschaft Internistische Onkologie' (AIO-PK0104). Gut. 2013 May;62(5):751-9. Epub 2012 Jul 7. [https://gut.bmj.com/content/62/5/751.long link to original article] '''contains verified protocol'''' [https://www.ncbi.nlm.nih.gov/pubmed/22773551 PubMed]<br />
# Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47. Epub 2015 Jun 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext link to original article]'''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26067687 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:c6c509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 300 mg/m<sup>2</sup>/day PVI {{#subobject:3ac41f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2002.09.029 Maisey et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & Mitomycin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
==== Chemotherapy ====<br />
*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion<br />
<br />
'''Continued for up to 24 weeks'''<br />
<br />
===Variant #2, 500 mg/m<sup>2</sup> intermittent {{#subobject:27a992|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/397816 Cullinan et al. 1985]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. FA<br> 2. FAM<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19900515)65:10%3C2207::AID-CNCR2820651007%3E3.0.CO;2-Y Cullinan et al. 1990]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Mallinson regimen<br> 2. FAP<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: this is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.''<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycles'''<br />
<br />
===Variant #2, 600 mg/m<sup>2</sup> weekly {{#subobject:3ca01f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Inferior to gemcitabine. Here for historical reference purposes, only.''<br />
==== Chemotherapy ====<br />
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per week<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# Cullinan SA, Moertel CG, Fleming TR, Rubin JR, Krook JE, Everson LK, Windschitl HE, Twito DI, Marschke RF, Foley JF, Pfeifle DM, Barlow JF. A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma: fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA. 1985 Apr 12;253(14):2061-7. [https://jamanetwork.com/journals/jama/fullarticle/397816 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2579257 PubMed]<br />
# Cullinan S, Moertel CG, Wieand HS, Schutt AJ, Krook JE, Foley JF, Norris BD, Kardinal CG, Tschetter LK, Barlow JF. A phase III trial on the therapy of advanced pancreatic carcinoma: evaluations of the Mallinson regimen and combined 5-fluorouracil, doxorubicin, and cisplatin. Cancer. 1990 May 15;65(10):2207-12. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19900515)65:10%3C2207::AID-CNCR2820651007%3E3.0.CO;2-Y link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2189551 PubMed]<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Maisey N, Chau I, Cunningham D, Norman A, Seymour M, Hickish T, Iveson T, O'Brien M, Tebbutt N, Harrington A, Hill M. Multicenter randomized phase III trial comparing protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin in inoperable pancreatic cancer. J Clin Oncol. 2002 Jul 15;20(14):3130-6. [http://ascopubs.org/doi/full/10.1200/JCO.2002.09.029 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12118027 PubMed]<br />
<br />
==FOLFIRINOX {{#subobject:aaa3c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e140cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior QoL by [http://groups.eortc.be/qol/eortc-qlq-c30 EORTC QLQ-C30]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given fourth''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given third with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:3a0f4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 900 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:c61ab9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360678/ Stathopoulos et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Irinotecan<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 900 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 1000 mg/m<sup>2</sup>, 8-week lead-in ("Burris regimen") {{#subobject:5d6dd0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.10323 Colucci et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2003.02.098 Moore et al. 2003 (NCIC CTG PA.1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Tanomastat<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2004.10.112 Van Cutsem et al. 2004]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Tipifarnib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2004.12.082 Rocha Lima et al. 2004]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Irinotecan<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx_2|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract Reni et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PEFG<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2006.07.0201 Abou-Alfa et al. 2006a]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Exatecan<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. GEM FDR<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|2. [[#GemOx_2|GEMOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GEM-CAP]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ Philip et al. 2010 (SWOG S0205)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981019/ Dahan et al. 2010 (FFCD 0301)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|LV5FU2-CDDP<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/23/11/2799/234953 Gonçalves et al. 2012 (BAYPAN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Sorafenib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(13)00303-1/fulltext Rougier et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Ziv-aflibercept<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_nab-Paclitaxel|Gemcitabine & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516046/ Deplanque et al. 2015 (AB07012)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Masitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext Middleton et al. 2017 (ViP)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Vandetanib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: Colucci et al. 2002 stopped treatment after 3 cycles (16 weeks).''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
***In Burris et al. 1997, patients with grade 2 or lower toxicities could have had doses increased to 1250 mg/m<sup>2</sup><br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 1000 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:c6349|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2002.11.149 Berlin et al. 2002 (ECOG E2297)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & Gemcitabine<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/16/10/1639/169072 Oettle et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Pemetrexed<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60661-3/fulltext Spano et al. 2008 (A4061016)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917317/ Kindler et al. 2010 (CALGB 80303)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Bevacizumab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract Kindler et al. 2011 (A4061028)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|2. Gemcitabine & S-1<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ Fuchs et al. 2015 (GAMMA)]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II (C)<br />
|Gemcitabine & Ganitumab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551155/ O'Neil et al. 2015]<br />
| style="background-color:#1a9851" |Phase II/III (C)<br />
|Gemcitabine & Rigosertib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ Catenacci et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II (C)<br />
|Gemcitabine & Vismodegib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #4, 1000 mg/m<sup>2</sup>, weekly {{#subobject:8bae67|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 Hong et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Simvastatin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #5, 1500 mg/m<sup>2</sup>, fixed-dose rate (FDR) {{#subobject:5114cc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|2. [[#GemOx_2|GEMOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 150 minutes (10 mg/m<sup>2</sup>/min) once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Colucci G, Giuliani F, Gebbia V, Biglietto M, Rabitti P, Uomo G, Cigolari S, Testa A, Maiello E, Lopez M. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell'Italia Meridionale. Cancer. 2002 Feb 15;94(4):902-10. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.10323 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11920457 PubMed]<br />
# '''ECOG E2297:''' Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, Benson AB 3rd. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol. 2002 Aug 1;20(15):3270-5. [http://ascopubs.org/doi/full/10.1200/JCO.2002.11.149 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12149301 PubMed]<br />
# '''NCIC CTG PA.1:''' Moore MJ, Hamm J, Dancey J, Eisenberg PD, Dagenais M, Fields A, Hagan K, Greenberg B, Colwell B, Zee B, Tu D, Ottaway J, Humphrey R, Seymour L; National Cancer Institute of Canada Clinical Trials Group. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Sep 1;21(17):3296-302. [http://ascopubs.org/doi/full/10.1200/JCO.2003.02.098 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12947065 PubMed]<br />
# Van Cutsem E, van de Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A, Schoffski P, Post S, Verslype C, Neumann H, Safran H, Humblet Y, Perez Ruixo J, Ma Y, Von Hoff D. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol. 2004 Apr 15;22(8):1430-8. [http://ascopubs.org/doi/full/10.1200/JCO.2004.10.112 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15084616 PubMed]<br />
# Rocha Lima CM, Green MR, Rotche R, Miller WH Jr, Jeffrey GM, Cisar LA, Morganti A, Orlando N, Gruia G, Miller LL. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol. 2004 Sep 15;22(18):3776-83. [http://ascopubs.org/doi/full/10.1200/JCO.2004.12.082 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15365074 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Oettle H, Richards D, Ramanathan RK, van Laethem JL, Peeters M, Fuchs M, Zimmermann A, John W, Von Hoff D, Arning M, Kindler HL. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol. 2005 Oct;16(10):1639-45. Epub 2005 Aug 8. Erratum in: Ann Oncol. 2006 Mar;17(3):535. [https://academic.oup.com/annonc/article/16/10/1639/169072 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16087696 PubMed]<br />
# Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15925814 PubMed]<br />
# Stathopoulos GP, Syrigos K, Aravantinos G, Polyzos A, Papakotoulas P, Fountzilas G, Potamianou A, Ziras N, Boukovinas J, Varthalitis J, Androulakis N, Kotsakis A, Samonis G, Georgoulias V. A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. Br J Cancer. 2006 Sep 4;95(5):587-92. Epub 2006 Aug 8. [https://www.nature.com/articles/6603301 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360678/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16909140 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Abou-Alfa GK, Letourneau R, Harker G, Modiano M, Hurwitz H, Tchekmedyian NS, Feit K, Ackerman J, De Jager RL, Eckhardt SG, O'Reilly EM. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J Clin Oncol. 2006 Sep 20;24(27):4441-7. [http://ascopubs.org/doi/full/10.1200/JCO.2006.07.0201 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16983112 PubMed]<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# '''A4061016:''' Spano JP, Chodkiewicz C, Maurel J, Wong R, Wasan H, Barone C, Létourneau R, Bajetta E, Pithavala Y, Bycott P, Trask P, Liau K, Ricart AD, Kim S, Rixe O. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet. 2008 Jun 21;371(9630):2101-8. Epub 2008 May 29. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60661-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18514303 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM); Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD); Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
# '''SWOG S0205:''' Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 1;28(22):3605-10. Epub 2010 Jul 6. [http://jco.ascopubs.org/content/28/22/3605.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20606093 PubMed]<br />
# '''CALGB 80303:''' Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, Innocenti F, Mulcahy MF, O'Reilly E, Wozniak TF, Picus J, Bhargava P, Mayer RJ, Schilsky RL, Goldberg RM. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010 Aug 1;28(22):3617-22. Epub 2010 Jul 6. [http://ascopubs.org/doi/10.1200/JCO.2010.28.1386 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917317/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20606091 PubMed]<br />
# '''FFCD 0301:''' Dahan L, Bonnetain F, Ychou M, Mitry E, Gasmi M, Raoul JL, Cattan S, Phelip JM, Hammel P, Chauffert B, Michel P, Legoux JL, Rougier P, Bedenne L, Seitz JF; Fédération Francophone de Cancérologie Digestive. Combination 5-fluorouracil, folinic acid and cisplatin (LV5FU2-CDDP) followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: final results of a randomised strategic phase III trial (FFCD 0301). Gut. 2010 Nov;59(11):1527-34. [https://gut.bmj.com/content/59/11/1527.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981019/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20947887 PubMed]<br />
# '''A4061028:''' Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306953 PubMed]<br />
## '''Subgroup analysis:''' Ioka T, Okusaka T, Ohkawa S, Boku N, Sawaki A, Fujii Y, Kamei Y, Takahashi S, Namazu K, Umeyama Y, Bycott P, Furuse J. Efficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer: subgroup analyses by region, including Japan, from the global randomized phase III trial. Jpn J Clin Oncol. 2015 May;45(5):439-48. Epub 2015 Feb 3. [https://academic.oup.com/jjco/article/45/5/439/1017164 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25647781 PubMed]<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
# '''BAYPAN:''' Gonçalves A, Gilabert M, François E, Dahan L, Perrier H, Lamy R, Re D, Largillier R, Gasmi M, Tchiknavorian X, Esterni B, Genre D, Moureau-Zabotto L, Giovannini M, Seitz JF, Delpero JR, Turrini O, Viens P, Raoul JL. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol. 2012 Nov;23(11):2799-805. Epub 2012 Jul 5. [https://academic.oup.com/annonc/article/23/11/2799/234953 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22771827 PubMed]<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
# Rougier P, Riess H, Manges R, Karasek P, Humblet Y, Barone C, Santoro A, Assadourian S, Hatteville L, Philip PA. Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. Eur J Cancer. 2013 Aug;49(12):2633-42. Epub 2013 Apr 30. [https://www.ejcancer.com/article/S0959-8049(13)00303-1/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23642329 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
## '''Update:''' Goldstein D, El-Maraghi RH, Hammel P, Heinemann V, Kunzmann V, Sastre J, Scheithauer W, Siena S, Tabernero J, Teixeira L, Tortora G, Van Laethem JL, Young R, Penenberg DN, Lu B, Romano A, Von Hoff DD. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst. 2015 Jan 31;107(2). [https://academic.oup.com/jnci/article/107/2/dju413/902453 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25638248 PubMed]<br />
# Hong JY, Nam EM, Lee J, Park JO, Lee SC, Song SY, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol. 2014 Jan;73(1):125-30. Epub 2013 Oct 27. [https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24162380 PubMed]<br />
# '''GAMMA:''' Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921-7. Epub 2015 Jan 21. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25609246 PubMed]<br />
# '''AB07012:''' Deplanque G, Demarchi M, Hebbar M, Flynn P, Melichar B, Atkins J, Nowara E, Moyé L, Piquemal D, Ritter D, Dubreuil P, Mansfield CD, Acin Y, Moussy A, Hermine O, Hammel P. A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer. Ann Oncol. 2015 Jun;26(6):1194-200. Epub 2015 Apr 9. [https://academic.oup.com/annonc/article/26/6/1194/161899 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516046/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25858497 PubMed]<br />
# O'Neil BH, Scott AJ, Ma WW, Cohen SJ, Leichman L, Aisner DL, Menter AR, Tejani MA, Cho JK, Granfortuna J, Coveler AL, Olowokure OO, Baranda JC, Cusnir M, Phillip P, Boles J, Nazemzadeh R, Rarick M, Cohen DJ, Radford J, Fehrenbacher L, Bajaj R, Bathini V, Fanta P, Berlin J, McRee AJ, Maguire R, Wilhelm F, Maniar M, Jimeno A, Gomes CL, Messersmith WA. A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. Ann Oncol. 2015 Sep;26(9):1923-9. Epub 2015 Jun 19. Erratum in: Ann Oncol. 2015 Dec;26(12):2505. Leichman, L [added]. Ann Oncol. 2016 Jun;27(6):1180. [https://academic.oup.com/annonc/article/26/9/1923/189392 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551155/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26091808 PubMed]<br />
# Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D, Wade J, Sleckman B, Lenz HJ, Stiff P, Kumar P, Xu P, Henderson L, Takebe N, Salgia R, Wang X, Stadler WM, de Sauvage FJ, Kindler HL. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015 Dec 20;33(36):4284-92. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/36/4284.long link to original article] '''contains protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527777 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
# '''ViP:''' Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr;18(4):486-499. Epub 2017 Mar 2. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28259610 PubMed]<br />
<br />
==GemOx {{#subobject:520af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine & '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:9d3266|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. [[#Gemcitabine_monotherapy_3|Gemcitabine, FDR]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
<br />
==Gemcitabine & nab-Paclitaxel {{#subobject:fbd698|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
NG: '''<u>N</u>'''ab-Paclitaxel & '''<u>G</u>'''emcitabine<br />
===Variant #1, with 8-week lead-in {{#subobject:63ba04|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] as follows, '''given first''':<br />
**Cycle 1: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15<br />
<br />
'''8-week cycle followed by 28-day cycles'''<br />
<br />
===Variant #2, no lead-in {{#subobject:ecc1c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ Von Hoff et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 or 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/34/4548.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969517 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
## '''Update:''' Goldstein D, El-Maraghi RH, Hammel P, Heinemann V, Kunzmann V, Sastre J, Scheithauer W, Siena S, Tabernero J, Teixeira L, Tortora G, Van Laethem JL, Young R, Penenberg DN, Lu B, Romano A, Von Hoff DD. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst. 2015 Jan 31;107(2). [https://academic.oup.com/jnci/article/107/2/dju413/902453 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25638248 PubMed]<br />
<br />
==GTX {{#subobject:f0d62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GTX: '''<u>G</u>'''emcitabine, '''<u>T</u>'''axotere (Docetaxel), '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:fc0e50|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.springerlink.com/content/75m422843l3461m0/ Fine et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: De Jesus-Acosta et al. 2012 lists the capecitabine dose as "750 mg/m<sup>2</sup>/day orally divided into two doses," but this is believed to be a typographical error since the original reference that it cites, Fine et al. 2007, uses capecitabine at 750 mg/m<sup>2</sup> PO twice per day. The 2009 ASCO abstract by Fine also lists this 750 mg/m<sup>2</sup> PO twice per day (1500 mg/m<sup>2</sup>/day) dose.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 75 minutes once per day on days 4 & 11<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 11<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75. Epub 2007 Apr 18. [http://www.springerlink.com/content/75m422843l3461m0/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17440727 PubMed]<br />
# '''Abstract:''' R. L. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. 2009 ASCO Annual Meeting abstract 4623. [http://ascopubs.org/doi/full/10.1200/jco.2009.27.15s.4623 link to abstract] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012 Feb;69(2):415-24. Epub 2011 Jul 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723 link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21800112 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:759f1a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:94d490|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|2. Gemcitabine & S-1<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<br />
=Metastatic disease, refractory=<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(08)01051-4/fulltext Ciuleanu et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Glufosfamide<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#OLF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Best supportive care. Placed here because one or more randomized clinical trials included a best supportive care arm in this disease context.''<br />
<br />
===References===<br />
# Ciuleanu TE, Pavlovsky AV, Bodoky G, Garin AM, Langmuir VK, Kroll S, Tidmarsh GT. A randomised Phase III trial of glufosfamide compared with best supportive care in metastatic pancreatic adenocarcinoma previously treated with gemcitabine. Eur J Cancer. 2009 Jun;45(9):1589-96. Epub 2009 Jan 31. [https://www.ejcancer.com/article/S0959-8049(08)01051-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19188061 PubMed]<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<br />
==Capecitabine monotherapy {{#subobject:38b5c7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3ab38a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs10637-018-0580-2 Hurwitz et al. 2018 (JANUS 1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Capecitabine & Ruxolitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''JANUS 1:''' Hurwitz H, Van Cutsem E, Bendell J, Hidalgo M, Li CP, Salvo MG, Macarulla T, Sahai V, Sama A, Greeno E, Yu KH, Verslype C, Dawkins F, Walker C, Clark J, O'Reilly EM. Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies. Invest New Drugs. 2018 Aug;36(4):683-695. Epub 2018 Mar 6. [https://link.springer.com/article/10.1007%2Fs10637-018-0580-2 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29508247 PubMed]<br />
<br />
==Capecitabine & Erlotinib {{#subobject:4655b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d5c799|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4787.full Kulke et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> (rounded to the nearest 150 mg tablet) PO twice per day on days 1 to 14<br />
*[[Erlotinib (Tarceva)]] 150 mg PO on days 1 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak EL, Muzikansky A, Lawrence C, Fuchs CS. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007 Oct 20;25(30):4787-92. [http://jco.ascopubs.org/content/25/30/4787.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947726 PubMed]<br />
<br />
==CapeOx {{#subobject:d09d5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:57ad5f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full Xiong et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] as follows:<br />
**Age less than 65 years old and ECOG performance status less than 2: 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
**Age greater than 65 years old and/or ECOG performance status greater than or equal to 2: 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] as follows:<br />
**Age less than 65 years old and ECOG performance status less than 2: 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**Age greater than 65 years old and/or ECOG performance status greater than or equal to 2: 110 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008 Oct 15;113(8):2046-52. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18756532 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:992c9d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FF: '''<u>F</u>'''luorouracil & '''<u>F</u>'''olinic acid<br />
===Variant #1, 2000/200 {{#subobject:b631e0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#OLF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Fluorouracil.2C_Folinic acid.2C_nanoliposomal_Irinotecan|Fluorouracil, Folinic acid, nanoliposomal Irinotecan]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|2. Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, '''given second''' (total dose per cycle: 8000 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, '''given first'''<br />
<br />
'''42-day cycles'''<br />
<br />
===Variant #2, 2800/400 {{#subobject:959e8e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2016.68.5776 Gill et al. 2016 (PANCREOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|mFOLFOX6<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# '''CONKO-003:''' Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
# '''NAPOLI-1:''' Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
# '''PANCREOX:''' Gill S, Ko YJ, Cripps C, Beaudoin A, Dhesy-Thind S, Zulfiqar M, Zalewski P, Do T, Cano P, Lam WYH, Dowden S, Grassin H, Stewart J, Moore M. PANCREOX: a randomized phase III study of fluorouracil/leucovorin with or without oxaliplatin for second-line advanced pancreatic cancer in patients who have received gemcitabine-based chemotherapy. J Clin Oncol. 2016 Nov 10;34(32):3914-3920. Epub 2016 Sep 30. [http://ascopubs.org/doi/full/10.1200/JCO.2016.68.5776 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27621395 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, nanoliposomal Irinotecan {{#subobject:72308d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a81310|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Fluorouracil_.26_Folinic acid_2|Fluorouracil & Folinic acid]]<br />
| style="background-color:#91cf60" |Superior OS<br />
|-<br />
|2. Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, started on day 1, '''given third'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given second'''<br />
*[[Irinotecan liposome (Onivyde)]] 70 mg/m<sup>2</sup> (irinotecan free base) IV over 90 minutes once on day 1, '''given first'''<br />
**Per Wang-Gillam et al. 2015 (NAPOLI-01), 70 mg/m<sup>2</sup> irinotecan free base is equivalent to 80 mg/m<sup>2</sup> nanoliposomal irinotecan. According to the trial's ClinicalTrials.gov page: "The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m<sup>2</sup> dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/m<sup>2</sup> of irinotecan free base."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# '''NAPOLI-1:''' Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
# '''NAPOLI-1:''' Wang-Gillam A, Hubner RA, Siveke JT, Von Hoff DD, Belanger B, de Jong FA, Mirakhur B, Chen LT; NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: Final overall survival analysis and characteristics of long-term survivors. Eur J Cancer. 2019 Feb 108;78-87. Epub 2019 Jan 14. https://www.ejcancer.com/article/S0959-8049(18)31553-3/fulltext '''contains verified protocol''' https://www.ncbi.nlm.nih.gov/pubmed/30654298<br />
<br />
==FOLFIRI {{#subobject:6fd426|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br />
===Variant #1 {{#subobject:6a9cae|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 Zaniboni et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, modified FOLFIRI.3 {{#subobject:4758e8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#FOLFOX|mFOLFOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Irinotecan (Camptosar)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 3<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
# Zaniboni A, Aitini E, Barni S, Ferrari D, Cascinu S, Catalano V, Valmadre G, Ferrara D, Veltri E, Codignola C, Labianca R. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jun;69(6):1641-5. Epub 2012 May 11. [http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22576338 PubMed]<br />
<br />
==FOLFOX {{#subobject:377e80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:33ef68|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#FOLFIRI|mFOLFIRI.3]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
<br />
==Irinotecan liposomal monotherapy {{#subobject:9a99c8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c50e15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749576/ Ko et al. 2013 (PEP0208)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Irinotecan liposome (Onivyde)]] 120 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''PEP0208:''' Ko AH, Tempero MA, Shan YS, Su WC, Lin YL, Dito E, Ong A, Wang YW, Yeh CG, Chen LT. A multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM-398) for patients with gemcitabine-refractory metastatic pancreatic cancer. Br J Cancer. 2013 Aug 20;109(4):920-5. [https://www.nature.com/articles/bjc2013408 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749576/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23880820 PubMed]<br />
<br />
==OLF {{#subobject:8b32c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OLF: '''<u>O</u>'''xaliplatin, '''<u>L</u>'''eucovorin (Folinic acid), '''<u>F</u>'''luorouracil<br />
<br>OFF: '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil, '''<u>F</u>'''olinic acid <br />
===Regimen {{#subobject:ae57d5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_.26_Folinic acid_2|Fluorouracil & Folinic acid]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
<br />
''Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m<sup>2</sup>," or 850 mg/m<sup>2</sup>.''<br />
====Chemotherapy====<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once per day on days 8 & 22, '''given first'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, '''given third''' (total dose per cycle: 8000 mg/m<sup>2</sup>)<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# '''CONKO-003:''' Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
<br />
==Olaparib monotherapy {{#subobject:0c2eb3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:21eb78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/3/244.long Kaufman et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients had germline BRCA1/2 mutations.''<br />
====Preceding treatment====<br />
*Gemcitabine, with progression<br />
====Chemotherapy====<br />
*[[Olaparib (Lynparza)]] 400 mg PO twice per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
# Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/33/3/244.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed]<br />
<br />
==Paclitaxel, nanoparticle albumin-bound monotherapy {{#subobject:ab9fc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8d38d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://insights.ovid.com/pubmed?pmid=22307213 Hosein et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Hosein PJ, de Lima Lopes G Jr, Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013 Apr;36(2):151-6. Epub 2012 Feb 2. [https://insights.ovid.com/pubmed?pmid=22307213 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22307213 PubMed]<br />
<br />
[[Category:Pancreatic cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdheryhttps://hemonc.org/w/index.php?title=Pancreatic_cancer&diff=36475Pancreatic cancer2019-03-28T19:58:57Z<p>Rozinachowdhery: Added FOLFIRINOX/modified FOLFIRINOX +/- Chemoradiation</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Chowdhery.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Rozinachowdhery|Rozina Chowdhery, MD]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br />
| style="background-color:#F0F0F0; width:15%" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2018:''' Sohal et al. [http://ascopubs.org/doi/full/10.1200/JCO.2018.78.9636 Metastatic pancreatic cancer: ASCO Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/29791286 PubMed]<br />
*'''2017:''' Khorana et al. [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.4948 Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/28398845 PubMed]<br />
===Older===<br />
*'''2016:''' Sohal et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019760/ Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2016:''' Balaban et al. [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.5561 Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/27247216 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2017:''' [https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Cancer-of-the-Pancreas/eUpdate-Treatment-Recommendations eUpdate – Cancer of the Pancreas Treatment Recommendations]<br />
*'''2015:''' Ducreux et al. [https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Cancer-of-the-Pancreas Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015)] [https://www.ncbi.nlm.nih.gov/pubmed/26314780 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf NCCN Guidelines - Pancreatic Adenocarcinoma]<br />
<br />
=Adjuvant therapy=<br />
==Capecitabine & Gemcitabine {{#subobject:17f9f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Regimen {{#subobject:e6a3e3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Treatment starts within 12 weeks of surgery.''<br />
====Preceding treatment====<br />
*[[Surgery#Pancreatic_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week on weeks 1 to 3<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# '''ESPAC-4:''' Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:29266e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:242770|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Fluorouracil.2FFluorouracil_.26_RT|5-FU/5-FU & RT]]<br> 2. 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|3. [[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3 version 2)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2011.38.2960 Schmidt et al. 2012 (CapRI)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU, Cisplatin, IFN alfa-2b, RT<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: reported efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*[[Surgery#Pancreatic_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# '''ESPAC-1:''' Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [https://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# '''ESPAC-3 version 2:''' Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# '''CapRI:''' Schmidt J, Abel U, Debus J, Harig S, Hoffmann K, Herrmann T, Bartsch D, Klein J, Mansmann U, Jäger D, Capussotti L, Kunz R, Büchler MW. Open-label, multicenter, randomized phase III trial of adjuvant chemoradiation plus interferon alfa-2b versus fluorouracil and folinic acid for patients with resected pancreatic adenocarcinoma. J Clin Oncol. 2012 Nov 20;30(33):4077-83. Epub 2012 Sep 24. [http://ascopubs.org/doi/full/10.1200/JCO.2011.38.2960 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23008325 PubMed]<br />
<br />
==Fluorouracil/Fluorouracil & RT {{#subobject:331d4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Fluorouracil/Fluorouracil & RT: Fluorouracil alternating with Fluorouracil & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:89426a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br> 2. [[#Observation|Observation]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|3. 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008 (RTOG 9704)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine.2FFluorouracil_.26_RT|Gemcitabine/5-FU & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior (*)<br />
|-<br />
|}<br />
''Note: reported efficacy for ESPAC-1 is based on the 2004 update. Reported efficacy for RTOG 9704 is based on the 2011 update.''<br />
====Preceding treatment====<br />
*[[Surgery#Pancreatic_cancer_surgery|Surgery]]<br />
====Chemotherapy, part 1====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose: 5000 mg/m<sup>2</sup>)<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 7000 mg/m<sup>2</sup>)<br />
<br />
'''6-week cycle for 2 cycles'''<br />
<br />
===References===<br />
# '''ESPAC-1:''' Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [https://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# '''RTOG 9704:''' Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
## '''Update:''' Regine WF, Winter KA, Abrams R, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Rich TA, Willett CG. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the US Intergroup/RTOG 9704 phase III trial. Ann Surg Oncol. 2011 May;18(5):1319-26. Epub 2011 Mar 10. [https://link.springer.com/article/10.1245%2Fs10434-011-1630-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548408/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21499862 PubMed]<br />
<br />
==mFOLFIRINOX {{#subobject:bbb2c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFIRINOX: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:a170cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1809775 Conroy et al. 2018 (NCIC CTG PA.6)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#d73027" |More toxic<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Surgery#Pancreatic_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given fourth'''<br />
*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given third'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.6:''' Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, Choné L, Francois E, Artru P, Biagi JJ, Lecomte T, Assenat E, Faroux R, Ychou M, Volet J, Sauvanet A, Breysacher G, Di Fiore F, Cripps C, Kavan P, Texereau P, Bouhier-Leporrier K, Khemissa-Akouz F, Legoux JL, Juzyna B, Gourgou S, O'Callaghan CJ, Jouffroy-Zeller C, Rat P, Malka D, Castan F, Bachet JB; Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med. 2018 Dec 20;379(25):2395-2406. [https://www.nejm.org/doi/full/10.1056/NEJMoa1809775 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30575490 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:34e70d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 2 out of 3 weeks {{#subobject:dc12dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Gemcitabine_.26_RT|Gemcitabine & RT]], then [[Surgery#Pancreatic_cancer_surgery|surgery]]<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 5 cycles'''<br />
<br />
===Variant #2, 3 out of 4 weeks {{#subobject:a756a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743365/ Ueno et al. 2009 (JSAP-02)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior DFS<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3 version 2)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_.26_Folinic_acid|Fluorouracil & Leucovorin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine|Capecitabine & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2017.72.6463 Sinn et al. 2017 (CONKO-005)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Erlotinib & Gemcitabine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1809775 Conroy et al. 2018 (NCIC CTG PA.6)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#mFOLFIRINOX|mFOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
<br />
''Note: efficacy for CONKO-001 is based on the 2013 update.''<br />
====Preceding treatment====<br />
*[[Surgery#Pancreatic_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# '''CONKO-001:''' Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
# '''JSAP-02:''' Ueno H, Kosuge T, Matsuyama Y, Yamamoto J, Nakao A, Egawa S, Doi R, Monden M, Hatori T, Tanaka M, Shimada M, Kanemitsu K. A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer. Br J Cancer. 2009 Sep 15;101(6):908-15. Epub 2009 Aug 18. [https://www.nature.com/articles/6605256 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743365/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19690548 PubMed]<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [https://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# '''ESPAC-3 version 2:''' Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# '''JASPAC 01:''' Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
# '''ESPAC-4:''' Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
# '''CONKO-005:''' Sinn M, Bahra M, Liersch T, Gellert K, Messmann H, Bechstein W, Waldschmidt D, Jacobasch L, Wilhelm M, Rau BM, Grützmann R, Weinmann A, Maschmeyer G, Pelzer U, Stieler JM, Striefler JK, Ghadimi M, Bischoff S, Dörken B, Oettle H, Riess H. CONKO-005: Adjuvant Chemotherapy With Gemcitabine Plus Erlotinib Versus Gemcitabine Alone in Patients After R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial. J Clin Oncol. 2017 Oct 10;35(29):3330-3337. Epub 2017 Aug 17. [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.6463 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28817370 PubMed]<br />
# '''NCIC CTG PA.6:''' Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, Choné L, Francois E, Artru P, Biagi JJ, Lecomte T, Assenat E, Faroux R, Ychou M, Volet J, Sauvanet A, Breysacher G, Di Fiore F, Cripps C, Kavan P, Texereau P, Bouhier-Leporrier K, Khemissa-Akouz F, Legoux JL, Juzyna B, Gourgou S, O'Callaghan CJ, Jouffroy-Zeller C, Rat P, Malka D, Castan F, Bachet JB; Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med. 2018 Dec 20;379(25):2395-2406. [https://www.nejm.org/doi/full/10.1056/NEJMoa1809775 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30575490 PubMed]<br />
<br />
==Gemcitabine/Fluorouracil & RT {{#subobject:f8c8d9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Gemcitabine/Fluorouracil & RT: Gemcitabine alternating with Fluorouracil & '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:3fef3f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008 (RTOG 9704)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil.2FFluorouracil_.26_RT|5-FU/5-FU & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior (*)<br />
|-<br />
|}<br />
''Note: reported efficacy is based on the 2011 update.''<br />
====Preceding treatment====<br />
*[[Surgery#Pancreatic_cancer_surgery|Surgery]]<br />
====Chemotherapy, part 1====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
# '''RTOG 9704:''' Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
## '''Update:''' Regine WF, Winter KA, Abrams R, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Rich TA, Willett CG. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the US Intergroup/RTOG 9704 phase III trial. Ann Surg Oncol. 2011 May;18(5):1319-26. Epub 2011 Mar 10. [https://link.springer.com/article/10.1245%2Fs10434-011-1630-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548408/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21499862 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1420941/ Klinkenbijl et al. 1999 (EORTC 40891)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & RT<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. [[#Fluorouracil.2FFluorouracil_.26_RT|5-FU/5-FU & RT]]<br> 3. 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Efficacy for ESPAC-1 is based on the 2004 update and efficacy for CONKO-001 is based on 2013 update.''<br />
====Preceding treatment====<br />
*[[Surgery#Pancreatic_cancer_surgery|Surgery]]<br />
===References===<br />
# '''EORTC 40891:''' Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH, Arnaud JP, Gonzalez DG, de Wit LT, Hennipman A, Wils J. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999 Dec;230(6):776-82. [https://insights.ovid.com/pubmed?pmid=10615932 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1420941/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/10615932 PubMed]<br />
## '''Update:''' Smeenk HG, van Eijck CH, Hop WC, Erdmann J, Tran KC, Debois M, van Cutsem E, van Dekken H, Klinkenbijl JH, Jeekel J. Long-term survival and metastatic pattern of pancreatic and periampullary cancer after adjuvant chemoradiation or observation: long-term results of EORTC trial 40891. Ann Surg. 2007 Nov;246(5):734-40. [https://insights.ovid.com/pubmed?pmid=17968163 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17968163 PubMed]<br />
# '''ESPAC-1:''' Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [https://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# '''CONKO-001:''' Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cdcc15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
====Preceding treatment====<br />
*[[Surgery#Pancreatic_cancer_surgery|Surgery]]<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 28<br />
<br />
'''42-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
# '''JASPAC 01:''' Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, potentially resectable=<br />
<br />
==Docetaxel, Gemcitabine, RT {{#subobject:49a407|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:78b0ba|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1245%2FASO.2005.04.503 Pipas et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 65 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Gemcitabine (Gemzar)]] 4000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29<br />
<br />
'''6-week course, followed immediately (day 43) by:'''<br />
<br />
====Chemoradiation====<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy to primary target volume. Then 5.4 Gy boost to secondary target volume of 1- to 1.5-cm margin on all sides, including proven nodal involvement. Total 50.4 Gy in 28 fractions.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
# Pipas JM, Barth RJ Jr, Zaki B, Tsapakos MJ, Suriawinata AA, Bettmann MA, Cates JM, Ripple GH, Sutton JE, Gordon SR, McDonnell CE, Perez RP, Redfield N, Meyer LP, Marshall JF, Cole BF, Colacchio TA. Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2005 Dec;12(12):995-1004. Epub 2005 Nov 1. [http://link.springer.com/article/10.1245%2FASO.2005.04.503 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16252135 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:55e32d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:6ce551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract Takahashi et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy per fraction, 5 days per week, 25 fractions, total dose of 50 Gy over 5 weeks.<br />
<br />
'''28-day cycle for 3 cycles''' ''(Radiation given over weeks 1-5 only)''<br />
====Subsequent treatment====<br />
*Restaging is performed 8 weeks after radiation complete (2 weeks after chemotherapy complete). [[Surgery#Pancreatic_cancer_surgery|Resection]] immediately thereafter, if feasible<br />
<br />
===Variant #2 {{#subobject:dc32dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 500 mg/m<sup>2</sup> IV over 50 minutes once per week for 6 weeks<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 180 cGy x 22 with 3 cm margin to GTV then 180 cGy x 6 with 2 cm margin to GTV, total 50.4 Gy over 6 weeks<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
*Restaging after radiation complete. 4 to 6 week break, followed by [[Surgery#Pancreatic_cancer_surgery|surgery]], followed by 4 to 8 week break, then [[#Gemcitabine_monotherapy|adjuvant gemcitabine]]<br />
<br />
===References===<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [https://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, Ioka T, Uehara H, Yano M, Ishikawa O. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013 Dec;258(6):1040-50.[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23799421 PubMed]<br />
<br />
==Gemcitabine, Cetuximab, RT {{#subobject:aea7b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c38534|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ Pipas et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**6 to 8 days prior radiation: 400 mg/m<sup>2</sup> IV over 2 hours once<br />
**During radiation: 250 mg/m<sup>2</sup> IV over 60 minutes once per week for 6 doses<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], delivered using IMRT. Gross tumor volume (GTV) was all known disease including imaging proven nodal disease. The primary planning target volume (PTV1) included the GTV with 2- to 3-cm margins in all directions as well as potential nodal involvement. Secondary planning target volume (PTV2) included the GTV with 1- to 1.5-cm margins on all sides including proven nodal involvement. Tertiary planning treatment volume (PTV3) included the area of the GTV adjacent to the vascular structures specifically the mesenteric and portal vessels with a 0.5-cm margin. The prescription dose delivered to PTV3 was 54 Gy in 28 fractions. Synchronously, PTV1 and PTV2 received 45 and 50.4 Gy, respectively. All fields were treated daily at five fractions per week.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
''One month following therapy, patients were restaged with CT scan of chest/abdomen/pelvis. Patients deemed to be candidates for surgical resection were offered laparotomy ∼6 to 10 weeks after completion of neoadjuvant therapy.''<br />
<br />
===References===<br />
# Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, Tsongalis GJ, Colacchio TA, Gordon SR, Sutton JE, Srivastava A, Smith KD, Gardner TB, Korc M, Davis TH, Preis M, Tarczewski SM, Mackenzie TA, Barth RJ Jr. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. 2012 Nov;23(11):2820-7. Epub 2012 May 9. [http://annonc.oxfordjournals.org/content/23/11/2820.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571859 PubMed]<br />
<br />
== FOLFIRINOX/modified FOLFIRINOX +/- Chemoradiation ==<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|Murphy et al. 2018 <br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: FOLFIRINOX should be limited to those with ECOG 0-1''<br />
<br />
==== Chemotherapy ====<br />
* Folinic acid (Leucovorin) 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, given second<br />
* Fluorouracil (5-FU) 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, given fourth (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
* Irinotecan (Camptosar) 180* mg/m<sup>2</sup> IV over 90 minutes once on day 1, given third with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin<br />
* Oxaliplatin (Eloxatin) 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, given first<br />
<br />
==== Supportive medications ====<br />
* Pegfilgrastim (Neulasta) 6 mg SC once on day 4<br />
'''14-day cycle for 8* cycles''' <br />
<br />
<nowiki>*</nowiki>Amendment after first 6 patients were enrolled increased neoadjuvant cycles from 4 to 8 if no progression was detected on restaging CT<br />
<br />
Followed by restaging with CT scan. If tumor was resectable (no vascular involvement), they received short-course proton chemoradiotherapy:<br />
<br />
==== Proton Chemoradiotherapy ====<br />
* Capecitabine 825 mg/m<sup>2</sup> PO BID, Monday – Friday for 2 weeks<br />
* Proton radiotherapy of 25 GyE in 5 treatments OR Intensity modulated radiotherapy (IMRT) of 30 Gy in 10 fractions<br />
<br />
=== References ===<br />
# Murphy J.E., Wo J.Y., Ryan D.P., Jiang W., Yeap B.Y., Drapek L.C., Blaszkowsky L.S., Kwak E.L., Allen J.N., Clark J.W., et al. Total neoadjuvant therapy with folfirinox followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: A phase 2 clinical trial. JAMA Oncol. 2018; 4:963–969. doi: 10.1001/jamaoncol.2018.0329. Link to original article: <nowiki>https://jamanetwork.com/journals/jamaoncology/fullarticle/2679565</nowiki> contains verified protocol Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/29800971<br />
<br />
==mFOLFIRINOX, Gemcitabine, RT {{#subobject:b71003|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFIRINOX, Gemcitabine, RT: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin, Gemcitabine, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:d87ec0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ Blazer et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Fluorouracil (5-FU)]] 1200 mg/m<sup>2</sup>/day IV continuous infusion over 46 hours, started on day 1 (total dose per cycle: 2400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once on day 1<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 4<br />
<br />
'''14-day cycle for 4 to 8 cycles'''<br />
<br />
''Followed by complete restaging. If tumor localized but still not resectable, chemoradiotherapy was administered:''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week<br />
*[[External beam radiotherapy]] was 36 Gy in 15 daily fractions<br />
<br />
'''3-week course'''<br />
<br />
===Variant #2 {{#subobject:7bb0e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ Hosein et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles. Protocol followed "per ACCORD-11 trial." Filgrastim was given at the discretion of the treating physician.'''<br />
<br />
''Treatment stopped at maximum response or tolerability. Resectable patients by imaging criteria were offered surgery, followed by postoperative chemoradiotherapy. Unresectable patients were offered chemoradiotherapy, followed by surgery (if they became resectable):''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV once per week<br />
*[[External beam radiotherapy]] at 50.4 Gy in 28 fractions.<br />
<br />
'''6-week course'''<br />
===References===<br />
# '''Retrospective:''' Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, Narayanan G, Ribeiro A, Portelance L, Merchan JR, Levi JU, Rocha-Lima CM. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012 May 29;12:199. [http://www.biomedcentral.com/1471-2407/12/199 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22642850 PubMed]<br />
# '''Retrospective:''' Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, Wuthrick E, Williams TM, Reardon J, Christopher Ellison E, Bloomston M, Bekaii-Saab T. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015 Apr;22(4):1153-9. [http://link.springer.com/article/10.1245%2Fs10434-014-4225-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25358667 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, unresectable=<br />
<br />
==Capecitabine monotherapy {{#subobject:dbd841|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dc4779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:6d97a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, Gem 3 out of 4 weeks x 4 {{#subobject:87edde|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Erlotinib & Gemcitabine x 2 more cycles (6 total) versus Capecitabine, Erlotinib, RT<br />
<br />
===Variant #2, Gem 3 out of 4 weeks x 6 {{#subobject:5a5e14|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
''Note: it is not clear from the protocol whether erlotinib is continued beyond the end of chemotherapy.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] as follows:<br />
**Cycles 1 to 4: 100 mg PO once per day<br />
**Cycles 5 & 6: 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 100 mg/day {{#subobject:b4258e|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #4, gemcitabine lead-in, erlotinib 150 mg/day {{#subobject:b7a41f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''GERCOR LAP07:''' Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Fluorouracil & RT {{#subobject:26f1c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:29784e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19811015)48:8%3C1705::AID-CNCR2820480803%3E3.0.CO;2-4 Moertel et al. 1981]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|RT<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ Herman et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Fluorouracil & RT with TNFerade<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on Mondays (total dose per week: 1000 mg/m<sup>2</sup>)<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 50.4 Gy total: 1.80 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy, followed by 1.80 Gy x 3 fractions boost to the tumor bed.<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
*Herman et al. 2013: Gemcitabine or Erlotinib & Gemcitabine maintenance, starting four weeks after chemoradiotherapy<br />
<br />
===References===<br />
# Moertel CG, Frytak S, Hahn RG, O'Connell MJ, Reitemeier RJ, Rubin J, Schutt AJ, Weiland LH, Childs DS, Holbrook MA, Lavin PT, Livstone E, Spiro H, Knowlton A, Kalser M, Barkin J, Lessner H, Mann-Kaplan R, Ramming K, Douglas HO Jr, Thomas P, Nave H, Bateman J, Lokich J, Brooks J, Chaffey J, Corson JM, Zamcheck N, Novak JW. Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer. 1981 Oct 15;48(8):1705-10. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19811015)48:8%3C1705::AID-CNCR2820480803%3E3.0.CO;2-4 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7284971 PubMed]<br />
# Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, Donehower RC, Pawlik TM, Ziegler MA, Cai H, Savage DT, Canto MI, Klapman J, Reid T, Shah RJ, Hoffe SE, Rosemurgy A, Wolfgang CL, Laheru DA. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013 Mar 1;31(7):886-94. Epub 2013 Jan 22. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.7516 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23341531 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:4f0be9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 3 out of 4 weeks x 4 {{#subobject:c511a7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Gemcitabine x 2 more cycles (6 total) versus Capecitabine & RT<br />
<br />
===Variant #2, 3 out of 4 weeks x 6 {{#subobject:cf89f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in ("Burris regimen") {{#subobject:82f8b2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.tandfonline.com/doi/abs/10.1179/joc.2004.16.6.589 Cantore et al. 2004]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Intraarterial FLEC<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://academic.oup.com/annonc/article/19/9/1592/208785 Chauffert et al. 2008 (FFCD/SFRO 2000-01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|CF & RT, then Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011 (ECOG E4201)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_RT_2|Gemcitabine & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent 4-week cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''Continued for at least 3 months'''<br />
====Subsequent treatment====<br />
*Louvet et al. 2005: 5-FU & RT consolidation was recommended but not mandated<br />
<br />
===References===<br />
# Cantore M, Fiorentini G, Luppi G, Rosati G, Caudana R, Piazza E, Comella G, Ceravolo C, Miserocchi L, Mambrini A, Del Freo A, Zamagni D, Rabbi C, Marangolo M. Gemcitabine versus FLEC regimen given intra-arterially to patients with unresectable pancreatic cancer: a prospective, randomized phase III trial of the Italian Society for Integrated Locoregional Therapy in Oncology. J Chemother. 2004 Dec;16(6):589-94. [https://www.tandfonline.com/doi/abs/10.1179/joc.2004.16.6.589 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15700852 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# '''FFCD/SFRO 2000-01:''' Chauffert B, Mornex F, Bonnetain F, Rougier P, Mariette C, Bouché O, Bosset JF, Aparicio T, Mineur L, Azzedine A, Hammel P, Butel J, Stremsdoerfer N, Maingon P, Bedenne L. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer: definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol. 2008 Sep;19(9):1592-9. Epub 2008 May 7. [https://academic.oup.com/annonc/article/19/9/1592/208785 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18467316 PubMed]<br />
# '''ECOG E4201:''' Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
# '''GERCOR LAP07:''' Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:a6e6fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 (600 mg/m<sup>2</sup>) {{#subobject:a6de29|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract Cardenes et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011 (ECOG E4201)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV over 30 to 60 minutes once per week during radiation<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy per fraction, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks.<br />
<br />
'''One course, followed in 4 weeks by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycle for up to 5 cycles'''<br />
<br />
===Variant #2 (400 mg/m<sup>2</sup>) {{#subobject:c1ac3c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract Epelbaum et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week for 7 weeks<br />
<br />
'''Radiation planning during this phase, followed by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 400 mg/m<sup>2</sup> IV over 30 minutes once per week (days 1, 8, 15)<br />
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks<br />
<br />
'''28 day cycle for 2 cycles, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Epelbaum R, Rosenblatt E, Nasrallah S, Faraggi D, Gaitini D, Mizrahi S, Kuten A. Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J Surg Oncol. 2002 Nov;81(3):138-43. [https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12407726 PubMed]<br />
# Cardenes HR, Moore AM, Johnson CS, Yu M, Helft P, Chiorean EG, Vinson J, Howard TJ, Stephens AW, Tai DF, Loehrer PJ Sr. A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study. Am J Clin Oncol. 2011 Oct;34(5):460-5.[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20881474 PubMed]<br />
# '''ECOG E4201:''' Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
<br />
==GemOx {{#subobject:19d87f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:5a25e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_2|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycle for at least 3 months'''<br />
<br />
''Subsequent chemoradiotherapy (45 Gy in 25 fractions for 5 weeks, associated with a daily FU 250 mg/m<sup>2</sup> continuous infusion, and a boost of 10 Gy in 8 fractions restricted to the initial tumor volume)'' ''was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
<br />
==Radiation therapy {{#subobject:5ac377|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:ce3d2d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.redjournal.org/article/S0360-3016(05)00096-9/fulltext Cohen et al. 2005 (ECOG E8282)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU, MMC, RT<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Radiotherapy====<br />
*[[External beam radiotherapy]]<br />
<br />
===References===<br />
# '''ECOG E8282:''' Cohen SJ, Dobelbower R Jr, Lipsitz S, Catalano PJ, Sischy B, Smith TJ, Haller DG; Eastern Cooperative Oncology Group. A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282. Int J Radiat Oncol Biol Phys. 2005 Aug 1;62(5):1345-50. [https://www.redjournal.org/article/S0360-3016(05)00096-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16029791 PubMed]<br />
<br />
=Metastatic disease, first-line=<br />
<br />
==Capecitabine monotherapy {{#subobject:4f5f03|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b31bbb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Capecitabine & Gemcitabine {{#subobject:2f0431|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Variant #1 {{#subobject:fcd708|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Note: this is essentially identical to the maintenance phase of variant #2, below.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:e8f0bf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO twice per day on days 1 to 21, 29 to 49<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO twice per day on days 1 to 21<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:a7e551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 650 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 24 weeks'''<br />
<br />
===References===<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:c30d8f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 25/1000, weekly dosing {{#subobject:20a0f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.10323 Colucci et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note that cisplatin is not given on day 22 of the first 8 weeks; otherwise, the schedule is identical to the schedule for gemcitabine. Treatment in Colucci et al. 2002 is given for a total of 3 cycles (16 weeks).''<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] as follows, '''given first, 60 minutes prior to gemcitabine''':<br />
**First 8 weeks: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Subsequent cycles: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 35/1000, 2 out of 3 weeks {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract Cascinu et al. 2008]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Cisplatin, Gemcitabine, Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8 (with 1500 mL NS)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #3, 50/1000, bi-weekly dosing {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Colucci G, Giuliani F, Gebbia V, Biglietto M, Rabitti P, Uomo G, Cigolari S, Testa A, Maiello E, Lopez M. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell'Italia Meridionale. Cancer. 2002 Feb 15;94(4):902-10. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.10323 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11920457 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 Jan;9(1):39-44. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18077217 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM); Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD); Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:bf797a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, no gemcitabine lead-in {{#subobject:43fe43|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext Kordes et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Erlotinib, Gemcitabine, Metformin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, gemcitabine lead-in, erlotinib 100 mg/day {{#subobject:fc43f2|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2008.20.0238 Van Cutsem et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Erlotinib, Gemcitabine, Bevacizumab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 150 mg/day {{#subobject:d49fb0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[https://gut.bmj.com/content/62/5/751.long Heinemann et al. 2012 (AIO-PK0104)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Capecitabine & Erlotinib<br />
| style="background-color:#1a9850" |Superior TTF1<br />
|-<br />
|}<br />
''Note: due to low accrual in NCIC CTG PA.3, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, Verslype C, Scheithauer W, Shang A, Cosaert J, Moore MJ. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009 May 1;27(13):2231-7. Epub 2009 Mar 23. [http://ascopubs.org/doi/full/10.1200/JCO.2008.20.0238 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19307500 PubMed]<br />
# '''AIO-PK0104:''' Heinemann V, Vehling-Kaiser U, Waldschmidt D, Kettner E, Märten A, Winkelmann C, Klein S, Kojouharoff G, Gauler TC, von Weikersthal LF, Clemens MR, Geissler M, Greten TF, Hegewisch-Becker S, Rubanov O, Baake G, Höhler T, Ko YD, Jung A, Neugebauer S, Boeck S. Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the 'Arbeitsgemeinschaft Internistische Onkologie' (AIO-PK0104). Gut. 2013 May;62(5):751-9. Epub 2012 Jul 7. [https://gut.bmj.com/content/62/5/751.long link to original article] '''contains verified protocol'''' [https://www.ncbi.nlm.nih.gov/pubmed/22773551 PubMed]<br />
# Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47. Epub 2015 Jun 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext link to original article]'''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26067687 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:c6c509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 300 mg/m<sup>2</sup>/day PVI {{#subobject:3ac41f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2002.09.029 Maisey et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & Mitomycin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
==== Chemotherapy ====<br />
*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion<br />
<br />
'''Continued for up to 24 weeks'''<br />
<br />
===Variant #2, 500 mg/m<sup>2</sup> intermittent {{#subobject:27a992|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/397816 Cullinan et al. 1985]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|1. FA<br> 2. FAM<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19900515)65:10%3C2207::AID-CNCR2820651007%3E3.0.CO;2-Y Cullinan et al. 1990]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|1. Mallinson regimen<br> 2. FAP<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: this is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.''<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycles'''<br />
<br />
===Variant #2, 600 mg/m<sup>2</sup> weekly {{#subobject:3ca01f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Inferior to gemcitabine. Here for historical reference purposes, only.''<br />
==== Chemotherapy ====<br />
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per week<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# Cullinan SA, Moertel CG, Fleming TR, Rubin JR, Krook JE, Everson LK, Windschitl HE, Twito DI, Marschke RF, Foley JF, Pfeifle DM, Barlow JF. A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma: fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA. 1985 Apr 12;253(14):2061-7. [https://jamanetwork.com/journals/jama/fullarticle/397816 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2579257 PubMed]<br />
# Cullinan S, Moertel CG, Wieand HS, Schutt AJ, Krook JE, Foley JF, Norris BD, Kardinal CG, Tschetter LK, Barlow JF. A phase III trial on the therapy of advanced pancreatic carcinoma: evaluations of the Mallinson regimen and combined 5-fluorouracil, doxorubicin, and cisplatin. Cancer. 1990 May 15;65(10):2207-12. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19900515)65:10%3C2207::AID-CNCR2820651007%3E3.0.CO;2-Y link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2189551 PubMed]<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Maisey N, Chau I, Cunningham D, Norman A, Seymour M, Hickish T, Iveson T, O'Brien M, Tebbutt N, Harrington A, Hill M. Multicenter randomized phase III trial comparing protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin in inoperable pancreatic cancer. J Clin Oncol. 2002 Jul 15;20(14):3130-6. [http://ascopubs.org/doi/full/10.1200/JCO.2002.09.029 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12118027 PubMed]<br />
<br />
==FOLFIRINOX {{#subobject:aaa3c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e140cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior QoL by [http://groups.eortc.be/qol/eortc-qlq-c30 EORTC QLQ-C30]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given fourth''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given third with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:3a0f4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 900 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:c61ab9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360678/ Stathopoulos et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Irinotecan<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 900 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 1000 mg/m<sup>2</sup>, 8-week lead-in ("Burris regimen") {{#subobject:5d6dd0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.10323 Colucci et al. 2002]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2003.02.098 Moore et al. 2003 (NCIC CTG PA.1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Tanomastat<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2004.10.112 Van Cutsem et al. 2004]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Tipifarnib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2004.12.082 Rocha Lima et al. 2004]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Irinotecan<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx_2|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract Reni et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PEFG<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2006.07.0201 Abou-Alfa et al. 2006a]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Exatecan<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. GEM FDR<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|2. [[#GemOx_2|GEMOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GEM-CAP]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ Philip et al. 2010 (SWOG S0205)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981019/ Dahan et al. 2010 (FFCD 0301)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|LV5FU2-CDDP<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/23/11/2799/234953 Gonçalves et al. 2012 (BAYPAN)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Sorafenib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(13)00303-1/fulltext Rougier et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Ziv-aflibercept<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_nab-Paclitaxel|Gemcitabine & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516046/ Deplanque et al. 2015 (AB07012)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Masitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext Middleton et al. 2017 (ViP)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Vandetanib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: Colucci et al. 2002 stopped treatment after 3 cycles (16 weeks).''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
***In Burris et al. 1997, patients with grade 2 or lower toxicities could have had doses increased to 1250 mg/m<sup>2</sup><br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 1000 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:c6349|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2002.11.149 Berlin et al. 2002 (ECOG E2297)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|5-FU & Gemcitabine<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[https://academic.oup.com/annonc/article/16/10/1639/169072 Oettle et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Pemetrexed<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60661-3/fulltext Spano et al. 2008 (A4061016)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917317/ Kindler et al. 2010 (CALGB 80303)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Bevacizumab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract Kindler et al. 2011 (A4061028)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|2. Gemcitabine & S-1<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ Fuchs et al. 2015 (GAMMA)]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II (C)<br />
|Gemcitabine & Ganitumab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551155/ O'Neil et al. 2015]<br />
| style="background-color:#1a9851" |Phase II/III (C)<br />
|Gemcitabine & Rigosertib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ Catenacci et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II (C)<br />
|Gemcitabine & Vismodegib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #4, 1000 mg/m<sup>2</sup>, weekly {{#subobject:8bae67|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 Hong et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Simvastatin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #5, 1500 mg/m<sup>2</sup>, fixed-dose rate (FDR) {{#subobject:5114cc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|2. [[#GemOx_2|GEMOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 150 minutes (10 mg/m<sup>2</sup>/min) once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Colucci G, Giuliani F, Gebbia V, Biglietto M, Rabitti P, Uomo G, Cigolari S, Testa A, Maiello E, Lopez M. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell'Italia Meridionale. Cancer. 2002 Feb 15;94(4):902-10. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.10323 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11920457 PubMed]<br />
# '''ECOG E2297:''' Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, Benson AB 3rd. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol. 2002 Aug 1;20(15):3270-5. [http://ascopubs.org/doi/full/10.1200/JCO.2002.11.149 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12149301 PubMed]<br />
# '''NCIC CTG PA.1:''' Moore MJ, Hamm J, Dancey J, Eisenberg PD, Dagenais M, Fields A, Hagan K, Greenberg B, Colwell B, Zee B, Tu D, Ottaway J, Humphrey R, Seymour L; National Cancer Institute of Canada Clinical Trials Group. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Sep 1;21(17):3296-302. [http://ascopubs.org/doi/full/10.1200/JCO.2003.02.098 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12947065 PubMed]<br />
# Van Cutsem E, van de Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A, Schoffski P, Post S, Verslype C, Neumann H, Safran H, Humblet Y, Perez Ruixo J, Ma Y, Von Hoff D. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol. 2004 Apr 15;22(8):1430-8. [http://ascopubs.org/doi/full/10.1200/JCO.2004.10.112 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15084616 PubMed]<br />
# Rocha Lima CM, Green MR, Rotche R, Miller WH Jr, Jeffrey GM, Cisar LA, Morganti A, Orlando N, Gruia G, Miller LL. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol. 2004 Sep 15;22(18):3776-83. [http://ascopubs.org/doi/full/10.1200/JCO.2004.12.082 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15365074 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Oettle H, Richards D, Ramanathan RK, van Laethem JL, Peeters M, Fuchs M, Zimmermann A, John W, Von Hoff D, Arning M, Kindler HL. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol. 2005 Oct;16(10):1639-45. Epub 2005 Aug 8. Erratum in: Ann Oncol. 2006 Mar;17(3):535. [https://academic.oup.com/annonc/article/16/10/1639/169072 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16087696 PubMed]<br />
# Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15925814 PubMed]<br />
# Stathopoulos GP, Syrigos K, Aravantinos G, Polyzos A, Papakotoulas P, Fountzilas G, Potamianou A, Ziras N, Boukovinas J, Varthalitis J, Androulakis N, Kotsakis A, Samonis G, Georgoulias V. A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. Br J Cancer. 2006 Sep 4;95(5):587-92. Epub 2006 Aug 8. [https://www.nature.com/articles/6603301 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360678/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16909140 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Abou-Alfa GK, Letourneau R, Harker G, Modiano M, Hurwitz H, Tchekmedyian NS, Feit K, Ackerman J, De Jager RL, Eckhardt SG, O'Reilly EM. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J Clin Oncol. 2006 Sep 20;24(27):4441-7. [http://ascopubs.org/doi/full/10.1200/JCO.2006.07.0201 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16983112 PubMed]<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# '''A4061016:''' Spano JP, Chodkiewicz C, Maurel J, Wong R, Wasan H, Barone C, Létourneau R, Bajetta E, Pithavala Y, Bycott P, Trask P, Liau K, Ricart AD, Kim S, Rixe O. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet. 2008 Jun 21;371(9630):2101-8. Epub 2008 May 29. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60661-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18514303 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM); Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD); Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
# '''SWOG S0205:''' Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 1;28(22):3605-10. Epub 2010 Jul 6. [http://jco.ascopubs.org/content/28/22/3605.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20606093 PubMed]<br />
# '''CALGB 80303:''' Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, Innocenti F, Mulcahy MF, O'Reilly E, Wozniak TF, Picus J, Bhargava P, Mayer RJ, Schilsky RL, Goldberg RM. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010 Aug 1;28(22):3617-22. Epub 2010 Jul 6. [http://ascopubs.org/doi/10.1200/JCO.2010.28.1386 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917317/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20606091 PubMed]<br />
# '''FFCD 0301:''' Dahan L, Bonnetain F, Ychou M, Mitry E, Gasmi M, Raoul JL, Cattan S, Phelip JM, Hammel P, Chauffert B, Michel P, Legoux JL, Rougier P, Bedenne L, Seitz JF; Fédération Francophone de Cancérologie Digestive. Combination 5-fluorouracil, folinic acid and cisplatin (LV5FU2-CDDP) followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: final results of a randomised strategic phase III trial (FFCD 0301). Gut. 2010 Nov;59(11):1527-34. [https://gut.bmj.com/content/59/11/1527.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981019/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20947887 PubMed]<br />
# '''A4061028:''' Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306953 PubMed]<br />
## '''Subgroup analysis:''' Ioka T, Okusaka T, Ohkawa S, Boku N, Sawaki A, Fujii Y, Kamei Y, Takahashi S, Namazu K, Umeyama Y, Bycott P, Furuse J. Efficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer: subgroup analyses by region, including Japan, from the global randomized phase III trial. Jpn J Clin Oncol. 2015 May;45(5):439-48. Epub 2015 Feb 3. [https://academic.oup.com/jjco/article/45/5/439/1017164 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25647781 PubMed]<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
# '''BAYPAN:''' Gonçalves A, Gilabert M, François E, Dahan L, Perrier H, Lamy R, Re D, Largillier R, Gasmi M, Tchiknavorian X, Esterni B, Genre D, Moureau-Zabotto L, Giovannini M, Seitz JF, Delpero JR, Turrini O, Viens P, Raoul JL. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol. 2012 Nov;23(11):2799-805. Epub 2012 Jul 5. [https://academic.oup.com/annonc/article/23/11/2799/234953 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22771827 PubMed]<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
# Rougier P, Riess H, Manges R, Karasek P, Humblet Y, Barone C, Santoro A, Assadourian S, Hatteville L, Philip PA. Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. Eur J Cancer. 2013 Aug;49(12):2633-42. Epub 2013 Apr 30. [https://www.ejcancer.com/article/S0959-8049(13)00303-1/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23642329 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
## '''Update:''' Goldstein D, El-Maraghi RH, Hammel P, Heinemann V, Kunzmann V, Sastre J, Scheithauer W, Siena S, Tabernero J, Teixeira L, Tortora G, Van Laethem JL, Young R, Penenberg DN, Lu B, Romano A, Von Hoff DD. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst. 2015 Jan 31;107(2). [https://academic.oup.com/jnci/article/107/2/dju413/902453 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25638248 PubMed]<br />
# Hong JY, Nam EM, Lee J, Park JO, Lee SC, Song SY, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol. 2014 Jan;73(1):125-30. Epub 2013 Oct 27. [https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24162380 PubMed]<br />
# '''GAMMA:''' Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921-7. Epub 2015 Jan 21. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25609246 PubMed]<br />
# '''AB07012:''' Deplanque G, Demarchi M, Hebbar M, Flynn P, Melichar B, Atkins J, Nowara E, Moyé L, Piquemal D, Ritter D, Dubreuil P, Mansfield CD, Acin Y, Moussy A, Hermine O, Hammel P. A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer. Ann Oncol. 2015 Jun;26(6):1194-200. Epub 2015 Apr 9. [https://academic.oup.com/annonc/article/26/6/1194/161899 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516046/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25858497 PubMed]<br />
# O'Neil BH, Scott AJ, Ma WW, Cohen SJ, Leichman L, Aisner DL, Menter AR, Tejani MA, Cho JK, Granfortuna J, Coveler AL, Olowokure OO, Baranda JC, Cusnir M, Phillip P, Boles J, Nazemzadeh R, Rarick M, Cohen DJ, Radford J, Fehrenbacher L, Bajaj R, Bathini V, Fanta P, Berlin J, McRee AJ, Maguire R, Wilhelm F, Maniar M, Jimeno A, Gomes CL, Messersmith WA. A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. Ann Oncol. 2015 Sep;26(9):1923-9. Epub 2015 Jun 19. Erratum in: Ann Oncol. 2015 Dec;26(12):2505. Leichman, L [added]. Ann Oncol. 2016 Jun;27(6):1180. [https://academic.oup.com/annonc/article/26/9/1923/189392 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551155/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26091808 PubMed]<br />
# Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D, Wade J, Sleckman B, Lenz HJ, Stiff P, Kumar P, Xu P, Henderson L, Takebe N, Salgia R, Wang X, Stadler WM, de Sauvage FJ, Kindler HL. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015 Dec 20;33(36):4284-92. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/36/4284.long link to original article] '''contains protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527777 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
# '''ViP:''' Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr;18(4):486-499. Epub 2017 Mar 2. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28259610 PubMed]<br />
<br />
==GemOx {{#subobject:520af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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GemOx: '''<u>Gem</u>'''citabine & '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:9d3266|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. [[#Gemcitabine_monotherapy_3|Gemcitabine, FDR]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
<br />
==Gemcitabine & nab-Paclitaxel {{#subobject:fbd698|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
NG: '''<u>N</u>'''ab-Paclitaxel & '''<u>G</u>'''emcitabine<br />
===Variant #1, with 8-week lead-in {{#subobject:63ba04|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] as follows, '''given first''':<br />
**Cycle 1: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15<br />
<br />
'''8-week cycle followed by 28-day cycles'''<br />
<br />
===Variant #2, no lead-in {{#subobject:ecc1c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ Von Hoff et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 or 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/34/4548.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969517 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
## '''Update:''' Goldstein D, El-Maraghi RH, Hammel P, Heinemann V, Kunzmann V, Sastre J, Scheithauer W, Siena S, Tabernero J, Teixeira L, Tortora G, Van Laethem JL, Young R, Penenberg DN, Lu B, Romano A, Von Hoff DD. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst. 2015 Jan 31;107(2). [https://academic.oup.com/jnci/article/107/2/dju413/902453 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25638248 PubMed]<br />
<br />
==GTX {{#subobject:f0d62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
GTX: '''<u>G</u>'''emcitabine, '''<u>T</u>'''axotere (Docetaxel), '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:fc0e50|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.springerlink.com/content/75m422843l3461m0/ Fine et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: De Jesus-Acosta et al. 2012 lists the capecitabine dose as "750 mg/m<sup>2</sup>/day orally divided into two doses," but this is believed to be a typographical error since the original reference that it cites, Fine et al. 2007, uses capecitabine at 750 mg/m<sup>2</sup> PO twice per day. The 2009 ASCO abstract by Fine also lists this 750 mg/m<sup>2</sup> PO twice per day (1500 mg/m<sup>2</sup>/day) dose.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 75 minutes once per day on days 4 & 11<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 11<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75. Epub 2007 Apr 18. [http://www.springerlink.com/content/75m422843l3461m0/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17440727 PubMed]<br />
# '''Abstract:''' R. L. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. 2009 ASCO Annual Meeting abstract 4623. [http://ascopubs.org/doi/full/10.1200/jco.2009.27.15s.4623 link to abstract] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012 Feb;69(2):415-24. Epub 2011 Jul 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723 link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21800112 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:759f1a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:94d490|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|2. Gemcitabine & S-1<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<br />
=Metastatic disease, refractory=<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(08)01051-4/fulltext Ciuleanu et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Glufosfamide<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#OLF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Best supportive care. Placed here because one or more randomized clinical trials included a best supportive care arm in this disease context.''<br />
<br />
===References===<br />
# Ciuleanu TE, Pavlovsky AV, Bodoky G, Garin AM, Langmuir VK, Kroll S, Tidmarsh GT. A randomised Phase III trial of glufosfamide compared with best supportive care in metastatic pancreatic adenocarcinoma previously treated with gemcitabine. Eur J Cancer. 2009 Jun;45(9):1589-96. Epub 2009 Jan 31. [https://www.ejcancer.com/article/S0959-8049(08)01051-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19188061 PubMed]<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<br />
==Capecitabine monotherapy {{#subobject:38b5c7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:3ab38a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs10637-018-0580-2 Hurwitz et al. 2018 (JANUS 1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Capecitabine & Ruxolitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''JANUS 1:''' Hurwitz H, Van Cutsem E, Bendell J, Hidalgo M, Li CP, Salvo MG, Macarulla T, Sahai V, Sama A, Greeno E, Yu KH, Verslype C, Dawkins F, Walker C, Clark J, O'Reilly EM. Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies. Invest New Drugs. 2018 Aug;36(4):683-695. Epub 2018 Mar 6. [https://link.springer.com/article/10.1007%2Fs10637-018-0580-2 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29508247 PubMed]<br />
<br />
==Capecitabine & Erlotinib {{#subobject:4655b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d5c799|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4787.full Kulke et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> (rounded to the nearest 150 mg tablet) PO twice per day on days 1 to 14<br />
*[[Erlotinib (Tarceva)]] 150 mg PO on days 1 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak EL, Muzikansky A, Lawrence C, Fuchs CS. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007 Oct 20;25(30):4787-92. [http://jco.ascopubs.org/content/25/30/4787.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947726 PubMed]<br />
<br />
==CapeOx {{#subobject:d09d5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:57ad5f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full Xiong et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] as follows:<br />
**Age less than 65 years old and ECOG performance status less than 2: 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
**Age greater than 65 years old and/or ECOG performance status greater than or equal to 2: 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] as follows:<br />
**Age less than 65 years old and ECOG performance status less than 2: 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**Age greater than 65 years old and/or ECOG performance status greater than or equal to 2: 110 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008 Oct 15;113(8):2046-52. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18756532 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:992c9d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FF: '''<u>F</u>'''luorouracil & '''<u>F</u>'''olinic acid<br />
===Variant #1, 2000/200 {{#subobject:b631e0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#OLF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Fluorouracil.2C_Folinic acid.2C_nanoliposomal_Irinotecan|Fluorouracil, Folinic acid, nanoliposomal Irinotecan]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|2. Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, '''given second''' (total dose per cycle: 8000 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, '''given first'''<br />
<br />
'''42-day cycles'''<br />
<br />
===Variant #2, 2800/400 {{#subobject:959e8e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2016.68.5776 Gill et al. 2016 (PANCREOX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|mFOLFOX6<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# '''CONKO-003:''' Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
# '''NAPOLI-1:''' Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
# '''PANCREOX:''' Gill S, Ko YJ, Cripps C, Beaudoin A, Dhesy-Thind S, Zulfiqar M, Zalewski P, Do T, Cano P, Lam WYH, Dowden S, Grassin H, Stewart J, Moore M. PANCREOX: a randomized phase III study of fluorouracil/leucovorin with or without oxaliplatin for second-line advanced pancreatic cancer in patients who have received gemcitabine-based chemotherapy. J Clin Oncol. 2016 Nov 10;34(32):3914-3920. Epub 2016 Sep 30. [http://ascopubs.org/doi/full/10.1200/JCO.2016.68.5776 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27621395 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, nanoliposomal Irinotecan {{#subobject:72308d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a81310|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. [[#Fluorouracil_.26_Folinic acid_2|Fluorouracil & Folinic acid]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|2. Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, started on day 1, '''given third'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given second'''<br />
*[[Irinotecan liposome (Onivyde)]] 70 mg/m<sup>2</sup> (irinotecan free base) IV over 90 minutes once on day 1, '''given first'''<br />
**Per Wang-Gillam et al. 2015 (NAPOLI-01), 70 mg/m<sup>2</sup> irinotecan free base is equivalent to 80 mg/m<sup>2</sup> nanoliposomal irinotecan. According to the trial's ClinicalTrials.gov page: "The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m<sup>2</sup> dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/m<sup>2</sup> of irinotecan free base."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# '''NAPOLI-1:''' Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
<br />
==FOLFIRI {{#subobject:6fd426|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br />
===Variant #1 {{#subobject:6a9cae|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 Zaniboni et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, modified FOLFIRI.3 {{#subobject:4758e8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#FOLFOX|mFOLFOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Irinotecan (Camptosar)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 3<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
# Zaniboni A, Aitini E, Barni S, Ferrari D, Cascinu S, Catalano V, Valmadre G, Ferrara D, Veltri E, Codignola C, Labianca R. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jun;69(6):1641-5. Epub 2012 May 11. [http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22576338 PubMed]<br />
<br />
==FOLFOX {{#subobject:377e80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:33ef68|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II (E)<br />
|[[#FOLFIRI|mFOLFIRI.3]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
<br />
==Irinotecan liposomal monotherapy {{#subobject:9a99c8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:c50e15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749576/ Ko et al. 2013 (PEP0208)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Irinotecan liposome (Onivyde)]] 120 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''PEP0208:''' Ko AH, Tempero MA, Shan YS, Su WC, Lin YL, Dito E, Ong A, Wang YW, Yeh CG, Chen LT. A multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM-398) for patients with gemcitabine-refractory metastatic pancreatic cancer. Br J Cancer. 2013 Aug 20;109(4):920-5. [https://www.nature.com/articles/bjc2013408 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749576/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23880820 PubMed]<br />
<br />
==OLF {{#subobject:8b32c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OLF: '''<u>O</u>'''xaliplatin, '''<u>L</u>'''eucovorin (Folinic acid), '''<u>F</u>'''luorouracil<br />
<br>OFF: '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil, '''<u>F</u>'''olinic acid <br />
===Regimen {{#subobject:ae57d5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_.26_Folinic acid_2|Fluorouracil & Folinic acid]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
<br />
''Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m<sup>2</sup>," or 850 mg/m<sup>2</sup>.''<br />
====Chemotherapy====<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once per day on days 8 & 22, '''given first'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, '''given third''' (total dose per cycle: 8000 mg/m<sup>2</sup>)<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# '''CONKO-003:''' Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
<br />
==Olaparib monotherapy {{#subobject:0c2eb3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:21eb78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/3/244.long Kaufman et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients had germline BRCA1/2 mutations.''<br />
====Preceding treatment====<br />
*Gemcitabine, with progression<br />
====Chemotherapy====<br />
*[[Olaparib (Lynparza)]] 400 mg PO twice per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
# Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/33/3/244.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed]<br />
<br />
==Paclitaxel, nanoparticle albumin-bound monotherapy {{#subobject:ab9fc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8d38d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://insights.ovid.com/pubmed?pmid=22307213 Hosein et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Hosein PJ, de Lima Lopes G Jr, Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013 Apr;36(2):151-6. Epub 2012 Feb 2. [https://insights.ovid.com/pubmed?pmid=22307213 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22307213 PubMed]<br />
<br />
[[Category:Pancreatic cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdheryhttps://hemonc.org/w/index.php?title=Pancreatic_NET&diff=36474Pancreatic NET2019-03-28T19:48:03Z<p>Rozinachowdhery: PRRT with 177Lu-dotatate addition</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Chowdhery.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Rozinachowdhery|Rozina Chowdhery, MD]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br />
| style="background-color:#F0F0F0; width: 15%" |[[File:Jeenavarghese.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Jvarghese|Jeena M. Varghese, MBBS]]<br>MD Anderson Cancer Center<br>Houston, TX</big><br>[https://www.linkedin.com/in/jeena-varghese-b2b45b9b/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
<big>Note: for more general neuroendocrine regimens, please visit the '''[[neuroendocrine tumors]]''' page.</big><br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2012:''' Öberg et al. [https://www.esmo.org/Guidelines/Endocrine-and-Neuroendocrine-Cancers/Neuroendocrine-Gastroenteropancreatic-Tumours Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf NCCN Guidelines - Neuroendocrine Tumors]<br />
<br />
=All lines of therapy=<br />
==Capecitabine & Temozolomide {{#subobject:738284|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:fc2dd9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665634/ Strosberg et al. 2011]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14<br />
*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day at bedtime on days 10 to 14<br />
<br />
====Supportive medications====<br />
*[[Ondansetron (Zofran)]] 8 mg (route not specified) prior to each dose of [[Temozolomide (Temodar)]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, Helm J, Kvols L. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011 Jan 15;117(2):268-75. Epub 2010 Sep 7. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.25425/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665634/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20824724 PubMed]<br />
<br />
==Doxorubicin & Streptozocin {{#subobject:5c625d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:a9c7ed|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199202203260804 Moertel et al. 1992]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|1. Chlorozotocin<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. [[#Fluorouracil_.26_Streptozocin_.26|5-FU & Streptozocin]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 22<br />
*[[Streptozocin (Zanosar)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. [https://www.nejm.org/doi/full/10.1056/NEJM199202203260804 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1310159 PubMed]<br />
<br />
==Everolimus monotherapy {{#subobject:78dff1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:5ea369|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ Yao et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208619/ Yao et al. 2011 (RADIANT-3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Everolimus (Afinitor)]] 10 mg PO once per day<br />
<br />
'''Given until progression of disease, unacceptable toxicity, drug interruption of 3 weeks or longer, or withdrawal of consent'''<br />
<br />
===References===<br />
# Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. Epub 2009 Nov 23. [http://jco.ascopubs.org/content/28/1/69.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19933912 PubMed]<br />
# '''RADIANT-3:''' Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Öberg K; RAD001 in Advanced Neuroendocrine Tumors Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1009290 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208619/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21306238 PubMed]<br />
# '''Review:''' Yao JC, Phan AT, Jehl V, Shah G, Meric-Bernstam F. Everolimus in advanced pancreatic neuroendocrine tumors: the clinical experience. Cancer Res. 2013 Mar 1;73(5):1449-53. Epub 2013 Feb 22. [http://cancerres.aacrjournals.org/content/73/5/1449.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23436795 PubMed]<br />
<br />
==Everolimus & Octreotide {{#subobject:d6b3eb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:b0f62f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ Yao et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Patients in Yao et al. 2010 who received this regimen had already been receiving octreotide LAR for at least 3 months before participating in the study.''<br />
====Endocrine & Chemotherapy====<br />
*[[Everolimus (Afinitor)]] 10 mg PO once per day<br />
*[[Octreotide LAR (Sandostatin LAR)]] up to 30 mg (whatever their prestudy dose was) IM once on day 1<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:f82bb5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: Everolimus "dose of 10 mg was associated with superior PFS...however, the study was not prospectively powered for these comparisons. These analyses should be considered exploratory."''<br />
====Endocrine & Chemotherapy====<br />
*[[Everolimus (Afinitor)]] 5 or 10 mg PO once per day on days 1 to 28<br />
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1<br />
<br />
'''28-day cycle for up to 12 cycles or until progression of disease, though treatment could be continued beyond this period if thought by the treating physician to be beneficial'''<br />
<br />
===References===<br />
# Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008 Sep 10;26(26):4311-8. [http://jco.ascopubs.org/content/26/26/4311.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18779618 PubMed]<br />
# Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. Epub 2009 Nov 23. [http://jco.ascopubs.org/content/28/1/69.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295034/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19933912 PubMed]<br />
<br />
==FAS {{#subobject:66b05e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FAS: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>S</u>'''treptozocin<br />
<br />
===Regimen {{#subobject:de76a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/22/23/4762.long Kouvaraki et al. 2004]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Streptozocin (Zanosar)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
<br />
'''28-day cycles, given until progression of disease, unacceptable toxicity, or patient intolerance'''<br />
<br />
===References===<br />
# '''Retrospective:''' Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, Yao JC. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004 Dec 1;22(23):4762-71. [http://jco.ascopubs.org/content/22/23/4762.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15570077 PubMed]<br />
<br />
==Fluorouracil & Streptozocin {{#subobject:6f7b84|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:e45011|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJM198011203032101 Moertel et al. 1980]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|Fluorouracil<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199202203260804 Moertel et al. 1992]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. Chlorozotocin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|2. [[#Doxorubicin_.26_Streptozocin|Doxorubicin & Streptozocin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Note: treatment details are from Moertel et al. 1992.''<br />
====Chemotherapy====<br />
*[[Streptozocin (Zanosar)]] 500 mg/m<sup>2</sup> IV once per day on days 1 to 5<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# Moertel CG, Hanley JA, Johnson LA. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1980 Nov 20;303(21):1189-94. [https://www.nejm.org/doi/full/10.1056/NEJM198011203032101 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6252466 PubMed]<br />
# Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. [https://www.nejm.org/doi/full/10.1056/NEJM199202203260804 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1310159 PubMed]<br />
<br />
==Lanreotide Depot/Autogel monotherapy {{#subobject:8bca3a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:a9ee08|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1316158 Caplin et al. 2014 (CLARINET)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740728/ Caplin et al. 2016 (CLARINET extension)]<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
====Hormonotherapy====<br />
*[[Lanreotide (Somatuline) | Lanreotide (Somatuline) Depot/Autogel]] 120 mg SC once on day 1<br />
<br />
'''28-day cycle for 96 weeks (CLARINET) or up to 8 years (CLARINET extension)'''<br />
<br />
===References===<br />
# '''CLARINET:''' Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33. [https://www.nejm.org/doi/full/10.1056/NEJMoa1316158 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25014687 PubMed]<br />
# '''CLARINET Extension:''' Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Gomez-Panzani E, Ruszniewski P; CLARINET Investigators. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. Endocr Relat Cancer. 2016 Mar;23(3):191-9. Epub 2016 Jan 7. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740728/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26743120 PubMed]<br />
<br />
==Lanreotide & Interferon alfa-2b {{#subobject:9c5a59|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:652f4d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 Fjällskog et al. 2002]<br />
| style="background-color:#ffffbe" |Pilot, <20 pts<br />
|-<br />
|}<br />
''Fjällskog et al. 2002 contained case reports of several patients treated with lanreotide & interferon alfa. Each patient received individualized therapy rather than a standard regimen.''<br />
====Endocrine & Immunotherapy====<br />
*[[Lanreotide (Somatuline)]] 3 mg SC twice per day<br />
*[[Interferon alfa-2b (Intron-A)]] 3 to 5 million units SC given once per day, 3 to 7 days per week (total of 9 to 25 million units per week)<br />
<br />
===References===<br />
# Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. [http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12025889 PubMed]<br />
<br />
==Octreotide monotherapy {{#subobject:665a8b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cd8cf6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://annonc.oxfordjournals.org/content/15/6/966.long Oberg et al. 2004]<br />
| style="background-color:#ffffbe" |Consensus guideline<br />
|-<br />
|}<br />
====Hormonotherapy====<br />
*[[Octreotide (Sandostatin)]] 0.1 to 0.5 mg SC given 2 to 4 times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms<br />
**"A reasonable starting dose is" 0.15 mg SC TID<br />
<br />
'''Treatment continued indefinitely unless patients have unmanageable side-effects or insufficient control of symptoms'''<br />
<br />
===References===<br />
# '''Review:''' Brentjens R, Saltz L. Islet cell tumors of the pancreas: the medical oncologist's perspective. Surg Clin North Am. 2001 Jun;81(3):527-42. [http://www.sciencedirect.com/science/article/pii/S0039610905701419 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/11459269 PubMed]<br />
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [http://annonc.oxfordjournals.org/content/15/6/966.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15151956 PubMed]<br />
<br />
==Octreotide LAR monotherapy {{#subobject:e356ea|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:f0bc1b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 25%" |Study<br />
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 25%" |Comparator<br />
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/28/4656.long Rinke et al. 2009 (PROMID)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior TTP<br />
|-<br />
|}<br />
====Hormonotherapy====<br />
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1, with potentially higher doses if needed for symptom control<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [http://annonc.oxfordjournals.org/content/15/6/966.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15151956 PubMed]<br />
# '''PROMID:''' Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. [http://jco.ascopubs.org/content/27/28/4656.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19704057 PubMed]<br />
<br />
==Octreotide & Interferon alfa {{#subobject:1cf4c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:cbf5c4|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 Fjällskog et al. 2002]<br />
| style="background-color:#ffffbe" |Pilot, <20 pts<br />
|-<br />
|}<br />
''Fjällskog et al. 2002 contained case reports of several patients treated with octreotide & interferon alfa. Each patient received individualized therapy rather than a standard regimen.''<br />
====Endocrine & Immunotherapy====<br />
*[[Octreotide (Sandostatin)]] 0.05 to 0.5 mg SC given 2 to 3 times per day<br />
*[[Interferon alfa-2b (Intron-A)]] 3 to 5 million units SC given once per day, 3 to 7 days per week (total of 9 to 25 million units per week)<br />
<br />
===References===<br />
# Janson ET, Oberg K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. [https://www.tandfonline.com/doi/full/10.3109/02841869309083916 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7686765 PubMed]<br />
# Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. [http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12025889 PubMed]<br />
<br />
==Placebo==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/28/4656.long Rinke et al. 2009 (PROMID)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Octreotide_LAR_monotherapy|Octreotide LAR]]<br />
| style="background-color:#d73027" |Inferior TTP<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1003825 Raymond et al. 2011 (A6181111)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
| rowspan="2" |[[#Sunitinib_monotherapy|Sunitinib]]<br />
| rowspan="2" style="background-color:#d73027" |Inferior PFS<br />
| style="background-color:#1a9850" |Less diarrhea<br />
|-<br />
| style="background-color:#91cf60" |Seems to have better insomnia<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208619/ Yao et al. 2011 (RADIANT-3)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Everolimus_monotherapy|Everolimus]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1316158 Caplin et al. 2014 (CLARINET)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lanreotide_Depot.2FAutogel_monotherapy|Lanreotide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only. Note: while the initial A6181111 publication seemed to have a significant survival disadvantage for this arm (p=0.02), this finding was no longer significant at the final update (p=0.094). The primary endpoint (PFS) remains significant.''<br />
<br />
===References===<br />
# '''PROMID:''' Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. [http://jco.ascopubs.org/content/27/28/4656.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19704057 PubMed]<br />
# '''A6181111:''' Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):501-13. Erratum in: N Engl J Med. 2011 Mar 17;364(11):1082. [https://www.nejm.org/doi/full/10.1056/NEJMoa1003825 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306237 PubMed]<br />
## '''HRQoL analysis:''' Vinik A, Bottomley A, Korytowsky B, Bang YJ, Raoul JL, Valle JW, Metrakos P, Hörsch D, Mundayat R, Reisman A, Wang Z, Chao RC, Raymond E. Patient-reported outcomes and quality of life with sunitinib versus placebo for pancreatic neuroendocrine tumors: results from an international phase III trial. Target Oncol. 2016 Dec;11(6):815-824. [https://link.springer.com/article/10.1007%2Fs11523-016-0462-5 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27924459 PubMed]<br />
## '''Update:''' Faivre S, Niccoli P, Castellano D, Valle JW, Hammel P, Raoul JL, Vinik A, Van Cutsem E, Bang YJ, Lee SH, Borbath I, Lombard-Bohas C, Metrakos P, Smith D, Chen JS, Ruszniewski P, Seitz JF, Patyna S, Lu DR, Ishak KJ, Raymond E. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol. 2017 Feb 1;28(2):339-343. [https://academic.oup.com/annonc/article/28/2/339/2676883 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27836885 PubMed]<br />
# '''RADIANT-3:''' Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Öberg K; RAD001 in Advanced Neuroendocrine Tumors Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. [https://www.nejm.org/doi/full/10.1056/NEJMoa1009290 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208619/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21306238 PubMed]<br />
# '''CLARINET:''' Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33. [https://www.nejm.org/doi/full/10.1056/NEJMoa1316158 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25014687 PubMed]<br />
<br />
== PRRT with <sup>177</sup>Lu-dotatate {{#subobject:ee13d2|Regimen=1}} ==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:80d0ef|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |'''Strosberg et al. 2018''' <br />
'''NETTER-1'''<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
| rowspan="2" |'''High-dose Octreotide LAR'''<br />
| rowspan="2" style="background-color:#1a9850" |Superior PFS<br />
| style="background-color:#d73027" |More cytopenias (neutropenia, thrombocytopenia and lymphopenia)<br />
|-<br />
| style="background-color:#fc8d59" |<br />
|-<br />
|}<br />
''Note: patients had well-differentiated (Ki67 ≤ 20%) midgut neuroendocrine tumors with somatostatin receptors present in all target lesions''<br />
<br />
==== Chemotherapy ====<br />
* 177Lu-Dotatate 7.4 GB1 (200 mCi) IV Q8 weeks x 4 cycles* <br />
* Octreotide LAR 30mg SC Q4 weeks <br />
Octreotide was given 2 hours after each infusion and then continued monthly <br />
<br />
<nowiki>*</nowiki>For renal protection, protection an IV amino acid solution was administered concomitantly for at least 4 hours, starting 30 minutes before drug infusion<br />
<br />
=== References ===<br />
# NETTER-1: Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. (2017) 376:125–35. 10.1056/NEJMoa1607427. Link to original article: <nowiki>https://www.nejm.org/doi/full/10.1056/NEJMoa1607427</nowiki> contains verified protocol Pubmed: <nowiki>https://www.ncbi.nlm.nih.gov/pubmed/28076709</nowiki> <br />
<br />
==Sunitinib monotherapy {{#subobject:ee13d2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:80d0ef|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 20%" |Study<br />
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
! style="width: 20%" |Comparator<br />
! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa1003825 Raymond et al. 2011 (A6181111)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
| rowspan="2" |[[#Placebo|Placebo]]<br />
| rowspan="2" style="background-color:#1a9850" |Superior PFS<br />
| style="background-color:#d73027" |More diarrhea<br />
|-<br />
| style="background-color:#fc8d59" |Seems to have worse insomnia<br />
|-<br />
|}<br />
''Note: while the initial publication seemed to have a significant survival advantage for this arm (p=0.02), this finding was no longer significant at the final update (p=0.094). The primary endpoint (PFS) remains significant.''<br />
====Chemotherapy====<br />
*[[Sunitinib (Sutent)]] 37.5 mg PO once per day<br />
<br />
'''Given indefinitely'''<br />
<br />
===References===<br />
# '''A6181111:''' Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):501-13. Erratum in: N Engl J Med. 2011 Mar 17;364(11):1082. [https://www.nejm.org/doi/full/10.1056/NEJMoa1003825 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306237 PubMed]<br />
## '''HRQoL analysis:''' Vinik A, Bottomley A, Korytowsky B, Bang YJ, Raoul JL, Valle JW, Metrakos P, Hörsch D, Mundayat R, Reisman A, Wang Z, Chao RC, Raymond E. Patient-reported outcomes and quality of life with sunitinib versus placebo for pancreatic neuroendocrine tumors: results from an international phase III trial. Target Oncol. 2016 Dec;11(6):815-824. [https://link.springer.com/article/10.1007%2Fs11523-016-0462-5 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27924459 PubMed]<br />
## '''Update:''' Faivre S, Niccoli P, Castellano D, Valle JW, Hammel P, Raoul JL, Vinik A, Van Cutsem E, Bang YJ, Lee SH, Borbath I, Lombard-Bohas C, Metrakos P, Smith D, Chen JS, Ruszniewski P, Seitz JF, Patyna S, Lu DR, Ishak KJ, Raymond E. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol. 2017 Feb 1;28(2):339-343. [https://academic.oup.com/annonc/article/28/2/339/2676883 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27836885 PubMed]<br />
<br />
==Temozolomide monotherapy {{#subobject:69ae1c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:6aac4c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://clincancerres.aacrjournals.org/content/13/10/2986.long Ekeblad et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Temozolomide (Temodar)]] as follows:<br />
**Cycle 1: 100 or 150 mg/m<sup>2</sup> PO once per day on days 1 to 5<br />
**Cycle 2 onwards: increased as tolerated up to 200 mg/m<sup>2</sup> PO once per day on days 1 to 5<br />
<br />
====Supportive medications====<br />
*[[Tropisetron (Navoban)]] (dose/route/schedule not specified) routinely used as an antiemetic<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007 May 15;13(10):2986-91. [http://clincancerres.aacrjournals.org/content/13/10/2986.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17505000 PubMed]<br />
<br />
==Temozolomide & Bevacizumab {{#subobject:ce7fe6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:be3718|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874232/ Chan et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Temozolomide (Temodar)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 7, 15 to 21<br />
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1 & 15<br />
<br />
====Supportive medications====<br />
*[[Trimethoprim/Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO once every Monday, Wednesday, and Friday; allergic patients received alternate Pneumocystis carinii (PCP) prophylaxis<br />
*[[Acyclovir (Zovirax)]] 400 mg PO three times per day as prophylaxis against varicella zoster<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Chan JA, Stuart K, Earle CC, Clark JW, Bhargava P, Miksad R, Blaszkowsky L, Enzinger PC, Meyerhardt JA, Zheng H, Fuchs CS, Kulke MH. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol. 2012 Aug 20;30(24):2963-8. Epub 2012 Jul 9. [http://jco.ascopubs.org/content/30/24/2963.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874232/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22778320 PubMed]<br />
<br />
==Temozolomide & Thalidomide {{#subobject:16afb7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:ceca5a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
! style="width: 50%" |Study<br />
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/3/401.long Kulke et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Temozolomide (Temodar)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 7, 15 to 21<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, Vincitore M, Michelini A, Fuchs CS. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006 Jan 20;24(3):401-6. [http://jco.ascopubs.org/content/24/3/401.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16421420 PubMed]<br />
<br />
[[Category:Pancreatic NET regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Endocrine cancers]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdheryhttps://hemonc.org/w/index.php?title=Pancreatic_cancer&diff=27252Pancreatic cancer2018-06-07T21:51:25Z<p>Rozinachowdhery: /* Chemotherapy[edit | edit source] */</p>
<hr />
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! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>Chicago, IL</big><br />
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{| class="wikitable" style="float:right; margin-right: 5px;"<br />
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|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
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{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2017:''' [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.4948 Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/28398845 PubMed]<br />
*'''2016:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019760/ Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2016:''' [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.5561 Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/27247216 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2015:''' [http://annonc.oxfordjournals.org/content/26/suppl_5/v56.full.pdf+html Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015)] [https://www.ncbi.nlm.nih.gov/pubmed/26314780 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf NCCN Guidelines - Pancreatic Adenocarcinoma]<br />
<br />
=Adjuvant therapy=<br />
==Capecitabine & Gemcitabine {{#subobject:17f9f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Regimen {{#subobject:e6a3e3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Treatment starts within 12 weeks of surgery.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week on weeks 1 to 3<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# '''ESPAC-4:''' Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:29266e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:242770|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
<br />
==Fluorouracil, then Fluorouracil & RT {{#subobject:331d4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:89426a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br> [[#Observation|Observation]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine.2C_then_Fluorouracil_.26_RT.2C_then_Gemcitabine|Gemcitabine, then Fluorouracil & RT, then Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 21<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 28<br />
<br />
'''6-week cycle for 2 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:34e70d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a756a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|Fluorouracil & Leucovorin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine|Capecitabine & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
<br />
''Note: efficacy for CONKO-001 is based on the 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
# Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Gemcitabine, then Fluorouracil & RT, then Gemcitabine {{#subobject:f8c8d9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:3fef3f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|Fluorouracil & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Efficacy for ESPAC-1 is based on the 2004 update and efficacy for CONKO-001 is based on 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cdcc15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, potentially resectable=<br />
<br />
==Docetaxel, Gemcitabine, RT {{#subobject:49a407|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:78b0ba|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1245%2FASO.2005.04.503 Pipas et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 65 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Gemcitabine (Gemzar)]] 4000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29<br />
<br />
'''6-week course, followed immediately (day 43) by:'''<br />
<br />
====Chemoradiation====<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy to primary target volume. Then 5.4 Gy boost to secondary target volume of 1- to 1.5-cm margin on all sides, including proven nodal involvement. Total 50.4 Gy in 28 fractions.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
# Pipas JM, Barth RJ Jr, Zaki B, Tsapakos MJ, Suriawinata AA, Bettmann MA, Cates JM, Ripple GH, Sutton JE, Gordon SR, McDonnell CE, Perez RP, Redfield N, Meyer LP, Marshall JF, Cole BF, Colacchio TA. Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2005 Dec;12(12):995-1004. Epub 2005 Nov 1. [http://link.springer.com/article/10.1245%2FASO.2005.04.503 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16252135 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:55e32d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen 1 {{#subobject:6ce551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract Takahashi et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*Concurrent radiation therapy, 2 Gy per fraction, 5 days per week, 25 fractions, total dose of 50 Gy over 5 weeks.<br />
<br />
'''28-day cycle for 3 cycles''' ''(Radiation given over weeks 1-5 only)''<br />
<br />
''Restaging is performed 8 weeks after radiation complete (2 weeks after chemotherapy complete). Resection immediately thereafter, if feasible.''<br />
<br />
===Regimen 2 {{#subobject:dc32dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 500 mg/m<sup>2</sup> IV over 50 minutes once per week for 6 weeks<br />
*Concurrent radiation therapy, 180 cGy x 22 with 3 cm margin to GTV then 180 cGy x 6 with 2 cm margin to GTV, total 50.4 Gy over 6 weeks<br />
<br />
''Restaging after radiation complete. 4 to 6 week break, followed by surgery, followed by 4 to 8 week break. Then adjuvant chemotherapy:''<br />
<br />
====Adjuvant chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 5 cycles'''<br />
<br />
===References===<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [https://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, Ioka T, Uehara H, Yano M, Ishikawa O. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013 Dec;258(6):1040-50.[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23799421 PubMed]<br />
<br />
==Gemcitabine, Cetuximab, RT {{#subobject:aea7b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c38534|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ Pipas et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**6 to 8 days prior radiation: 400 mg/m<sup>2</sup> IV over 2 hours once<br />
**During radiation: 250 mg/m<sup>2</sup> over 60 minutes once per week for 6 doses<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, delivered using IMRT. Gross tumor volume (GTV) was all known disease including imaging proven nodal disease. The primary planning target volume (PTV1) included the GTV with 2- to 3-cm margins in all directions as well as potential nodal involvement. Secondary planning target volume (PTV2) included the GTV with 1- to 1.5-cm margins on all sides including proven nodal involvement. Tertiary planning treatment volume (PTV3) included the area of the GTV adjacent to the vascular structures specifically the mesenteric and portal vessels with a 0.5-cm margin. The prescription dose delivered to PTV3 was 54 Gy in 28 fractions. Synchronously, PTV1 and PTV2 received 45 and 50.4 Gy, respectively. All fields were treated daily at five fractions per week.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
''One month following therapy, patients were restaged with CT scan of chest/abdomen/pelvis. Patients deemed to be candidates for surgical resection were offered laparotomy ∼6 to 10 weeks after completion of neoadjuvant therapy.''<br />
<br />
===References===<br />
# Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, Tsongalis GJ, Colacchio TA, Gordon SR, Sutton JE, Srivastava A, Smith KD, Gardner TB, Korc M, Davis TH, Preis M, Tarczewski SM, Mackenzie TA, Barth RJ Jr. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. 2012 Nov;23(11):2820-7. Epub 2012 May 9. [http://annonc.oxfordjournals.org/content/23/11/2820.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571859 PubMed]<br />
<br />
==mFOLFIRINOX, Gemcitabine, RT {{#subobject:b71003|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFIRINOX, Gemcitabine, RT: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin, Gemcitabine, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:d87ec0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ Blazer et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion for 46 h on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once on day 1<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 4<br />
<br />
'''14-day cycle for 4 to 8 cycles'''<br />
<br />
''Followed by complete restaging. If tumor localized but still not resectable, chemoradiotherapy was administered:''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup>/week concurrent with radiation<br />
*Radiation was 36 Gy in 15 daily fractions<br />
<br />
===Variant #2 {{#subobject:7bb0e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ Hosein et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion for 46 hours on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles. Protocol followed "per ACCORD-11 trial." Filgrastim was given at the discretion of the treating physician.'''<br />
<br />
''Treatment stopped at maximum response or tolerability. Resectable patients by imaging criteria were offered surgery, followed by postoperative chemoradiotherapy. Unresectable patients were offered chemoradiotherapy, followed by surgery (if they became resectable):''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup>/week<br />
*Radiation at 50.4 Gy in 28 fractions.<br />
<br />
===References===<br />
# '''Retrospective:''' Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, Narayanan G, Ribeiro A, Portelance L, Merchan JR, Levi JU, Rocha-Lima CM. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012 May 29;12:199. [http://www.biomedcentral.com/1471-2407/12/199 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22642850 PubMed]<br />
# '''Retrospective:''' Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, Wuthrick E, Williams TM, Reardon J, Christopher Ellison E, Bloomston M, Bekaii-Saab T. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015 Apr;22(4):1153-9. [http://link.springer.com/article/10.1245%2Fs10434-014-4225-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25358667 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, unresectable=<br />
<br />
==Capecitabine monotherapy {{#subobject:dbd841|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dc4779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:6d97a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, Gem 3 out of 4 weeks x 4 {{#subobject:87edde|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Erlotinib & Gemcitabine x 2 more cycles (6 total) versus Capecitabine, Erlotinib, RT<br />
<br />
===Variant #2, Gem 3 out of 4 weeks x 6 {{#subobject:5a5e14|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
''Note: it is not clear from the protocol whether erlotinib is continued beyond the end of chemotherapy.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] as follows:<br />
**Cycles 1 to 4: 100 mg PO once per day<br />
**Cycles 5 & 6: 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:b4258e|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #4, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:b7a41f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''GERCOR LAP07:''' Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Fluorouracil & RT {{#subobject:26f1c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:29784e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ Herman et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Fluorouracil & RT with TNFerade<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion once per day on radiation days (total dose per week: 1000 mg/m<sup>2</sup>)<br />
*Concurrent radiation therapy, 50.4 Gy total: 1.80 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy, followed by 1.80 Gy x 3 fractions boost to the tumor bed.<br />
<br />
'''One course'''<br />
====Subsequent treatment until progression or toxicity (starting four weeks after chemoradiotherapy)====<br />
*Gemcitabine or Erlotinib & Gemcitabine maintenance<br />
<br />
===References===<br />
# Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, Donehower RC, Pawlik TM, Ziegler MA, Cai H, Savage DT, Canto MI, Klapman J, Reid T, Shah RJ, Hoffe SE, Rosemurgy A, Wolfgang CL, Laheru DA. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013 Mar 1;31(7):886-94. Epub 2013 Jan 22. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.7516 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23341531 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:4f0be9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 3 out of 4 weeks x 4 {{#subobject:c511a7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Gemcitabine x 2 more cycles (6 total) versus Capecitabine & RT<br />
<br />
===Variant #2, 3 out of 4 weeks x 6 {{#subobject:cf89f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in {{#subobject:82f8b2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#GemOx|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_.26_RT_2|Gemcitabine & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent 4-week cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''Continued for at least 3 months'''<br />
<br />
''Per '''Louvet et al. 2005''', subsequent chemoradiotherapy'' ''(45 Gy in 25 fractions for 5 weeks, associated with a daily FU 250 mg/m2 continuous infusion, and a boost of 10 Gy in 8 fractions restricted to the initial tumor volume)'' ''was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:a6e6fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 (600 mg/m<sup>2</sup>) {{#subobject:a6de29|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract Cardenes et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV over 30 to 60 minutes once per week during radiation<br />
*Concurrent radiation therapy, 1.8 Gy per fraction, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks.<br />
<br />
'''One course, followed in 4 weeks by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycle for 5 cycles or until disease progression'''<br />
<br />
===Variant #2 (400 mg/m<sup>2</sup>) {{#subobject:c1ac3c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract Epelbaum et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week for 7 weeks<br />
<br />
'''Radiation planning during this phase, followed by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 400 mg/m<sup>2</sup> IV over 30 minutes once per week (days 1, 8, 15)<br />
*Concurrent radiation therapy, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks<br />
<br />
'''28 day cycle for 2 cycles, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycles until disease progression'''<br />
<br />
===References===<br />
# Epelbaum R, Rosenblatt E, Nasrallah S, Faraggi D, Gaitini D, Mizrahi S, Kuten A. Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J Surg Oncol. 2002 Nov;81(3):138-43. [https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12407726 PubMed]<br />
# Cardenes HR, Moore AM, Johnson CS, Yu M, Helft P, Chiorean EG, Vinson J, Howard TJ, Stephens AW, Tai DF, Loehrer PJ Sr. A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study. Am J Clin Oncol. 2011 Oct;34(5):460-5.[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20881474 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
<br />
==GemOx {{#subobject:19d87f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:5a25e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_2|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycle for at least 3 months'''<br />
<br />
''Subsequent chemoradiotherapy (45 Gy in 25 fractions for 5 weeks, associated with a daily FU 250 mg/m2 continuous infusion, and a boost of 10 Gy in 8 fractions restricted to the initial tumor volume)'' ''was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
<br />
=Metastatic disease, first-line=<br />
<br />
==Capecitabine monotherapy {{#subobject:4f5f03|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b31bbb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Capecitabine & Gemcitabine {{#subobject:2f0431|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Variant #1 {{#subobject:fcd708|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Note: this is essentially identical to the maintenance phase of Cunningham et al. 2009, below.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:e8f0bf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21, 29 to 49<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:a7e551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 650 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 24 weeks'''<br />
<br />
===References===<br />
# Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:c30d8f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, weekly dosing {{#subobject:20a0f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note that cisplatin is not given on day 22 of the first 8 weeks; otherwise, the schedule is identical to the schedule for gemcitabine.''<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] as follows, '''given 60 minutes prior to gemcitabine''':<br />
**First 8 weeks: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Subsequent cycles: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, bi-weekly dosing {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycles'''<br />
<br />
=== '''Variant #3, Day 1, 8 dosing''' ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract Cascinu et al. 2008 (GISCAD)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Cisplatin, Gemcitabine, Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|}Chemotherapy<br />
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8 (with 1500 mL NS)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 Jan;9(1):39-44. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18077217 PubMed]<br />
# Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:bf797a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, no gemcitabine lead-in {{#subobject:43fe43|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext Kordes et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Erlotinib, Gemcitabine, Metformin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:fc43f2|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:d49fb0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47. Epub 2015 Jun 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext link to original article]'''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26067687 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:c6c509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:3ca01f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Inferior to gemcitabine. Here for historical reference purposes, only.''<br />
<br />
==== Chemotherapy ====<br />
* [[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once weekly<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
<br />
==FOLFIRINOX {{#subobject:aaa3c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e140cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior QoL by [http://groups.eortc.be/qol/eortc-qlq-c30 EORTC QLQ-C30]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 1200 mg/m<sup>2</sup>/day IV continuous 46-hour infusion on days 1 to 2; '''given last''' (total dose per cycle: 2400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1; '''given third together with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:3a0f4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 8-week lead-in {{#subobject:5d6dd0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx_2|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract Reni et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PEFG<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|GEM FDR<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GEM-CAP]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ Philip et al. 2010 (SWOG S0205)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_nab-Paclitaxel|Gemcitabine & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext Middleton et al. 2017 (ViP)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Vandetanib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
***In Burris et al. 1997, patients with grade 2 or lower toxicities could have had doses increased to 1250 mg/m<sup>2</sup><br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 4 week cycles {{#subobject:c6349|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract Kindler et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ Fuchs et al. 2015 (GAMMA)]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & [[Ganitumab (AMG 479)|Ganitumab]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ Catenacci et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & Vismodegib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 3 week cycles {{#subobject:8bae67|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 Hong et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|Gemcitabine & Simvastatin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, fixed-dose rate (FDR) {{#subobject:5114cc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 150 minutes (10 mg/m<sup>2</sup>/min) once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15925814 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
# '''SWOG S0205:''' Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 1;28(22):3605-10. Epub 2010 Jul 6. [http://jco.ascopubs.org/content/28/22/3605.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20606093 PubMed]<br />
# Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306953 PubMed]<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
# Hong JY, Nam EM, Lee J, Park JO, Lee SC, Song SY, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol. 2014 Jan;73(1):125-30. Epub 2013 Oct 27. [https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24162380 PubMed]<br />
# '''GAMMA:''' Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921-7. Epub 2015 Jan 21. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25609246 PubMed]<br />
# Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D, Wade J, Sleckman B, Lenz HJ, Stiff P, Kumar P, Xu P, Henderson L, Takebe N, Salgia R, Wang X, Stadler WM, de Sauvage FJ, Kindler HL. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015 Dec 20;33(36):4284-92. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/36/4284.long link to original article] '''contains protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527777 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
# '''ViP:''' Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr;18(4):486-499. Epub 2017 Mar 2. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28259610 PubMed]<br />
<br />
==GemOx {{#subobject:520af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:9d3266|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine, FDR]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
<br />
==Gemcitabine & nab-Paclitaxel {{#subobject:fbd698|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:63ba04|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] as follows, '''given first''':<br />
**Cycle 1: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15<br />
<br />
'''8-week cycle followed by 28-day cycles until disease progression or intolerance'''<br />
<br />
===Variant #2 {{#subobject:ecc1c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ Von Hoff et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 or 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/34/4548.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969517 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
<br />
==GTX {{#subobject:f0d62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GTX: '''<u>G</u>'''emcitabine, '''<u>T</u>'''axotere (Docetaxel), '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:fc0e50|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.springerlink.com/content/75m422843l3461m0/ Fine et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: De Jesus-Acosta et al. 2012 lists the capecitabine dose as "750 mg/m<sup>2</sup>/day orally divided into two doses," but this is believed to be a typographical error since the original reference that it cites, Fine et al. 2007, uses capecitabine at 750 mg/m<sup>2</sup> PO BID. The 2009 ASCO abstract by Fine also lists this 750 mg/m<sup>2</sup> PO BID (1500 mg/m<sup>2</sup>/day) dose.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 75 minutes once per day on days 4 & 11<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 11<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75. Epub 2007 Apr 18. [http://www.springerlink.com/content/75m422843l3461m0/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17440727 PubMed]<br />
# '''Abstract:''' R. L. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. 2009 ASCO Annual Meeting abstract 4623. [http://ascopubs.org/doi/full/10.1200/jco.2009.27.15s.4623 link to abstract] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012 Feb;69(2):415-24. Epub 2011 Jul 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723 link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21800112 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:759f1a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:94d490|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<br />
=Metastatic disease, refractory=<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#OFF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Best supportive care. Placed here because one or more randomized clinical trials included a best supportive care arm in this disease context.''<br />
<br />
===References===<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<br />
==Capecitabine & Erlotinib {{#subobject:4655b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d5c799|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4787.full Kulke et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> (rounded to the nearest 150 mg tablet) PO BID on days 1 to 14<br />
*[[Erlotinib (Tarceva)]] 150 mg PO on days 1 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak EL, Muzikansky A, Lawrence C, Fuchs CS. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007 Oct 20;25(30):4787-92. [http://jco.ascopubs.org/content/25/30/4787.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947726 PubMed]<br />
<br />
==CapeOx {{#subobject:d09d5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:57ad5f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full Xiong et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 1000 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 110 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008 Oct 15;113(8):2046-52. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18756532 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, nanoliposomal Irinotecan {{#subobject:72308d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a81310|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''started on day 1 after folinic acid'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given prior to fluorouracil'''<br />
*[[Irinotecan liposome (Onivyde)]] 70 mg/m<sup>2</sup> (irinotecan free base) IV over 90 minutes once on day 1, '''given first'''<br />
**Per Wang-Gillam et al. 2015 (NAPOLI-01), 70 mg/m<sup>2</sup> irinotecan free base is equivalent to 80 mg/m<sup>2</sup> nanoliposomal irinotecan. According to the trial's ClinicalTrials.gov page: "The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m<sup>2</sup> dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/ m2 of irinotecan free base."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
<br />
==FOLFIRI {{#subobject:6fd426|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br />
===Variant #1 {{#subobject:6a9cae|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 Zaniboni et al. 2012 (GISCAD)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, and 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, modified FOLFIRI.3 {{#subobject:4758e8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFOX|mFOLFOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Irinotecan (Camptosar)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 3<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
# Zaniboni A, Aitini E, Barni S, Ferrari D, Cascinu S, Catalano V, Valmadre G, Ferrara D, Veltri E, Codignola C, Labianca R. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jun;69(6):1641-5. Epub 2012 May 11. [http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22576338 PubMed]<br />
<br />
==FOLFOX {{#subobject:377e80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:33ef68|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFIRI|mFOLFIRI.3]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
<br />
==OFF {{#subobject:8b32c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OFF: '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil, '''<u>F</u>'''olinic acid <br />
===Regimen {{#subobject:ae57d5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
<br />
''Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m<sup>2</sup>," or 850 mg/m<sup>2</sup>.''<br />
====Chemotherapy====<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once per day on days 8 & 22, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous 24-hour infusion on days 1, 8, 15, 22, '''started after folinic acid bolus'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, '''given prior to fluorouracil'''<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
# Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
<br />
==Olaparib monotherapy {{#subobject:0c2eb3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:21eb78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/3/244.long Kaufman et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients had germline BRCA1/2 mutations and had previously received gemcitabine.''<br />
====Chemotherapy====<br />
*[[Olaparib (Lynparza)]] 400 mg PO BID<br />
<br />
'''Continued until progression'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
# Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/33/3/244.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed]<br />
<br />
==Paclitaxel, nanoparticle albumin-bound monotherapy {{#subobject:ab9fc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8d38d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract Hosein et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Hosein PJ, de Lima Lopes G Jr, Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013 Apr;36(2):151-6. Epub 2012 Feb 2. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22307213 PubMed]<br />
<br />
[[Category:Pancreatic cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdheryhttps://hemonc.org/w/index.php?title=Pancreatic_cancer&diff=27251Pancreatic cancer2018-06-07T21:50:09Z<p>Rozinachowdhery: /* Fluorouracil monotherapy */</p>
<hr />
<div><!--'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]]. If this is your first time visiting, we suggest you read the [[tutorial]].'''--><br />
<!--Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are [[How_to_contribute|invited to contribute to the site]].-->{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>Chicago, IL</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2017:''' [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.4948 Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/28398845 PubMed]<br />
*'''2016:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019760/ Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2016:''' [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.5561 Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/27247216 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2015:''' [http://annonc.oxfordjournals.org/content/26/suppl_5/v56.full.pdf+html Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015)] [https://www.ncbi.nlm.nih.gov/pubmed/26314780 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf NCCN Guidelines - Pancreatic Adenocarcinoma]<br />
<br />
=Adjuvant therapy=<br />
==Capecitabine & Gemcitabine {{#subobject:17f9f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Regimen {{#subobject:e6a3e3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Treatment starts within 12 weeks of surgery.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week on weeks 1 to 3<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# '''ESPAC-4:''' Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:29266e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:242770|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
<br />
==Fluorouracil, then Fluorouracil & RT {{#subobject:331d4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:89426a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br> [[#Observation|Observation]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine.2C_then_Fluorouracil_.26_RT.2C_then_Gemcitabine|Gemcitabine, then Fluorouracil & RT, then Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 21<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 28<br />
<br />
'''6-week cycle for 2 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:34e70d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a756a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|Fluorouracil & Leucovorin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine|Capecitabine & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
<br />
''Note: efficacy for CONKO-001 is based on the 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
# Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Gemcitabine, then Fluorouracil & RT, then Gemcitabine {{#subobject:f8c8d9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:3fef3f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|Fluorouracil & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Efficacy for ESPAC-1 is based on the 2004 update and efficacy for CONKO-001 is based on 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cdcc15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, potentially resectable=<br />
<br />
==Docetaxel, Gemcitabine, RT {{#subobject:49a407|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:78b0ba|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1245%2FASO.2005.04.503 Pipas et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 65 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Gemcitabine (Gemzar)]] 4000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29<br />
<br />
'''6-week course, followed immediately (day 43) by:'''<br />
<br />
====Chemoradiation====<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy to primary target volume. Then 5.4 Gy boost to secondary target volume of 1- to 1.5-cm margin on all sides, including proven nodal involvement. Total 50.4 Gy in 28 fractions.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
# Pipas JM, Barth RJ Jr, Zaki B, Tsapakos MJ, Suriawinata AA, Bettmann MA, Cates JM, Ripple GH, Sutton JE, Gordon SR, McDonnell CE, Perez RP, Redfield N, Meyer LP, Marshall JF, Cole BF, Colacchio TA. Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2005 Dec;12(12):995-1004. Epub 2005 Nov 1. [http://link.springer.com/article/10.1245%2FASO.2005.04.503 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16252135 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:55e32d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen 1 {{#subobject:6ce551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract Takahashi et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*Concurrent radiation therapy, 2 Gy per fraction, 5 days per week, 25 fractions, total dose of 50 Gy over 5 weeks.<br />
<br />
'''28-day cycle for 3 cycles''' ''(Radiation given over weeks 1-5 only)''<br />
<br />
''Restaging is performed 8 weeks after radiation complete (2 weeks after chemotherapy complete). Resection immediately thereafter, if feasible.''<br />
<br />
===Regimen 2 {{#subobject:dc32dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 500 mg/m<sup>2</sup> IV over 50 minutes once per week for 6 weeks<br />
*Concurrent radiation therapy, 180 cGy x 22 with 3 cm margin to GTV then 180 cGy x 6 with 2 cm margin to GTV, total 50.4 Gy over 6 weeks<br />
<br />
''Restaging after radiation complete. 4 to 6 week break, followed by surgery, followed by 4 to 8 week break. Then adjuvant chemotherapy:''<br />
<br />
====Adjuvant chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 5 cycles'''<br />
<br />
===References===<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [https://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, Ioka T, Uehara H, Yano M, Ishikawa O. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013 Dec;258(6):1040-50.[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23799421 PubMed]<br />
<br />
==Gemcitabine, Cetuximab, RT {{#subobject:aea7b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c38534|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ Pipas et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**6 to 8 days prior radiation: 400 mg/m<sup>2</sup> IV over 2 hours once<br />
**During radiation: 250 mg/m<sup>2</sup> over 60 minutes once per week for 6 doses<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, delivered using IMRT. Gross tumor volume (GTV) was all known disease including imaging proven nodal disease. The primary planning target volume (PTV1) included the GTV with 2- to 3-cm margins in all directions as well as potential nodal involvement. Secondary planning target volume (PTV2) included the GTV with 1- to 1.5-cm margins on all sides including proven nodal involvement. Tertiary planning treatment volume (PTV3) included the area of the GTV adjacent to the vascular structures specifically the mesenteric and portal vessels with a 0.5-cm margin. The prescription dose delivered to PTV3 was 54 Gy in 28 fractions. Synchronously, PTV1 and PTV2 received 45 and 50.4 Gy, respectively. All fields were treated daily at five fractions per week.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
''One month following therapy, patients were restaged with CT scan of chest/abdomen/pelvis. Patients deemed to be candidates for surgical resection were offered laparotomy ∼6 to 10 weeks after completion of neoadjuvant therapy.''<br />
<br />
===References===<br />
# Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, Tsongalis GJ, Colacchio TA, Gordon SR, Sutton JE, Srivastava A, Smith KD, Gardner TB, Korc M, Davis TH, Preis M, Tarczewski SM, Mackenzie TA, Barth RJ Jr. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. 2012 Nov;23(11):2820-7. Epub 2012 May 9. [http://annonc.oxfordjournals.org/content/23/11/2820.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571859 PubMed]<br />
<br />
==mFOLFIRINOX, Gemcitabine, RT {{#subobject:b71003|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFIRINOX, Gemcitabine, RT: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin, Gemcitabine, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:d87ec0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ Blazer et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion for 46 h on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once on day 1<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 4<br />
<br />
'''14-day cycle for 4 to 8 cycles'''<br />
<br />
''Followed by complete restaging. If tumor localized but still not resectable, chemoradiotherapy was administered:''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup>/week concurrent with radiation<br />
*Radiation was 36 Gy in 15 daily fractions<br />
<br />
===Variant #2 {{#subobject:7bb0e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ Hosein et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion for 46 hours on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles. Protocol followed "per ACCORD-11 trial." Filgrastim was given at the discretion of the treating physician.'''<br />
<br />
''Treatment stopped at maximum response or tolerability. Resectable patients by imaging criteria were offered surgery, followed by postoperative chemoradiotherapy. Unresectable patients were offered chemoradiotherapy, followed by surgery (if they became resectable):''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup>/week<br />
*Radiation at 50.4 Gy in 28 fractions.<br />
<br />
===References===<br />
# '''Retrospective:''' Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, Narayanan G, Ribeiro A, Portelance L, Merchan JR, Levi JU, Rocha-Lima CM. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012 May 29;12:199. [http://www.biomedcentral.com/1471-2407/12/199 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22642850 PubMed]<br />
# '''Retrospective:''' Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, Wuthrick E, Williams TM, Reardon J, Christopher Ellison E, Bloomston M, Bekaii-Saab T. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015 Apr;22(4):1153-9. [http://link.springer.com/article/10.1245%2Fs10434-014-4225-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25358667 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, unresectable=<br />
<br />
==Capecitabine monotherapy {{#subobject:dbd841|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dc4779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:6d97a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, Gem 3 out of 4 weeks x 4 {{#subobject:87edde|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Erlotinib & Gemcitabine x 2 more cycles (6 total) versus Capecitabine, Erlotinib, RT<br />
<br />
===Variant #2, Gem 3 out of 4 weeks x 6 {{#subobject:5a5e14|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
''Note: it is not clear from the protocol whether erlotinib is continued beyond the end of chemotherapy.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] as follows:<br />
**Cycles 1 to 4: 100 mg PO once per day<br />
**Cycles 5 & 6: 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:b4258e|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #4, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:b7a41f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''GERCOR LAP07:''' Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Fluorouracil & RT {{#subobject:26f1c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:29784e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ Herman et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Fluorouracil & RT with TNFerade<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion once per day on radiation days (total dose per week: 1000 mg/m<sup>2</sup>)<br />
*Concurrent radiation therapy, 50.4 Gy total: 1.80 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy, followed by 1.80 Gy x 3 fractions boost to the tumor bed.<br />
<br />
'''One course'''<br />
====Subsequent treatment until progression or toxicity (starting four weeks after chemoradiotherapy)====<br />
*Gemcitabine or Erlotinib & Gemcitabine maintenance<br />
<br />
===References===<br />
# Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, Donehower RC, Pawlik TM, Ziegler MA, Cai H, Savage DT, Canto MI, Klapman J, Reid T, Shah RJ, Hoffe SE, Rosemurgy A, Wolfgang CL, Laheru DA. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013 Mar 1;31(7):886-94. Epub 2013 Jan 22. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.7516 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23341531 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:4f0be9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 3 out of 4 weeks x 4 {{#subobject:c511a7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Gemcitabine x 2 more cycles (6 total) versus Capecitabine & RT<br />
<br />
===Variant #2, 3 out of 4 weeks x 6 {{#subobject:cf89f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in {{#subobject:82f8b2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#GemOx|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_.26_RT_2|Gemcitabine & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent 4-week cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''Continued for at least 3 months'''<br />
<br />
''Per '''Louvet et al. 2005''', subsequent chemoradiotherapy'' ''(45 Gy in 25 fractions for 5 weeks, associated with a daily FU 250 mg/m2 continuous infusion, and a boost of 10 Gy in 8 fractions restricted to the initial tumor volume)'' ''was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:a6e6fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 (600 mg/m<sup>2</sup>) {{#subobject:a6de29|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract Cardenes et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV over 30 to 60 minutes once per week during radiation<br />
*Concurrent radiation therapy, 1.8 Gy per fraction, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks.<br />
<br />
'''One course, followed in 4 weeks by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycle for 5 cycles or until disease progression'''<br />
<br />
===Variant #2 (400 mg/m<sup>2</sup>) {{#subobject:c1ac3c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract Epelbaum et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week for 7 weeks<br />
<br />
'''Radiation planning during this phase, followed by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 400 mg/m<sup>2</sup> IV over 30 minutes once per week (days 1, 8, 15)<br />
*Concurrent radiation therapy, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks<br />
<br />
'''28 day cycle for 2 cycles, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycles until disease progression'''<br />
<br />
===References===<br />
# Epelbaum R, Rosenblatt E, Nasrallah S, Faraggi D, Gaitini D, Mizrahi S, Kuten A. Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J Surg Oncol. 2002 Nov;81(3):138-43. [https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12407726 PubMed]<br />
# Cardenes HR, Moore AM, Johnson CS, Yu M, Helft P, Chiorean EG, Vinson J, Howard TJ, Stephens AW, Tai DF, Loehrer PJ Sr. A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study. Am J Clin Oncol. 2011 Oct;34(5):460-5.[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20881474 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
<br />
==GemOx {{#subobject:19d87f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:5a25e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_2|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycle for at least 3 months'''<br />
<br />
''Subsequent chemoradiotherapy (45 Gy in 25 fractions for 5 weeks, associated with a daily FU 250 mg/m2 continuous infusion, and a boost of 10 Gy in 8 fractions restricted to the initial tumor volume)'' ''was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
<br />
=Metastatic disease, first-line=<br />
<br />
==Capecitabine monotherapy {{#subobject:4f5f03|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b31bbb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Capecitabine & Gemcitabine {{#subobject:2f0431|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Variant #1 {{#subobject:fcd708|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Note: this is essentially identical to the maintenance phase of Cunningham et al. 2009, below.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:e8f0bf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21, 29 to 49<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:a7e551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 650 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 24 weeks'''<br />
<br />
===References===<br />
# Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:c30d8f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, weekly dosing {{#subobject:20a0f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note that cisplatin is not given on day 22 of the first 8 weeks; otherwise, the schedule is identical to the schedule for gemcitabine.''<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] as follows, '''given 60 minutes prior to gemcitabine''':<br />
**First 8 weeks: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Subsequent cycles: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, bi-weekly dosing {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycles'''<br />
<br />
=== '''Variant #3, Day 1, 8 dosing''' ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract Cascinu et al. 2008 (GISCAD)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Cisplatin, Gemcitabine, Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|}Chemotherapy<br />
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8 (with 1500 mL NS)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 Jan;9(1):39-44. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18077217 PubMed]<br />
# Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:bf797a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, no gemcitabine lead-in {{#subobject:43fe43|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext Kordes et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Erlotinib, Gemcitabine, Metformin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:fc43f2|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:d49fb0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47. Epub 2015 Jun 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext link to original article]'''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26067687 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:c6c509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:3ca01f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Inferior to gemcitabine. Here for historical reference purposes, only.''<br />
<br />
==== Chemotherapy[edit | edit source] ====<br />
* [[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once weekly<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
<br />
==FOLFIRINOX {{#subobject:aaa3c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e140cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior QoL by [http://groups.eortc.be/qol/eortc-qlq-c30 EORTC QLQ-C30]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 1200 mg/m<sup>2</sup>/day IV continuous 46-hour infusion on days 1 to 2; '''given last''' (total dose per cycle: 2400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1; '''given third together with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:3a0f4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 8-week lead-in {{#subobject:5d6dd0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx_2|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract Reni et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PEFG<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|GEM FDR<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GEM-CAP]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ Philip et al. 2010 (SWOG S0205)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_nab-Paclitaxel|Gemcitabine & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext Middleton et al. 2017 (ViP)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Vandetanib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
***In Burris et al. 1997, patients with grade 2 or lower toxicities could have had doses increased to 1250 mg/m<sup>2</sup><br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 4 week cycles {{#subobject:c6349|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract Kindler et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ Fuchs et al. 2015 (GAMMA)]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & [[Ganitumab (AMG 479)|Ganitumab]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ Catenacci et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & Vismodegib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 3 week cycles {{#subobject:8bae67|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 Hong et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|Gemcitabine & Simvastatin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, fixed-dose rate (FDR) {{#subobject:5114cc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 150 minutes (10 mg/m<sup>2</sup>/min) once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15925814 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
# '''SWOG S0205:''' Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 1;28(22):3605-10. Epub 2010 Jul 6. [http://jco.ascopubs.org/content/28/22/3605.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20606093 PubMed]<br />
# Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306953 PubMed]<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
# Hong JY, Nam EM, Lee J, Park JO, Lee SC, Song SY, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol. 2014 Jan;73(1):125-30. Epub 2013 Oct 27. [https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24162380 PubMed]<br />
# '''GAMMA:''' Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921-7. Epub 2015 Jan 21. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25609246 PubMed]<br />
# Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D, Wade J, Sleckman B, Lenz HJ, Stiff P, Kumar P, Xu P, Henderson L, Takebe N, Salgia R, Wang X, Stadler WM, de Sauvage FJ, Kindler HL. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015 Dec 20;33(36):4284-92. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/36/4284.long link to original article] '''contains protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527777 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
# '''ViP:''' Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr;18(4):486-499. Epub 2017 Mar 2. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28259610 PubMed]<br />
<br />
==GemOx {{#subobject:520af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:9d3266|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine, FDR]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
<br />
==Gemcitabine & nab-Paclitaxel {{#subobject:fbd698|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:63ba04|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] as follows, '''given first''':<br />
**Cycle 1: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15<br />
<br />
'''8-week cycle followed by 28-day cycles until disease progression or intolerance'''<br />
<br />
===Variant #2 {{#subobject:ecc1c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ Von Hoff et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 or 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/34/4548.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969517 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
<br />
==GTX {{#subobject:f0d62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GTX: '''<u>G</u>'''emcitabine, '''<u>T</u>'''axotere (Docetaxel), '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:fc0e50|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.springerlink.com/content/75m422843l3461m0/ Fine et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: De Jesus-Acosta et al. 2012 lists the capecitabine dose as "750 mg/m<sup>2</sup>/day orally divided into two doses," but this is believed to be a typographical error since the original reference that it cites, Fine et al. 2007, uses capecitabine at 750 mg/m<sup>2</sup> PO BID. The 2009 ASCO abstract by Fine also lists this 750 mg/m<sup>2</sup> PO BID (1500 mg/m<sup>2</sup>/day) dose.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 75 minutes once per day on days 4 & 11<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 11<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75. Epub 2007 Apr 18. [http://www.springerlink.com/content/75m422843l3461m0/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17440727 PubMed]<br />
# '''Abstract:''' R. L. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. 2009 ASCO Annual Meeting abstract 4623. [http://ascopubs.org/doi/full/10.1200/jco.2009.27.15s.4623 link to abstract] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012 Feb;69(2):415-24. Epub 2011 Jul 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723 link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21800112 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:759f1a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:94d490|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<br />
=Metastatic disease, refractory=<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#OFF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Best supportive care. Placed here because one or more randomized clinical trials included a best supportive care arm in this disease context.''<br />
<br />
===References===<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<br />
==Capecitabine & Erlotinib {{#subobject:4655b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d5c799|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4787.full Kulke et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> (rounded to the nearest 150 mg tablet) PO BID on days 1 to 14<br />
*[[Erlotinib (Tarceva)]] 150 mg PO on days 1 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak EL, Muzikansky A, Lawrence C, Fuchs CS. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007 Oct 20;25(30):4787-92. [http://jco.ascopubs.org/content/25/30/4787.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947726 PubMed]<br />
<br />
==CapeOx {{#subobject:d09d5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:57ad5f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full Xiong et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 1000 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 110 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008 Oct 15;113(8):2046-52. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18756532 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, nanoliposomal Irinotecan {{#subobject:72308d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a81310|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''started on day 1 after folinic acid'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given prior to fluorouracil'''<br />
*[[Irinotecan liposome (Onivyde)]] 70 mg/m<sup>2</sup> (irinotecan free base) IV over 90 minutes once on day 1, '''given first'''<br />
**Per Wang-Gillam et al. 2015 (NAPOLI-01), 70 mg/m<sup>2</sup> irinotecan free base is equivalent to 80 mg/m<sup>2</sup> nanoliposomal irinotecan. According to the trial's ClinicalTrials.gov page: "The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m<sup>2</sup> dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/ m2 of irinotecan free base."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
<br />
==FOLFIRI {{#subobject:6fd426|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br />
===Variant #1 {{#subobject:6a9cae|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 Zaniboni et al. 2012 (GISCAD)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, and 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, modified FOLFIRI.3 {{#subobject:4758e8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFOX|mFOLFOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Irinotecan (Camptosar)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 3<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
# Zaniboni A, Aitini E, Barni S, Ferrari D, Cascinu S, Catalano V, Valmadre G, Ferrara D, Veltri E, Codignola C, Labianca R. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jun;69(6):1641-5. Epub 2012 May 11. [http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22576338 PubMed]<br />
<br />
==FOLFOX {{#subobject:377e80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:33ef68|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFIRI|mFOLFIRI.3]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
<br />
==OFF {{#subobject:8b32c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OFF: '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil, '''<u>F</u>'''olinic acid <br />
===Regimen {{#subobject:ae57d5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
<br />
''Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m<sup>2</sup>," or 850 mg/m<sup>2</sup>.''<br />
====Chemotherapy====<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once per day on days 8 & 22, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous 24-hour infusion on days 1, 8, 15, 22, '''started after folinic acid bolus'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, '''given prior to fluorouracil'''<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
# Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
<br />
==Olaparib monotherapy {{#subobject:0c2eb3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:21eb78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/3/244.long Kaufman et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients had germline BRCA1/2 mutations and had previously received gemcitabine.''<br />
====Chemotherapy====<br />
*[[Olaparib (Lynparza)]] 400 mg PO BID<br />
<br />
'''Continued until progression'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
# Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/33/3/244.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed]<br />
<br />
==Paclitaxel, nanoparticle albumin-bound monotherapy {{#subobject:ab9fc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8d38d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract Hosein et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Hosein PJ, de Lima Lopes G Jr, Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013 Apr;36(2):151-6. Epub 2012 Feb 2. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22307213 PubMed]<br />
<br />
[[Category:Pancreatic cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdheryhttps://hemonc.org/w/index.php?title=Pancreatic_cancer&diff=27250Pancreatic cancer2018-06-07T21:37:22Z<p>Rozinachowdhery: /* Variant #2, bi-weekly dosing */</p>
<hr />
<div><!--'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]]. If this is your first time visiting, we suggest you read the [[tutorial]].'''--><br />
<!--Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are [[How_to_contribute|invited to contribute to the site]].-->{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>Chicago, IL</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2017:''' [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.4948 Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/28398845 PubMed]<br />
*'''2016:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019760/ Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2016:''' [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.5561 Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/27247216 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2015:''' [http://annonc.oxfordjournals.org/content/26/suppl_5/v56.full.pdf+html Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015)] [https://www.ncbi.nlm.nih.gov/pubmed/26314780 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf NCCN Guidelines - Pancreatic Adenocarcinoma]<br />
<br />
=Adjuvant therapy=<br />
==Capecitabine & Gemcitabine {{#subobject:17f9f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Regimen {{#subobject:e6a3e3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Treatment starts within 12 weeks of surgery.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week on weeks 1 to 3<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# '''ESPAC-4:''' Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:29266e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:242770|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
<br />
==Fluorouracil, then Fluorouracil & RT {{#subobject:331d4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:89426a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br> [[#Observation|Observation]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine.2C_then_Fluorouracil_.26_RT.2C_then_Gemcitabine|Gemcitabine, then Fluorouracil & RT, then Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 21<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 28<br />
<br />
'''6-week cycle for 2 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:34e70d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a756a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|Fluorouracil & Leucovorin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine|Capecitabine & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
<br />
''Note: efficacy for CONKO-001 is based on the 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
# Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Gemcitabine, then Fluorouracil & RT, then Gemcitabine {{#subobject:f8c8d9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:3fef3f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|Fluorouracil & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Efficacy for ESPAC-1 is based on the 2004 update and efficacy for CONKO-001 is based on 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cdcc15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, potentially resectable=<br />
<br />
==Docetaxel, Gemcitabine, RT {{#subobject:49a407|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:78b0ba|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1245%2FASO.2005.04.503 Pipas et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 65 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Gemcitabine (Gemzar)]] 4000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29<br />
<br />
'''6-week course, followed immediately (day 43) by:'''<br />
<br />
====Chemoradiation====<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy to primary target volume. Then 5.4 Gy boost to secondary target volume of 1- to 1.5-cm margin on all sides, including proven nodal involvement. Total 50.4 Gy in 28 fractions.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
# Pipas JM, Barth RJ Jr, Zaki B, Tsapakos MJ, Suriawinata AA, Bettmann MA, Cates JM, Ripple GH, Sutton JE, Gordon SR, McDonnell CE, Perez RP, Redfield N, Meyer LP, Marshall JF, Cole BF, Colacchio TA. Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2005 Dec;12(12):995-1004. Epub 2005 Nov 1. [http://link.springer.com/article/10.1245%2FASO.2005.04.503 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16252135 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:55e32d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen 1 {{#subobject:6ce551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract Takahashi et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*Concurrent radiation therapy, 2 Gy per fraction, 5 days per week, 25 fractions, total dose of 50 Gy over 5 weeks.<br />
<br />
'''28-day cycle for 3 cycles''' ''(Radiation given over weeks 1-5 only)''<br />
<br />
''Restaging is performed 8 weeks after radiation complete (2 weeks after chemotherapy complete). Resection immediately thereafter, if feasible.''<br />
<br />
===Regimen 2 {{#subobject:dc32dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 500 mg/m<sup>2</sup> IV over 50 minutes once per week for 6 weeks<br />
*Concurrent radiation therapy, 180 cGy x 22 with 3 cm margin to GTV then 180 cGy x 6 with 2 cm margin to GTV, total 50.4 Gy over 6 weeks<br />
<br />
''Restaging after radiation complete. 4 to 6 week break, followed by surgery, followed by 4 to 8 week break. Then adjuvant chemotherapy:''<br />
<br />
====Adjuvant chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 5 cycles'''<br />
<br />
===References===<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [https://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, Ioka T, Uehara H, Yano M, Ishikawa O. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013 Dec;258(6):1040-50.[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23799421 PubMed]<br />
<br />
==Gemcitabine, Cetuximab, RT {{#subobject:aea7b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c38534|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ Pipas et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**6 to 8 days prior radiation: 400 mg/m<sup>2</sup> IV over 2 hours once<br />
**During radiation: 250 mg/m<sup>2</sup> over 60 minutes once per week for 6 doses<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, delivered using IMRT. Gross tumor volume (GTV) was all known disease including imaging proven nodal disease. The primary planning target volume (PTV1) included the GTV with 2- to 3-cm margins in all directions as well as potential nodal involvement. Secondary planning target volume (PTV2) included the GTV with 1- to 1.5-cm margins on all sides including proven nodal involvement. Tertiary planning treatment volume (PTV3) included the area of the GTV adjacent to the vascular structures specifically the mesenteric and portal vessels with a 0.5-cm margin. The prescription dose delivered to PTV3 was 54 Gy in 28 fractions. Synchronously, PTV1 and PTV2 received 45 and 50.4 Gy, respectively. All fields were treated daily at five fractions per week.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
''One month following therapy, patients were restaged with CT scan of chest/abdomen/pelvis. Patients deemed to be candidates for surgical resection were offered laparotomy ∼6 to 10 weeks after completion of neoadjuvant therapy.''<br />
<br />
===References===<br />
# Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, Tsongalis GJ, Colacchio TA, Gordon SR, Sutton JE, Srivastava A, Smith KD, Gardner TB, Korc M, Davis TH, Preis M, Tarczewski SM, Mackenzie TA, Barth RJ Jr. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. 2012 Nov;23(11):2820-7. Epub 2012 May 9. [http://annonc.oxfordjournals.org/content/23/11/2820.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571859 PubMed]<br />
<br />
==mFOLFIRINOX, Gemcitabine, RT {{#subobject:b71003|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFIRINOX, Gemcitabine, RT: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin, Gemcitabine, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:d87ec0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ Blazer et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion for 46 h on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once on day 1<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 4<br />
<br />
'''14-day cycle for 4 to 8 cycles'''<br />
<br />
''Followed by complete restaging. If tumor localized but still not resectable, chemoradiotherapy was administered:''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup>/week concurrent with radiation<br />
*Radiation was 36 Gy in 15 daily fractions<br />
<br />
===Variant #2 {{#subobject:7bb0e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ Hosein et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion for 46 hours on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles. Protocol followed "per ACCORD-11 trial." Filgrastim was given at the discretion of the treating physician.'''<br />
<br />
''Treatment stopped at maximum response or tolerability. Resectable patients by imaging criteria were offered surgery, followed by postoperative chemoradiotherapy. Unresectable patients were offered chemoradiotherapy, followed by surgery (if they became resectable):''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup>/week<br />
*Radiation at 50.4 Gy in 28 fractions.<br />
<br />
===References===<br />
# '''Retrospective:''' Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, Narayanan G, Ribeiro A, Portelance L, Merchan JR, Levi JU, Rocha-Lima CM. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012 May 29;12:199. [http://www.biomedcentral.com/1471-2407/12/199 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22642850 PubMed]<br />
# '''Retrospective:''' Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, Wuthrick E, Williams TM, Reardon J, Christopher Ellison E, Bloomston M, Bekaii-Saab T. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015 Apr;22(4):1153-9. [http://link.springer.com/article/10.1245%2Fs10434-014-4225-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25358667 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, unresectable=<br />
<br />
==Capecitabine monotherapy {{#subobject:dbd841|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dc4779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:6d97a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, Gem 3 out of 4 weeks x 4 {{#subobject:87edde|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Erlotinib & Gemcitabine x 2 more cycles (6 total) versus Capecitabine, Erlotinib, RT<br />
<br />
===Variant #2, Gem 3 out of 4 weeks x 6 {{#subobject:5a5e14|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
''Note: it is not clear from the protocol whether erlotinib is continued beyond the end of chemotherapy.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] as follows:<br />
**Cycles 1 to 4: 100 mg PO once per day<br />
**Cycles 5 & 6: 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:b4258e|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #4, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:b7a41f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''GERCOR LAP07:''' Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Fluorouracil & RT {{#subobject:26f1c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:29784e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ Herman et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Fluorouracil & RT with TNFerade<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion once per day on radiation days (total dose per week: 1000 mg/m<sup>2</sup>)<br />
*Concurrent radiation therapy, 50.4 Gy total: 1.80 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy, followed by 1.80 Gy x 3 fractions boost to the tumor bed.<br />
<br />
'''One course'''<br />
====Subsequent treatment until progression or toxicity (starting four weeks after chemoradiotherapy)====<br />
*Gemcitabine or Erlotinib & Gemcitabine maintenance<br />
<br />
===References===<br />
# Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, Donehower RC, Pawlik TM, Ziegler MA, Cai H, Savage DT, Canto MI, Klapman J, Reid T, Shah RJ, Hoffe SE, Rosemurgy A, Wolfgang CL, Laheru DA. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013 Mar 1;31(7):886-94. Epub 2013 Jan 22. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.7516 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23341531 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:4f0be9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 3 out of 4 weeks x 4 {{#subobject:c511a7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Gemcitabine x 2 more cycles (6 total) versus Capecitabine & RT<br />
<br />
===Variant #2, 3 out of 4 weeks x 6 {{#subobject:cf89f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in {{#subobject:82f8b2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#GemOx|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_.26_RT_2|Gemcitabine & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent 4-week cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''Continued for at least 3 months'''<br />
<br />
''Per '''Louvet et al. 2005''', subsequent chemoradiotherapy'' ''(45 Gy in 25 fractions for 5 weeks, associated with a daily FU 250 mg/m2 continuous infusion, and a boost of 10 Gy in 8 fractions restricted to the initial tumor volume)'' ''was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:a6e6fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 (600 mg/m<sup>2</sup>) {{#subobject:a6de29|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract Cardenes et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV over 30 to 60 minutes once per week during radiation<br />
*Concurrent radiation therapy, 1.8 Gy per fraction, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks.<br />
<br />
'''One course, followed in 4 weeks by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycle for 5 cycles or until disease progression'''<br />
<br />
===Variant #2 (400 mg/m<sup>2</sup>) {{#subobject:c1ac3c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract Epelbaum et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week for 7 weeks<br />
<br />
'''Radiation planning during this phase, followed by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 400 mg/m<sup>2</sup> IV over 30 minutes once per week (days 1, 8, 15)<br />
*Concurrent radiation therapy, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks<br />
<br />
'''28 day cycle for 2 cycles, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycles until disease progression'''<br />
<br />
===References===<br />
# Epelbaum R, Rosenblatt E, Nasrallah S, Faraggi D, Gaitini D, Mizrahi S, Kuten A. Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J Surg Oncol. 2002 Nov;81(3):138-43. [https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12407726 PubMed]<br />
# Cardenes HR, Moore AM, Johnson CS, Yu M, Helft P, Chiorean EG, Vinson J, Howard TJ, Stephens AW, Tai DF, Loehrer PJ Sr. A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study. Am J Clin Oncol. 2011 Oct;34(5):460-5.[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20881474 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
<br />
==GemOx {{#subobject:19d87f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:5a25e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_2|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycle for at least 3 months'''<br />
<br />
''Subsequent chemoradiotherapy (45 Gy in 25 fractions for 5 weeks, associated with a daily FU 250 mg/m2 continuous infusion, and a boost of 10 Gy in 8 fractions restricted to the initial tumor volume)'' ''was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
<br />
=Metastatic disease, first-line=<br />
<br />
==Capecitabine monotherapy {{#subobject:4f5f03|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b31bbb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Capecitabine & Gemcitabine {{#subobject:2f0431|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Variant #1 {{#subobject:fcd708|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Note: this is essentially identical to the maintenance phase of Cunningham et al. 2009, below.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:e8f0bf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21, 29 to 49<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:a7e551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 650 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 24 weeks'''<br />
<br />
===References===<br />
# Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:c30d8f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, weekly dosing {{#subobject:20a0f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note that cisplatin is not given on day 22 of the first 8 weeks; otherwise, the schedule is identical to the schedule for gemcitabine.''<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] as follows, '''given 60 minutes prior to gemcitabine''':<br />
**First 8 weeks: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Subsequent cycles: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, bi-weekly dosing {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycles'''<br />
<br />
=== '''Variant #3, Day 1, 8 dosing''' ===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract Cascinu et al. 2008 (GISCAD)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Cisplatin, Gemcitabine, Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|}Chemotherapy<br />
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8 (with 1500 mL NS)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 Jan;9(1):39-44. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18077217 PubMed]<br />
# Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:bf797a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, no gemcitabine lead-in {{#subobject:43fe43|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext Kordes et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Erlotinib, Gemcitabine, Metformin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:fc43f2|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:d49fb0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47. Epub 2015 Jun 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext link to original article]'''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26067687 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:c6c509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:3ca01f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Inferior to gemcitabine. Here for historical reference purposes, only.''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
<br />
==FOLFIRINOX {{#subobject:aaa3c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e140cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior QoL by [http://groups.eortc.be/qol/eortc-qlq-c30 EORTC QLQ-C30]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 1200 mg/m<sup>2</sup>/day IV continuous 46-hour infusion on days 1 to 2; '''given last''' (total dose per cycle: 2400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1; '''given third together with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:3a0f4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 8-week lead-in {{#subobject:5d6dd0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx_2|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract Reni et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PEFG<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|GEM FDR<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GEM-CAP]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ Philip et al. 2010 (SWOG S0205)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_nab-Paclitaxel|Gemcitabine & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext Middleton et al. 2017 (ViP)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Vandetanib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
***In Burris et al. 1997, patients with grade 2 or lower toxicities could have had doses increased to 1250 mg/m<sup>2</sup><br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 4 week cycles {{#subobject:c6349|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract Kindler et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ Fuchs et al. 2015 (GAMMA)]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & [[Ganitumab (AMG 479)|Ganitumab]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ Catenacci et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & Vismodegib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 3 week cycles {{#subobject:8bae67|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 Hong et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|Gemcitabine & Simvastatin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, fixed-dose rate (FDR) {{#subobject:5114cc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 150 minutes (10 mg/m<sup>2</sup>/min) once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15925814 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
# '''SWOG S0205:''' Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 1;28(22):3605-10. Epub 2010 Jul 6. [http://jco.ascopubs.org/content/28/22/3605.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20606093 PubMed]<br />
# Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306953 PubMed]<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
# Hong JY, Nam EM, Lee J, Park JO, Lee SC, Song SY, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol. 2014 Jan;73(1):125-30. Epub 2013 Oct 27. [https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24162380 PubMed]<br />
# '''GAMMA:''' Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921-7. Epub 2015 Jan 21. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25609246 PubMed]<br />
# Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D, Wade J, Sleckman B, Lenz HJ, Stiff P, Kumar P, Xu P, Henderson L, Takebe N, Salgia R, Wang X, Stadler WM, de Sauvage FJ, Kindler HL. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015 Dec 20;33(36):4284-92. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/36/4284.long link to original article] '''contains protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527777 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
# '''ViP:''' Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr;18(4):486-499. Epub 2017 Mar 2. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28259610 PubMed]<br />
<br />
==GemOx {{#subobject:520af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:9d3266|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine, FDR]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
<br />
==Gemcitabine & nab-Paclitaxel {{#subobject:fbd698|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:63ba04|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] as follows, '''given first''':<br />
**Cycle 1: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15<br />
<br />
'''8-week cycle followed by 28-day cycles until disease progression or intolerance'''<br />
<br />
===Variant #2 {{#subobject:ecc1c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ Von Hoff et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 or 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/34/4548.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969517 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
<br />
==GTX {{#subobject:f0d62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GTX: '''<u>G</u>'''emcitabine, '''<u>T</u>'''axotere (Docetaxel), '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:fc0e50|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.springerlink.com/content/75m422843l3461m0/ Fine et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: De Jesus-Acosta et al. 2012 lists the capecitabine dose as "750 mg/m<sup>2</sup>/day orally divided into two doses," but this is believed to be a typographical error since the original reference that it cites, Fine et al. 2007, uses capecitabine at 750 mg/m<sup>2</sup> PO BID. The 2009 ASCO abstract by Fine also lists this 750 mg/m<sup>2</sup> PO BID (1500 mg/m<sup>2</sup>/day) dose.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 75 minutes once per day on days 4 & 11<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 11<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75. Epub 2007 Apr 18. [http://www.springerlink.com/content/75m422843l3461m0/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17440727 PubMed]<br />
# '''Abstract:''' R. L. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. 2009 ASCO Annual Meeting abstract 4623. [http://ascopubs.org/doi/full/10.1200/jco.2009.27.15s.4623 link to abstract] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012 Feb;69(2):415-24. Epub 2011 Jul 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723 link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21800112 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:759f1a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:94d490|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<br />
=Metastatic disease, refractory=<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#OFF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Best supportive care. Placed here because one or more randomized clinical trials included a best supportive care arm in this disease context.''<br />
<br />
===References===<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<br />
==Capecitabine & Erlotinib {{#subobject:4655b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d5c799|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4787.full Kulke et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> (rounded to the nearest 150 mg tablet) PO BID on days 1 to 14<br />
*[[Erlotinib (Tarceva)]] 150 mg PO on days 1 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak EL, Muzikansky A, Lawrence C, Fuchs CS. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007 Oct 20;25(30):4787-92. [http://jco.ascopubs.org/content/25/30/4787.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947726 PubMed]<br />
<br />
==CapeOx {{#subobject:d09d5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:57ad5f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full Xiong et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 1000 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 110 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008 Oct 15;113(8):2046-52. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18756532 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, nanoliposomal Irinotecan {{#subobject:72308d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a81310|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''started on day 1 after folinic acid'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given prior to fluorouracil'''<br />
*[[Irinotecan liposome (Onivyde)]] 70 mg/m<sup>2</sup> (irinotecan free base) IV over 90 minutes once on day 1, '''given first'''<br />
**Per Wang-Gillam et al. 2015 (NAPOLI-01), 70 mg/m<sup>2</sup> irinotecan free base is equivalent to 80 mg/m<sup>2</sup> nanoliposomal irinotecan. According to the trial's ClinicalTrials.gov page: "The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m<sup>2</sup> dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/ m2 of irinotecan free base."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
<br />
==FOLFIRI {{#subobject:6fd426|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br />
===Variant #1 {{#subobject:6a9cae|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 Zaniboni et al. 2012 (GISCAD)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, and 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, modified FOLFIRI.3 {{#subobject:4758e8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFOX|mFOLFOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Irinotecan (Camptosar)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 3<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
# Zaniboni A, Aitini E, Barni S, Ferrari D, Cascinu S, Catalano V, Valmadre G, Ferrara D, Veltri E, Codignola C, Labianca R. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jun;69(6):1641-5. Epub 2012 May 11. [http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22576338 PubMed]<br />
<br />
==FOLFOX {{#subobject:377e80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:33ef68|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFIRI|mFOLFIRI.3]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
<br />
==OFF {{#subobject:8b32c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OFF: '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil, '''<u>F</u>'''olinic acid <br />
===Regimen {{#subobject:ae57d5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
<br />
''Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m<sup>2</sup>," or 850 mg/m<sup>2</sup>.''<br />
====Chemotherapy====<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once per day on days 8 & 22, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous 24-hour infusion on days 1, 8, 15, 22, '''started after folinic acid bolus'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, '''given prior to fluorouracil'''<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
# Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
<br />
==Olaparib monotherapy {{#subobject:0c2eb3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:21eb78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/3/244.long Kaufman et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients had germline BRCA1/2 mutations and had previously received gemcitabine.''<br />
====Chemotherapy====<br />
*[[Olaparib (Lynparza)]] 400 mg PO BID<br />
<br />
'''Continued until progression'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
# Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/33/3/244.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed]<br />
<br />
==Paclitaxel, nanoparticle albumin-bound monotherapy {{#subobject:ab9fc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8d38d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract Hosein et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Hosein PJ, de Lima Lopes G Jr, Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013 Apr;36(2):151-6. Epub 2012 Feb 2. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22307213 PubMed]<br />
<br />
[[Category:Pancreatic cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdheryhttps://hemonc.org/w/index.php?title=Pancreatic_cancer&diff=27246Pancreatic cancer2018-06-07T16:32:45Z<p>Rozinachowdhery: /* GemOx */</p>
<hr />
<div><!--'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]]. If this is your first time visiting, we suggest you read the [[tutorial]].'''--><br />
<!--Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are [[How_to_contribute|invited to contribute to the site]].-->{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>Chicago, IL</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2017:''' [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.4948 Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/28398845 PubMed]<br />
*'''2016:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019760/ Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2016:''' [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.5561 Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/27247216 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2015:''' [http://annonc.oxfordjournals.org/content/26/suppl_5/v56.full.pdf+html Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015)] [https://www.ncbi.nlm.nih.gov/pubmed/26314780 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf NCCN Guidelines - Pancreatic Adenocarcinoma]<br />
<br />
=Adjuvant therapy=<br />
==Capecitabine & Gemcitabine {{#subobject:17f9f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Regimen {{#subobject:e6a3e3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Treatment starts within 12 weeks of surgery.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week on weeks 1 to 3<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# '''ESPAC-4:''' Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:29266e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:242770|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
<br />
==Fluorouracil, then Fluorouracil & RT {{#subobject:331d4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:89426a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br> [[#Observation|Observation]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine.2C_then_Fluorouracil_.26_RT.2C_then_Gemcitabine|Gemcitabine, then Fluorouracil & RT, then Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 21<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 28<br />
<br />
'''6-week cycle for 2 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:34e70d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a756a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|Fluorouracil & Leucovorin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine|Capecitabine & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
<br />
''Note: efficacy for CONKO-001 is based on the 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
# Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Gemcitabine, then Fluorouracil & RT, then Gemcitabine {{#subobject:f8c8d9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:3fef3f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|Fluorouracil & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Efficacy for ESPAC-1 is based on the 2004 update and efficacy for CONKO-001 is based on 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cdcc15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, potentially resectable=<br />
<br />
==Docetaxel, Gemcitabine, RT {{#subobject:49a407|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:78b0ba|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1245%2FASO.2005.04.503 Pipas et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 65 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Gemcitabine (Gemzar)]] 4000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29<br />
<br />
'''6-week course, followed immediately (day 43) by:'''<br />
<br />
====Chemoradiation====<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy to primary target volume. Then 5.4 Gy boost to secondary target volume of 1- to 1.5-cm margin on all sides, including proven nodal involvement. Total 50.4 Gy in 28 fractions.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
# Pipas JM, Barth RJ Jr, Zaki B, Tsapakos MJ, Suriawinata AA, Bettmann MA, Cates JM, Ripple GH, Sutton JE, Gordon SR, McDonnell CE, Perez RP, Redfield N, Meyer LP, Marshall JF, Cole BF, Colacchio TA. Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2005 Dec;12(12):995-1004. Epub 2005 Nov 1. [http://link.springer.com/article/10.1245%2FASO.2005.04.503 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16252135 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:55e32d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen 1 {{#subobject:6ce551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract Takahashi et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*Concurrent radiation therapy, 2 Gy per fraction, 5 days per week, 25 fractions, total dose of 50 Gy over 5 weeks.<br />
<br />
'''28-day cycle for 3 cycles''' ''(Radiation given over weeks 1-5 only)''<br />
<br />
''Restaging is performed 8 weeks after radiation complete (2 weeks after chemotherapy complete). Resection immediately thereafter, if feasible.''<br />
<br />
===Regimen 2 {{#subobject:dc32dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 500 mg/m<sup>2</sup> IV over 50 minutes once per week for 6 weeks<br />
*Concurrent radiation therapy, 180 cGy x 22 with 3 cm margin to GTV then 180 cGy x 6 with 2 cm margin to GTV, total 50.4 Gy over 6 weeks<br />
<br />
''Restaging after radiation complete. 4 to 6 week break, followed by surgery, followed by 4 to 8 week break. Then adjuvant chemotherapy:''<br />
<br />
====Adjuvant chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 5 cycles'''<br />
<br />
===References===<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [https://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, Ioka T, Uehara H, Yano M, Ishikawa O. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013 Dec;258(6):1040-50.[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23799421 PubMed]<br />
<br />
==Gemcitabine, Cetuximab, RT {{#subobject:aea7b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c38534|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ Pipas et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**6 to 8 days prior radiation: 400 mg/m<sup>2</sup> IV over 2 hours once<br />
**During radiation: 250 mg/m<sup>2</sup> over 60 minutes once per week for 6 doses<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, delivered using IMRT. Gross tumor volume (GTV) was all known disease including imaging proven nodal disease. The primary planning target volume (PTV1) included the GTV with 2- to 3-cm margins in all directions as well as potential nodal involvement. Secondary planning target volume (PTV2) included the GTV with 1- to 1.5-cm margins on all sides including proven nodal involvement. Tertiary planning treatment volume (PTV3) included the area of the GTV adjacent to the vascular structures specifically the mesenteric and portal vessels with a 0.5-cm margin. The prescription dose delivered to PTV3 was 54 Gy in 28 fractions. Synchronously, PTV1 and PTV2 received 45 and 50.4 Gy, respectively. All fields were treated daily at five fractions per week.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
''One month following therapy, patients were restaged with CT scan of chest/abdomen/pelvis. Patients deemed to be candidates for surgical resection were offered laparotomy ∼6 to 10 weeks after completion of neoadjuvant therapy.''<br />
<br />
===References===<br />
# Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, Tsongalis GJ, Colacchio TA, Gordon SR, Sutton JE, Srivastava A, Smith KD, Gardner TB, Korc M, Davis TH, Preis M, Tarczewski SM, Mackenzie TA, Barth RJ Jr. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. 2012 Nov;23(11):2820-7. Epub 2012 May 9. [http://annonc.oxfordjournals.org/content/23/11/2820.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571859 PubMed]<br />
<br />
==mFOLFIRINOX, Gemcitabine, RT {{#subobject:b71003|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFIRINOX, Gemcitabine, RT: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin, Gemcitabine, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:d87ec0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ Blazer et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion for 46 h on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once on day 1<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 4<br />
<br />
'''14-day cycle for 4 to 8 cycles'''<br />
<br />
''Followed by complete restaging. If tumor localized but still not resectable, chemoradiotherapy was administered:''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup>/week concurrent with radiation<br />
*Radiation was 36 Gy in 15 daily fractions<br />
<br />
===Variant #2 {{#subobject:7bb0e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ Hosein et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion for 46 hours on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles. Protocol followed "per ACCORD-11 trial." Filgrastim was given at the discretion of the treating physician.'''<br />
<br />
''Treatment stopped at maximum response or tolerability. Resectable patients by imaging criteria were offered surgery, followed by postoperative chemoradiotherapy. Unresectable patients were offered chemoradiotherapy, followed by surgery (if they became resectable):''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup>/week<br />
*Radiation at 50.4 Gy in 28 fractions.<br />
<br />
===References===<br />
# '''Retrospective:''' Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, Narayanan G, Ribeiro A, Portelance L, Merchan JR, Levi JU, Rocha-Lima CM. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012 May 29;12:199. [http://www.biomedcentral.com/1471-2407/12/199 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22642850 PubMed]<br />
# '''Retrospective:''' Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, Wuthrick E, Williams TM, Reardon J, Christopher Ellison E, Bloomston M, Bekaii-Saab T. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015 Apr;22(4):1153-9. [http://link.springer.com/article/10.1245%2Fs10434-014-4225-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25358667 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, unresectable=<br />
<br />
==Capecitabine monotherapy {{#subobject:dbd841|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dc4779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:6d97a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, Gem 3 out of 4 weeks x 4 {{#subobject:87edde|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Erlotinib & Gemcitabine x 2 more cycles (6 total) versus Capecitabine, Erlotinib, RT<br />
<br />
===Variant #2, Gem 3 out of 4 weeks x 6 {{#subobject:5a5e14|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
''Note: it is not clear from the protocol whether erlotinib is continued beyond the end of chemotherapy.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] as follows:<br />
**Cycles 1 to 4: 100 mg PO once per day<br />
**Cycles 5 & 6: 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:b4258e|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #4, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:b7a41f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''GERCOR LAP07:''' Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Fluorouracil & RT {{#subobject:26f1c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:29784e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ Herman et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Fluorouracil & RT with TNFerade<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion once per day on radiation days (total dose per week: 1000 mg/m<sup>2</sup>)<br />
*Concurrent radiation therapy, 50.4 Gy total: 1.80 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy, followed by 1.80 Gy x 3 fractions boost to the tumor bed.<br />
<br />
'''One course'''<br />
====Subsequent treatment until progression or toxicity (starting four weeks after chemoradiotherapy)====<br />
*Gemcitabine or Erlotinib & Gemcitabine maintenance<br />
<br />
===References===<br />
# Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, Donehower RC, Pawlik TM, Ziegler MA, Cai H, Savage DT, Canto MI, Klapman J, Reid T, Shah RJ, Hoffe SE, Rosemurgy A, Wolfgang CL, Laheru DA. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013 Mar 1;31(7):886-94. Epub 2013 Jan 22. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.7516 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23341531 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:4f0be9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 3 out of 4 weeks x 4 {{#subobject:c511a7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Gemcitabine x 2 more cycles (6 total) versus Capecitabine & RT<br />
<br />
===Variant #2, 3 out of 4 weeks x 6 {{#subobject:cf89f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in {{#subobject:82f8b2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#GemOx|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_.26_RT_2|Gemcitabine & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent 4-week cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''Continued for at least 3 months'''<br />
<br />
''Per '''Louvet et al. 2005''', subsequent chemoradiotherapy'' ''(45 Gy in 25 fractions for 5 weeks, associated with a daily FU 250 mg/m2 continuous infusion, and a boost of 10 Gy in 8 fractions restricted to the initial tumor volume)'' ''was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:a6e6fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 (600 mg/m<sup>2</sup>) {{#subobject:a6de29|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract Cardenes et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV over 30 to 60 minutes once per week during radiation<br />
*Concurrent radiation therapy, 1.8 Gy per fraction, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks.<br />
<br />
'''One course, followed in 4 weeks by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycle for 5 cycles or until disease progression'''<br />
<br />
===Variant #2 (400 mg/m<sup>2</sup>) {{#subobject:c1ac3c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract Epelbaum et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week for 7 weeks<br />
<br />
'''Radiation planning during this phase, followed by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 400 mg/m<sup>2</sup> IV over 30 minutes once per week (days 1, 8, 15)<br />
*Concurrent radiation therapy, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks<br />
<br />
'''28 day cycle for 2 cycles, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycles until disease progression'''<br />
<br />
===References===<br />
# Epelbaum R, Rosenblatt E, Nasrallah S, Faraggi D, Gaitini D, Mizrahi S, Kuten A. Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J Surg Oncol. 2002 Nov;81(3):138-43. [https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12407726 PubMed]<br />
# Cardenes HR, Moore AM, Johnson CS, Yu M, Helft P, Chiorean EG, Vinson J, Howard TJ, Stephens AW, Tai DF, Loehrer PJ Sr. A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study. Am J Clin Oncol. 2011 Oct;34(5):460-5.[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20881474 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
<br />
==GemOx {{#subobject:19d87f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:5a25e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_2|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycle for at least 3 months'''<br />
<br />
''Subsequent chemoradiotherapy (45 Gy in 25 fractions for 5 weeks, associated with a daily FU 250 mg/m2 continuous infusion, and a boost of 10 Gy in 8 fractions restricted to the initial tumor volume)'' ''was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
<br />
=Metastatic disease, first-line=<br />
<br />
==Capecitabine monotherapy {{#subobject:4f5f03|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b31bbb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Capecitabine & Gemcitabine {{#subobject:2f0431|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Variant #1 {{#subobject:fcd708|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Note: this is essentially identical to the maintenance phase of Cunningham et al. 2009, below.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:e8f0bf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21, 29 to 49<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:a7e551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 650 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 24 weeks'''<br />
<br />
===References===<br />
# Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:c30d8f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, weekly dosing {{#subobject:20a0f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note that cisplatin is not given on day 22 of the first 8 weeks; otherwise, the schedule is identical to the schedule for gemcitabine.''<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] as follows, '''given 60 minutes prior to gemcitabine''':<br />
**First 8 weeks: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Subsequent cycles: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, bi-weekly dosing {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract Cascinu et al. 2008 (GISCAD)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Cisplatin, Gemcitabine, Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 Jan;9(1):39-44. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18077217 PubMed]<br />
# Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:bf797a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, no gemcitabine lead-in {{#subobject:43fe43|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext Kordes et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Erlotinib, Gemcitabine, Metformin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:fc43f2|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:d49fb0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47. Epub 2015 Jun 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext link to original article]'''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26067687 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:c6c509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:3ca01f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Inferior to gemcitabine. Here for historical reference purposes, only.''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
<br />
==FOLFIRINOX {{#subobject:aaa3c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e140cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior QoL by [http://groups.eortc.be/qol/eortc-qlq-c30 EORTC QLQ-C30]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 1200 mg/m<sup>2</sup>/day IV continuous 46-hour infusion on days 1 to 2; '''given last''' (total dose per cycle: 2400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1; '''given third together with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:3a0f4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 8-week lead-in {{#subobject:5d6dd0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx_2|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract Reni et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PEFG<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|GEM FDR<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GEM-CAP]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ Philip et al. 2010 (SWOG S0205)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_nab-Paclitaxel|Gemcitabine & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext Middleton et al. 2017 (ViP)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Vandetanib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
***In Burris et al. 1997, patients with grade 2 or lower toxicities could have had doses increased to 1250 mg/m<sup>2</sup><br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 4 week cycles {{#subobject:c6349|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract Kindler et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ Fuchs et al. 2015 (GAMMA)]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & [[Ganitumab (AMG 479)|Ganitumab]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ Catenacci et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & Vismodegib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 3 week cycles {{#subobject:8bae67|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 Hong et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|Gemcitabine & Simvastatin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, fixed-dose rate (FDR) {{#subobject:5114cc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 150 minutes (10 mg/m<sup>2</sup>/min) once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15925814 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
# '''SWOG S0205:''' Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 1;28(22):3605-10. Epub 2010 Jul 6. [http://jco.ascopubs.org/content/28/22/3605.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20606093 PubMed]<br />
# Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306953 PubMed]<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
# Hong JY, Nam EM, Lee J, Park JO, Lee SC, Song SY, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol. 2014 Jan;73(1):125-30. Epub 2013 Oct 27. [https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24162380 PubMed]<br />
# '''GAMMA:''' Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921-7. Epub 2015 Jan 21. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25609246 PubMed]<br />
# Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D, Wade J, Sleckman B, Lenz HJ, Stiff P, Kumar P, Xu P, Henderson L, Takebe N, Salgia R, Wang X, Stadler WM, de Sauvage FJ, Kindler HL. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015 Dec 20;33(36):4284-92. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/36/4284.long link to original article] '''contains protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527777 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
# '''ViP:''' Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr;18(4):486-499. Epub 2017 Mar 2. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28259610 PubMed]<br />
<br />
==GemOx {{#subobject:520af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:9d3266|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine, FDR]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
<br />
==Gemcitabine & nab-Paclitaxel {{#subobject:fbd698|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:63ba04|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] as follows, '''given first''':<br />
**Cycle 1: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15<br />
<br />
'''8-week cycle followed by 28-day cycles until disease progression or intolerance'''<br />
<br />
===Variant #2 {{#subobject:ecc1c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ Von Hoff et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 or 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/34/4548.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969517 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
<br />
==GTX {{#subobject:f0d62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GTX: '''<u>G</u>'''emcitabine, '''<u>T</u>'''axotere (Docetaxel), '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:fc0e50|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.springerlink.com/content/75m422843l3461m0/ Fine et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: De Jesus-Acosta et al. 2012 lists the capecitabine dose as "750 mg/m<sup>2</sup>/day orally divided into two doses," but this is believed to be a typographical error since the original reference that it cites, Fine et al. 2007, uses capecitabine at 750 mg/m<sup>2</sup> PO BID. The 2009 ASCO abstract by Fine also lists this 750 mg/m<sup>2</sup> PO BID (1500 mg/m<sup>2</sup>/day) dose.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 75 minutes once per day on days 4 & 11<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 11<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75. Epub 2007 Apr 18. [http://www.springerlink.com/content/75m422843l3461m0/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17440727 PubMed]<br />
# '''Abstract:''' R. L. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. 2009 ASCO Annual Meeting abstract 4623. [http://ascopubs.org/doi/full/10.1200/jco.2009.27.15s.4623 link to abstract] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012 Feb;69(2):415-24. Epub 2011 Jul 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723 link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21800112 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:759f1a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:94d490|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<br />
=Metastatic disease, refractory=<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#OFF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Best supportive care. Placed here because one or more randomized clinical trials included a best supportive care arm in this disease context.''<br />
<br />
===References===<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<br />
==Capecitabine & Erlotinib {{#subobject:4655b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d5c799|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4787.full Kulke et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> (rounded to the nearest 150 mg tablet) PO BID on days 1 to 14<br />
*[[Erlotinib (Tarceva)]] 150 mg PO on days 1 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak EL, Muzikansky A, Lawrence C, Fuchs CS. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007 Oct 20;25(30):4787-92. [http://jco.ascopubs.org/content/25/30/4787.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947726 PubMed]<br />
<br />
==CapeOx {{#subobject:d09d5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:57ad5f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full Xiong et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 1000 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 110 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008 Oct 15;113(8):2046-52. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18756532 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, nanoliposomal Irinotecan {{#subobject:72308d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a81310|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''started on day 1 after folinic acid'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given prior to fluorouracil'''<br />
*[[Irinotecan liposome (Onivyde)]] 70 mg/m<sup>2</sup> (irinotecan free base) IV over 90 minutes once on day 1, '''given first'''<br />
**Per Wang-Gillam et al. 2015 (NAPOLI-01), 70 mg/m<sup>2</sup> irinotecan free base is equivalent to 80 mg/m<sup>2</sup> nanoliposomal irinotecan. According to the trial's ClinicalTrials.gov page: "The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m<sup>2</sup> dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/ m2 of irinotecan free base."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
<br />
==FOLFIRI {{#subobject:6fd426|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br />
===Variant #1 {{#subobject:6a9cae|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 Zaniboni et al. 2012 (GISCAD)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, and 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, modified FOLFIRI.3 {{#subobject:4758e8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFOX|mFOLFOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Irinotecan (Camptosar)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 3<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
# Zaniboni A, Aitini E, Barni S, Ferrari D, Cascinu S, Catalano V, Valmadre G, Ferrara D, Veltri E, Codignola C, Labianca R. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jun;69(6):1641-5. Epub 2012 May 11. [http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22576338 PubMed]<br />
<br />
==FOLFOX {{#subobject:377e80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:33ef68|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFIRI|mFOLFIRI.3]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
<br />
==OFF {{#subobject:8b32c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OFF: '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil, '''<u>F</u>'''olinic acid <br />
===Regimen {{#subobject:ae57d5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
<br />
''Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m<sup>2</sup>," or 850 mg/m<sup>2</sup>.''<br />
====Chemotherapy====<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once per day on days 8 & 22, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous 24-hour infusion on days 1, 8, 15, 22, '''started after folinic acid bolus'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, '''given prior to fluorouracil'''<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
# Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
<br />
==Olaparib monotherapy {{#subobject:0c2eb3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:21eb78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/3/244.long Kaufman et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients had germline BRCA1/2 mutations and had previously received gemcitabine.''<br />
====Chemotherapy====<br />
*[[Olaparib (Lynparza)]] 400 mg PO BID<br />
<br />
'''Continued until progression'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
# Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/33/3/244.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed]<br />
<br />
==Paclitaxel, nanoparticle albumin-bound monotherapy {{#subobject:ab9fc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8d38d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract Hosein et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Hosein PJ, de Lima Lopes G Jr, Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013 Apr;36(2):151-6. Epub 2012 Feb 2. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22307213 PubMed]<br />
<br />
[[Category:Pancreatic cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdheryhttps://hemonc.org/w/index.php?title=Pancreatic_cancer&diff=27245Pancreatic cancer2018-06-07T16:30:00Z<p>Rozinachowdhery: /* Variant #2 (400 mg/m2) */</p>
<hr />
<div><!--'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]]. If this is your first time visiting, we suggest you read the [[tutorial]].'''--><br />
<!--Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are [[How_to_contribute|invited to contribute to the site]].-->{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>Chicago, IL</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2017:''' [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.4948 Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/28398845 PubMed]<br />
*'''2016:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019760/ Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2016:''' [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.5561 Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/27247216 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2015:''' [http://annonc.oxfordjournals.org/content/26/suppl_5/v56.full.pdf+html Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015)] [https://www.ncbi.nlm.nih.gov/pubmed/26314780 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf NCCN Guidelines - Pancreatic Adenocarcinoma]<br />
<br />
=Adjuvant therapy=<br />
==Capecitabine & Gemcitabine {{#subobject:17f9f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Regimen {{#subobject:e6a3e3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Treatment starts within 12 weeks of surgery.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week on weeks 1 to 3<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# '''ESPAC-4:''' Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:29266e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:242770|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
<br />
==Fluorouracil, then Fluorouracil & RT {{#subobject:331d4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:89426a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br> [[#Observation|Observation]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine.2C_then_Fluorouracil_.26_RT.2C_then_Gemcitabine|Gemcitabine, then Fluorouracil & RT, then Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 21<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 28<br />
<br />
'''6-week cycle for 2 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:34e70d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a756a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|Fluorouracil & Leucovorin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine|Capecitabine & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
<br />
''Note: efficacy for CONKO-001 is based on the 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
# Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Gemcitabine, then Fluorouracil & RT, then Gemcitabine {{#subobject:f8c8d9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:3fef3f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|Fluorouracil & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Efficacy for ESPAC-1 is based on the 2004 update and efficacy for CONKO-001 is based on 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cdcc15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, potentially resectable=<br />
<br />
==Docetaxel, Gemcitabine, RT {{#subobject:49a407|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:78b0ba|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1245%2FASO.2005.04.503 Pipas et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 65 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Gemcitabine (Gemzar)]] 4000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29<br />
<br />
'''6-week course, followed immediately (day 43) by:'''<br />
<br />
====Chemoradiation====<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy to primary target volume. Then 5.4 Gy boost to secondary target volume of 1- to 1.5-cm margin on all sides, including proven nodal involvement. Total 50.4 Gy in 28 fractions.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
# Pipas JM, Barth RJ Jr, Zaki B, Tsapakos MJ, Suriawinata AA, Bettmann MA, Cates JM, Ripple GH, Sutton JE, Gordon SR, McDonnell CE, Perez RP, Redfield N, Meyer LP, Marshall JF, Cole BF, Colacchio TA. Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2005 Dec;12(12):995-1004. Epub 2005 Nov 1. [http://link.springer.com/article/10.1245%2FASO.2005.04.503 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16252135 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:55e32d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen 1 {{#subobject:6ce551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract Takahashi et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*Concurrent radiation therapy, 2 Gy per fraction, 5 days per week, 25 fractions, total dose of 50 Gy over 5 weeks.<br />
<br />
'''28-day cycle for 3 cycles''' ''(Radiation given over weeks 1-5 only)''<br />
<br />
''Restaging is performed 8 weeks after radiation complete (2 weeks after chemotherapy complete). Resection immediately thereafter, if feasible.''<br />
<br />
===Regimen 2 {{#subobject:dc32dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 500 mg/m<sup>2</sup> IV over 50 minutes once per week for 6 weeks<br />
*Concurrent radiation therapy, 180 cGy x 22 with 3 cm margin to GTV then 180 cGy x 6 with 2 cm margin to GTV, total 50.4 Gy over 6 weeks<br />
<br />
''Restaging after radiation complete. 4 to 6 week break, followed by surgery, followed by 4 to 8 week break. Then adjuvant chemotherapy:''<br />
<br />
====Adjuvant chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 5 cycles'''<br />
<br />
===References===<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [https://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, Ioka T, Uehara H, Yano M, Ishikawa O. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013 Dec;258(6):1040-50.[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23799421 PubMed]<br />
<br />
==Gemcitabine, Cetuximab, RT {{#subobject:aea7b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c38534|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ Pipas et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**6 to 8 days prior radiation: 400 mg/m<sup>2</sup> IV over 2 hours once<br />
**During radiation: 250 mg/m<sup>2</sup> over 60 minutes once per week for 6 doses<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, delivered using IMRT. Gross tumor volume (GTV) was all known disease including imaging proven nodal disease. The primary planning target volume (PTV1) included the GTV with 2- to 3-cm margins in all directions as well as potential nodal involvement. Secondary planning target volume (PTV2) included the GTV with 1- to 1.5-cm margins on all sides including proven nodal involvement. Tertiary planning treatment volume (PTV3) included the area of the GTV adjacent to the vascular structures specifically the mesenteric and portal vessels with a 0.5-cm margin. The prescription dose delivered to PTV3 was 54 Gy in 28 fractions. Synchronously, PTV1 and PTV2 received 45 and 50.4 Gy, respectively. All fields were treated daily at five fractions per week.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
''One month following therapy, patients were restaged with CT scan of chest/abdomen/pelvis. Patients deemed to be candidates for surgical resection were offered laparotomy ∼6 to 10 weeks after completion of neoadjuvant therapy.''<br />
<br />
===References===<br />
# Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, Tsongalis GJ, Colacchio TA, Gordon SR, Sutton JE, Srivastava A, Smith KD, Gardner TB, Korc M, Davis TH, Preis M, Tarczewski SM, Mackenzie TA, Barth RJ Jr. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. 2012 Nov;23(11):2820-7. Epub 2012 May 9. [http://annonc.oxfordjournals.org/content/23/11/2820.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571859 PubMed]<br />
<br />
==mFOLFIRINOX, Gemcitabine, RT {{#subobject:b71003|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFIRINOX, Gemcitabine, RT: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin, Gemcitabine, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:d87ec0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ Blazer et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion for 46 h on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once on day 1<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 4<br />
<br />
'''14-day cycle for 4 to 8 cycles'''<br />
<br />
''Followed by complete restaging. If tumor localized but still not resectable, chemoradiotherapy was administered:''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup>/week concurrent with radiation<br />
*Radiation was 36 Gy in 15 daily fractions<br />
<br />
===Variant #2 {{#subobject:7bb0e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ Hosein et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion for 46 hours on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles. Protocol followed "per ACCORD-11 trial." Filgrastim was given at the discretion of the treating physician.'''<br />
<br />
''Treatment stopped at maximum response or tolerability. Resectable patients by imaging criteria were offered surgery, followed by postoperative chemoradiotherapy. Unresectable patients were offered chemoradiotherapy, followed by surgery (if they became resectable):''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup>/week<br />
*Radiation at 50.4 Gy in 28 fractions.<br />
<br />
===References===<br />
# '''Retrospective:''' Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, Narayanan G, Ribeiro A, Portelance L, Merchan JR, Levi JU, Rocha-Lima CM. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012 May 29;12:199. [http://www.biomedcentral.com/1471-2407/12/199 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22642850 PubMed]<br />
# '''Retrospective:''' Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, Wuthrick E, Williams TM, Reardon J, Christopher Ellison E, Bloomston M, Bekaii-Saab T. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015 Apr;22(4):1153-9. [http://link.springer.com/article/10.1245%2Fs10434-014-4225-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25358667 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, unresectable=<br />
<br />
==Capecitabine monotherapy {{#subobject:dbd841|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dc4779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:6d97a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, Gem 3 out of 4 weeks x 4 {{#subobject:87edde|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Erlotinib & Gemcitabine x 2 more cycles (6 total) versus Capecitabine, Erlotinib, RT<br />
<br />
===Variant #2, Gem 3 out of 4 weeks x 6 {{#subobject:5a5e14|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
''Note: it is not clear from the protocol whether erlotinib is continued beyond the end of chemotherapy.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] as follows:<br />
**Cycles 1 to 4: 100 mg PO once per day<br />
**Cycles 5 & 6: 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:b4258e|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #4, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:b7a41f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''GERCOR LAP07:''' Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Fluorouracil & RT {{#subobject:26f1c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:29784e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ Herman et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Fluorouracil & RT with TNFerade<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion once per day on radiation days (total dose per week: 1000 mg/m<sup>2</sup>)<br />
*Concurrent radiation therapy, 50.4 Gy total: 1.80 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy, followed by 1.80 Gy x 3 fractions boost to the tumor bed.<br />
<br />
'''One course'''<br />
====Subsequent treatment until progression or toxicity (starting four weeks after chemoradiotherapy)====<br />
*Gemcitabine or Erlotinib & Gemcitabine maintenance<br />
<br />
===References===<br />
# Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, Donehower RC, Pawlik TM, Ziegler MA, Cai H, Savage DT, Canto MI, Klapman J, Reid T, Shah RJ, Hoffe SE, Rosemurgy A, Wolfgang CL, Laheru DA. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013 Mar 1;31(7):886-94. Epub 2013 Jan 22. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.7516 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23341531 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:4f0be9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 3 out of 4 weeks x 4 {{#subobject:c511a7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Gemcitabine x 2 more cycles (6 total) versus Capecitabine & RT<br />
<br />
===Variant #2, 3 out of 4 weeks x 6 {{#subobject:cf89f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in {{#subobject:82f8b2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#GemOx|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_.26_RT_2|Gemcitabine & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent 4-week cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''Continued for at least 3 months'''<br />
<br />
''Per '''Louvet et al. 2005''', subsequent chemoradiotherapy'' ''(45 Gy in 25 fractions for 5 weeks, associated with a daily FU 250 mg/m2 continuous infusion, and a boost of 10 Gy in 8 fractions restricted to the initial tumor volume)'' ''was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:a6e6fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 (600 mg/m<sup>2</sup>) {{#subobject:a6de29|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract Cardenes et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV over 30 to 60 minutes once per week during radiation<br />
*Concurrent radiation therapy, 1.8 Gy per fraction, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks.<br />
<br />
'''One course, followed in 4 weeks by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycle for 5 cycles or until disease progression'''<br />
<br />
===Variant #2 (400 mg/m<sup>2</sup>) {{#subobject:c1ac3c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract Epelbaum et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week for 7 weeks<br />
<br />
'''Radiation planning during this phase, followed by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 400 mg/m<sup>2</sup> IV over 30 minutes once per week (days 1, 8, 15)<br />
*Concurrent radiation therapy, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks<br />
<br />
'''28 day cycle for 2 cycles, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycles until disease progression'''<br />
<br />
===References===<br />
# Epelbaum R, Rosenblatt E, Nasrallah S, Faraggi D, Gaitini D, Mizrahi S, Kuten A. Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J Surg Oncol. 2002 Nov;81(3):138-43. [https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12407726 PubMed]<br />
# Cardenes HR, Moore AM, Johnson CS, Yu M, Helft P, Chiorean EG, Vinson J, Howard TJ, Stephens AW, Tai DF, Loehrer PJ Sr. A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study. Am J Clin Oncol. 2011 Oct;34(5):460-5.[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20881474 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
<br />
==GemOx {{#subobject:19d87f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:5a25e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_2|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycle for at least 3 months'''<br />
<br />
''Subsequent chemoradiotherapy was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
<br />
=Metastatic disease, first-line=<br />
<br />
==Capecitabine monotherapy {{#subobject:4f5f03|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b31bbb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Capecitabine & Gemcitabine {{#subobject:2f0431|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Variant #1 {{#subobject:fcd708|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Note: this is essentially identical to the maintenance phase of Cunningham et al. 2009, below.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:e8f0bf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21, 29 to 49<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:a7e551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 650 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 24 weeks'''<br />
<br />
===References===<br />
# Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:c30d8f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, weekly dosing {{#subobject:20a0f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note that cisplatin is not given on day 22 of the first 8 weeks; otherwise, the schedule is identical to the schedule for gemcitabine.''<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] as follows, '''given 60 minutes prior to gemcitabine''':<br />
**First 8 weeks: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Subsequent cycles: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, bi-weekly dosing {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract Cascinu et al. 2008 (GISCAD)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Cisplatin, Gemcitabine, Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 Jan;9(1):39-44. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18077217 PubMed]<br />
# Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:bf797a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, no gemcitabine lead-in {{#subobject:43fe43|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext Kordes et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Erlotinib, Gemcitabine, Metformin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:fc43f2|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:d49fb0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47. Epub 2015 Jun 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext link to original article]'''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26067687 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:c6c509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:3ca01f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Inferior to gemcitabine. Here for historical reference purposes, only.''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
<br />
==FOLFIRINOX {{#subobject:aaa3c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e140cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior QoL by [http://groups.eortc.be/qol/eortc-qlq-c30 EORTC QLQ-C30]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 1200 mg/m<sup>2</sup>/day IV continuous 46-hour infusion on days 1 to 2; '''given last''' (total dose per cycle: 2400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1; '''given third together with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:3a0f4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 8-week lead-in {{#subobject:5d6dd0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx_2|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract Reni et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PEFG<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|GEM FDR<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GEM-CAP]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ Philip et al. 2010 (SWOG S0205)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_nab-Paclitaxel|Gemcitabine & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext Middleton et al. 2017 (ViP)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Vandetanib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
***In Burris et al. 1997, patients with grade 2 or lower toxicities could have had doses increased to 1250 mg/m<sup>2</sup><br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 4 week cycles {{#subobject:c6349|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract Kindler et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ Fuchs et al. 2015 (GAMMA)]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & [[Ganitumab (AMG 479)|Ganitumab]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ Catenacci et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & Vismodegib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 3 week cycles {{#subobject:8bae67|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 Hong et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|Gemcitabine & Simvastatin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, fixed-dose rate (FDR) {{#subobject:5114cc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 150 minutes (10 mg/m<sup>2</sup>/min) once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15925814 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
# '''SWOG S0205:''' Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 1;28(22):3605-10. Epub 2010 Jul 6. [http://jco.ascopubs.org/content/28/22/3605.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20606093 PubMed]<br />
# Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306953 PubMed]<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
# Hong JY, Nam EM, Lee J, Park JO, Lee SC, Song SY, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol. 2014 Jan;73(1):125-30. Epub 2013 Oct 27. [https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24162380 PubMed]<br />
# '''GAMMA:''' Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921-7. Epub 2015 Jan 21. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25609246 PubMed]<br />
# Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D, Wade J, Sleckman B, Lenz HJ, Stiff P, Kumar P, Xu P, Henderson L, Takebe N, Salgia R, Wang X, Stadler WM, de Sauvage FJ, Kindler HL. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015 Dec 20;33(36):4284-92. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/36/4284.long link to original article] '''contains protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527777 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
# '''ViP:''' Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr;18(4):486-499. Epub 2017 Mar 2. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28259610 PubMed]<br />
<br />
==GemOx {{#subobject:520af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:9d3266|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine, FDR]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
<br />
==Gemcitabine & nab-Paclitaxel {{#subobject:fbd698|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:63ba04|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] as follows, '''given first''':<br />
**Cycle 1: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15<br />
<br />
'''8-week cycle followed by 28-day cycles until disease progression or intolerance'''<br />
<br />
===Variant #2 {{#subobject:ecc1c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ Von Hoff et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 or 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/34/4548.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969517 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
<br />
==GTX {{#subobject:f0d62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
GTX: '''<u>G</u>'''emcitabine, '''<u>T</u>'''axotere (Docetaxel), '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:fc0e50|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.springerlink.com/content/75m422843l3461m0/ Fine et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: De Jesus-Acosta et al. 2012 lists the capecitabine dose as "750 mg/m<sup>2</sup>/day orally divided into two doses," but this is believed to be a typographical error since the original reference that it cites, Fine et al. 2007, uses capecitabine at 750 mg/m<sup>2</sup> PO BID. The 2009 ASCO abstract by Fine also lists this 750 mg/m<sup>2</sup> PO BID (1500 mg/m<sup>2</sup>/day) dose.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 75 minutes once per day on days 4 & 11<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 11<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75. Epub 2007 Apr 18. [http://www.springerlink.com/content/75m422843l3461m0/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17440727 PubMed]<br />
# '''Abstract:''' R. L. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. 2009 ASCO Annual Meeting abstract 4623. [http://ascopubs.org/doi/full/10.1200/jco.2009.27.15s.4623 link to abstract] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012 Feb;69(2):415-24. Epub 2011 Jul 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723 link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21800112 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:759f1a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:94d490|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<br />
=Metastatic disease, refractory=<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#OFF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Best supportive care. Placed here because one or more randomized clinical trials included a best supportive care arm in this disease context.''<br />
<br />
===References===<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<br />
==Capecitabine & Erlotinib {{#subobject:4655b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d5c799|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4787.full Kulke et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> (rounded to the nearest 150 mg tablet) PO BID on days 1 to 14<br />
*[[Erlotinib (Tarceva)]] 150 mg PO on days 1 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak EL, Muzikansky A, Lawrence C, Fuchs CS. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007 Oct 20;25(30):4787-92. [http://jco.ascopubs.org/content/25/30/4787.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947726 PubMed]<br />
<br />
==CapeOx {{#subobject:d09d5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:57ad5f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full Xiong et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 1000 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 110 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008 Oct 15;113(8):2046-52. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18756532 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, nanoliposomal Irinotecan {{#subobject:72308d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a81310|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''started on day 1 after folinic acid'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given prior to fluorouracil'''<br />
*[[Irinotecan liposome (Onivyde)]] 70 mg/m<sup>2</sup> (irinotecan free base) IV over 90 minutes once on day 1, '''given first'''<br />
**Per Wang-Gillam et al. 2015 (NAPOLI-01), 70 mg/m<sup>2</sup> irinotecan free base is equivalent to 80 mg/m<sup>2</sup> nanoliposomal irinotecan. According to the trial's ClinicalTrials.gov page: "The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m<sup>2</sup> dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/ m2 of irinotecan free base."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
<br />
==FOLFIRI {{#subobject:6fd426|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br />
===Variant #1 {{#subobject:6a9cae|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 Zaniboni et al. 2012 (GISCAD)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, and 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, modified FOLFIRI.3 {{#subobject:4758e8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFOX|mFOLFOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Irinotecan (Camptosar)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 3<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
# Zaniboni A, Aitini E, Barni S, Ferrari D, Cascinu S, Catalano V, Valmadre G, Ferrara D, Veltri E, Codignola C, Labianca R. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jun;69(6):1641-5. Epub 2012 May 11. [http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22576338 PubMed]<br />
<br />
==FOLFOX {{#subobject:377e80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:33ef68|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFIRI|mFOLFIRI.3]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
<br />
==OFF {{#subobject:8b32c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OFF: '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil, '''<u>F</u>'''olinic acid <br />
===Regimen {{#subobject:ae57d5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
<br />
''Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m<sup>2</sup>," or 850 mg/m<sup>2</sup>.''<br />
====Chemotherapy====<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once per day on days 8 & 22, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous 24-hour infusion on days 1, 8, 15, 22, '''started after folinic acid bolus'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, '''given prior to fluorouracil'''<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
# Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
<br />
==Olaparib monotherapy {{#subobject:0c2eb3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:21eb78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/3/244.long Kaufman et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients had germline BRCA1/2 mutations and had previously received gemcitabine.''<br />
====Chemotherapy====<br />
*[[Olaparib (Lynparza)]] 400 mg PO BID<br />
<br />
'''Continued until progression'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
# Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/33/3/244.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed]<br />
<br />
==Paclitaxel, nanoparticle albumin-bound monotherapy {{#subobject:ab9fc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8d38d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract Hosein et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Hosein PJ, de Lima Lopes G Jr, Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013 Apr;36(2):151-6. Epub 2012 Feb 2. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22307213 PubMed]<br />
<br />
[[Category:Pancreatic cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdheryhttps://hemonc.org/w/index.php?title=Pancreatic_cancer&diff=27244Pancreatic cancer2018-06-07T16:20:43Z<p>Rozinachowdhery: /* Variant #3, 8-week lead-in */</p>
<hr />
<div><!--'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]]. If this is your first time visiting, we suggest you read the [[tutorial]].'''--><br />
<!--Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are [[How_to_contribute|invited to contribute to the site]].-->{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>Chicago, IL</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2017:''' [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.4948 Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/28398845 PubMed]<br />
*'''2016:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019760/ Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2016:''' [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.5561 Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/27247216 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2015:''' [http://annonc.oxfordjournals.org/content/26/suppl_5/v56.full.pdf+html Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015)] [https://www.ncbi.nlm.nih.gov/pubmed/26314780 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf NCCN Guidelines - Pancreatic Adenocarcinoma]<br />
<br />
=Adjuvant therapy=<br />
==Capecitabine & Gemcitabine {{#subobject:17f9f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Regimen {{#subobject:e6a3e3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Treatment starts within 12 weeks of surgery.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week on weeks 1 to 3<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# '''ESPAC-4:''' Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:29266e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:242770|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
<br />
==Fluorouracil, then Fluorouracil & RT {{#subobject:331d4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:89426a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br> [[#Observation|Observation]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine.2C_then_Fluorouracil_.26_RT.2C_then_Gemcitabine|Gemcitabine, then Fluorouracil & RT, then Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 21<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 28<br />
<br />
'''6-week cycle for 2 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:34e70d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a756a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|Fluorouracil & Leucovorin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine|Capecitabine & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
<br />
''Note: efficacy for CONKO-001 is based on the 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
# Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Gemcitabine, then Fluorouracil & RT, then Gemcitabine {{#subobject:f8c8d9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:3fef3f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|Fluorouracil & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Efficacy for ESPAC-1 is based on the 2004 update and efficacy for CONKO-001 is based on 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cdcc15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, potentially resectable=<br />
<br />
==Docetaxel, Gemcitabine, RT {{#subobject:49a407|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:78b0ba|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1245%2FASO.2005.04.503 Pipas et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 65 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Gemcitabine (Gemzar)]] 4000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29<br />
<br />
'''6-week course, followed immediately (day 43) by:'''<br />
<br />
====Chemoradiation====<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy to primary target volume. Then 5.4 Gy boost to secondary target volume of 1- to 1.5-cm margin on all sides, including proven nodal involvement. Total 50.4 Gy in 28 fractions.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
# Pipas JM, Barth RJ Jr, Zaki B, Tsapakos MJ, Suriawinata AA, Bettmann MA, Cates JM, Ripple GH, Sutton JE, Gordon SR, McDonnell CE, Perez RP, Redfield N, Meyer LP, Marshall JF, Cole BF, Colacchio TA. Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2005 Dec;12(12):995-1004. Epub 2005 Nov 1. [http://link.springer.com/article/10.1245%2FASO.2005.04.503 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16252135 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:55e32d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen 1 {{#subobject:6ce551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract Takahashi et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*Concurrent radiation therapy, 2 Gy per fraction, 5 days per week, 25 fractions, total dose of 50 Gy over 5 weeks.<br />
<br />
'''28-day cycle for 3 cycles''' ''(Radiation given over weeks 1-5 only)''<br />
<br />
''Restaging is performed 8 weeks after radiation complete (2 weeks after chemotherapy complete). Resection immediately thereafter, if feasible.''<br />
<br />
===Regimen 2 {{#subobject:dc32dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 500 mg/m<sup>2</sup> IV over 50 minutes once per week for 6 weeks<br />
*Concurrent radiation therapy, 180 cGy x 22 with 3 cm margin to GTV then 180 cGy x 6 with 2 cm margin to GTV, total 50.4 Gy over 6 weeks<br />
<br />
''Restaging after radiation complete. 4 to 6 week break, followed by surgery, followed by 4 to 8 week break. Then adjuvant chemotherapy:''<br />
<br />
====Adjuvant chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 5 cycles'''<br />
<br />
===References===<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [https://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, Ioka T, Uehara H, Yano M, Ishikawa O. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013 Dec;258(6):1040-50.[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23799421 PubMed]<br />
<br />
==Gemcitabine, Cetuximab, RT {{#subobject:aea7b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c38534|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ Pipas et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**6 to 8 days prior radiation: 400 mg/m<sup>2</sup> IV over 2 hours once<br />
**During radiation: 250 mg/m<sup>2</sup> over 60 minutes once per week for 6 doses<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, delivered using IMRT. Gross tumor volume (GTV) was all known disease including imaging proven nodal disease. The primary planning target volume (PTV1) included the GTV with 2- to 3-cm margins in all directions as well as potential nodal involvement. Secondary planning target volume (PTV2) included the GTV with 1- to 1.5-cm margins on all sides including proven nodal involvement. Tertiary planning treatment volume (PTV3) included the area of the GTV adjacent to the vascular structures specifically the mesenteric and portal vessels with a 0.5-cm margin. The prescription dose delivered to PTV3 was 54 Gy in 28 fractions. Synchronously, PTV1 and PTV2 received 45 and 50.4 Gy, respectively. All fields were treated daily at five fractions per week.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
''One month following therapy, patients were restaged with CT scan of chest/abdomen/pelvis. Patients deemed to be candidates for surgical resection were offered laparotomy ∼6 to 10 weeks after completion of neoadjuvant therapy.''<br />
<br />
===References===<br />
# Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, Tsongalis GJ, Colacchio TA, Gordon SR, Sutton JE, Srivastava A, Smith KD, Gardner TB, Korc M, Davis TH, Preis M, Tarczewski SM, Mackenzie TA, Barth RJ Jr. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. 2012 Nov;23(11):2820-7. Epub 2012 May 9. [http://annonc.oxfordjournals.org/content/23/11/2820.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571859 PubMed]<br />
<br />
==mFOLFIRINOX, Gemcitabine, RT {{#subobject:b71003|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFIRINOX, Gemcitabine, RT: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin, Gemcitabine, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:d87ec0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ Blazer et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion for 46 h on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once on day 1<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 4<br />
<br />
'''14-day cycle for 4 to 8 cycles'''<br />
<br />
''Followed by complete restaging. If tumor localized but still not resectable, chemoradiotherapy was administered:''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup>/week concurrent with radiation<br />
*Radiation was 36 Gy in 15 daily fractions<br />
<br />
===Variant #2 {{#subobject:7bb0e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ Hosein et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion for 46 hours on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles. Protocol followed "per ACCORD-11 trial." Filgrastim was given at the discretion of the treating physician.'''<br />
<br />
''Treatment stopped at maximum response or tolerability. Resectable patients by imaging criteria were offered surgery, followed by postoperative chemoradiotherapy. Unresectable patients were offered chemoradiotherapy, followed by surgery (if they became resectable):''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup>/week<br />
*Radiation at 50.4 Gy in 28 fractions.<br />
<br />
===References===<br />
# '''Retrospective:''' Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, Narayanan G, Ribeiro A, Portelance L, Merchan JR, Levi JU, Rocha-Lima CM. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012 May 29;12:199. [http://www.biomedcentral.com/1471-2407/12/199 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22642850 PubMed]<br />
# '''Retrospective:''' Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, Wuthrick E, Williams TM, Reardon J, Christopher Ellison E, Bloomston M, Bekaii-Saab T. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015 Apr;22(4):1153-9. [http://link.springer.com/article/10.1245%2Fs10434-014-4225-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25358667 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, unresectable=<br />
<br />
==Capecitabine monotherapy {{#subobject:dbd841|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dc4779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:6d97a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, Gem 3 out of 4 weeks x 4 {{#subobject:87edde|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Erlotinib & Gemcitabine x 2 more cycles (6 total) versus Capecitabine, Erlotinib, RT<br />
<br />
===Variant #2, Gem 3 out of 4 weeks x 6 {{#subobject:5a5e14|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
''Note: it is not clear from the protocol whether erlotinib is continued beyond the end of chemotherapy.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] as follows:<br />
**Cycles 1 to 4: 100 mg PO once per day<br />
**Cycles 5 & 6: 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:b4258e|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #4, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:b7a41f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''GERCOR LAP07:''' Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Fluorouracil & RT {{#subobject:26f1c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:29784e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ Herman et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Fluorouracil & RT with TNFerade<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion once per day on radiation days (total dose per week: 1000 mg/m<sup>2</sup>)<br />
*Concurrent radiation therapy, 50.4 Gy total: 1.80 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy, followed by 1.80 Gy x 3 fractions boost to the tumor bed.<br />
<br />
'''One course'''<br />
====Subsequent treatment until progression or toxicity (starting four weeks after chemoradiotherapy)====<br />
*Gemcitabine or Erlotinib & Gemcitabine maintenance<br />
<br />
===References===<br />
# Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, Donehower RC, Pawlik TM, Ziegler MA, Cai H, Savage DT, Canto MI, Klapman J, Reid T, Shah RJ, Hoffe SE, Rosemurgy A, Wolfgang CL, Laheru DA. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013 Mar 1;31(7):886-94. Epub 2013 Jan 22. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.7516 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23341531 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:4f0be9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 3 out of 4 weeks x 4 {{#subobject:c511a7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Gemcitabine x 2 more cycles (6 total) versus Capecitabine & RT<br />
<br />
===Variant #2, 3 out of 4 weeks x 6 {{#subobject:cf89f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in {{#subobject:82f8b2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#GemOx|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_.26_RT_2|Gemcitabine & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent 4-week cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''Continued for at least 3 months'''<br />
<br />
''Per '''Louvet et al. 2005''', subsequent chemoradiotherapy'' ''(45 Gy in 25 fractions for 5 weeks, associated with a daily FU 250 mg/m2 continuous infusion, and a boost of 10 Gy in 8 fractions restricted to the initial tumor volume)'' ''was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:a6e6fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 (600 mg/m<sup>2</sup>) {{#subobject:a6de29|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract Cardenes et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV over 30 to 60 minutes once per week during radiation<br />
*Concurrent radiation therapy, 1.8 Gy per fraction, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks.<br />
<br />
'''One course, followed in 4 weeks by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycle for 5 cycles or until disease progression'''<br />
<br />
===Variant #2 (400 mg/m<sup>2</sup>) {{#subobject:c1ac3c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract Epelbaum et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week for 7 weeks<br />
<br />
'''Radiation planning during this phase, followed by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 400 mg/m<sup>2</sup> IV over 30 minutes once per week (days 1, 8, 15)<br />
*Concurrent radiation therapy, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks<br />
<br />
'''28 day cycle for 2 cycles (completion of radiation), followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycles until disease progression'''<br />
<br />
===References===<br />
# Epelbaum R, Rosenblatt E, Nasrallah S, Faraggi D, Gaitini D, Mizrahi S, Kuten A. Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J Surg Oncol. 2002 Nov;81(3):138-43. [https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12407726 PubMed]<br />
# Cardenes HR, Moore AM, Johnson CS, Yu M, Helft P, Chiorean EG, Vinson J, Howard TJ, Stephens AW, Tai DF, Loehrer PJ Sr. A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study. Am J Clin Oncol. 2011 Oct;34(5):460-5.[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20881474 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
<br />
==GemOx {{#subobject:19d87f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:5a25e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_2|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycle for at least 3 months'''<br />
<br />
''Subsequent chemoradiotherapy was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
<br />
=Metastatic disease, first-line=<br />
<br />
==Capecitabine monotherapy {{#subobject:4f5f03|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b31bbb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Capecitabine & Gemcitabine {{#subobject:2f0431|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Variant #1 {{#subobject:fcd708|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Note: this is essentially identical to the maintenance phase of Cunningham et al. 2009, below.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:e8f0bf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21, 29 to 49<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:a7e551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 650 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 24 weeks'''<br />
<br />
===References===<br />
# Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:c30d8f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, weekly dosing {{#subobject:20a0f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note that cisplatin is not given on day 22 of the first 8 weeks; otherwise, the schedule is identical to the schedule for gemcitabine.''<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] as follows, '''given 60 minutes prior to gemcitabine''':<br />
**First 8 weeks: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Subsequent cycles: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, bi-weekly dosing {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract Cascinu et al. 2008 (GISCAD)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Cisplatin, Gemcitabine, Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 Jan;9(1):39-44. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18077217 PubMed]<br />
# Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:bf797a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, no gemcitabine lead-in {{#subobject:43fe43|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext Kordes et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Erlotinib, Gemcitabine, Metformin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:fc43f2|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:d49fb0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47. Epub 2015 Jun 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext link to original article]'''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26067687 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:c6c509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:3ca01f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Inferior to gemcitabine. Here for historical reference purposes, only.''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
<br />
==FOLFIRINOX {{#subobject:aaa3c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e140cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior QoL by [http://groups.eortc.be/qol/eortc-qlq-c30 EORTC QLQ-C30]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 1200 mg/m<sup>2</sup>/day IV continuous 46-hour infusion on days 1 to 2; '''given last''' (total dose per cycle: 2400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1; '''given third together with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:3a0f4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 8-week lead-in {{#subobject:5d6dd0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx_2|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract Reni et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PEFG<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|GEM FDR<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GEM-CAP]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ Philip et al. 2010 (SWOG S0205)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_nab-Paclitaxel|Gemcitabine & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext Middleton et al. 2017 (ViP)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Vandetanib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
***In Burris et al. 1997, patients with grade 2 or lower toxicities could have had doses increased to 1250 mg/m<sup>2</sup><br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 4 week cycles {{#subobject:c6349|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract Kindler et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ Fuchs et al. 2015 (GAMMA)]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & [[Ganitumab (AMG 479)|Ganitumab]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ Catenacci et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & Vismodegib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 3 week cycles {{#subobject:8bae67|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 Hong et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|Gemcitabine & Simvastatin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, fixed-dose rate (FDR) {{#subobject:5114cc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 150 minutes (10 mg/m<sup>2</sup>/min) once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15925814 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
# '''SWOG S0205:''' Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 1;28(22):3605-10. Epub 2010 Jul 6. [http://jco.ascopubs.org/content/28/22/3605.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20606093 PubMed]<br />
# Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306953 PubMed]<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
# Hong JY, Nam EM, Lee J, Park JO, Lee SC, Song SY, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol. 2014 Jan;73(1):125-30. Epub 2013 Oct 27. [https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24162380 PubMed]<br />
# '''GAMMA:''' Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921-7. Epub 2015 Jan 21. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25609246 PubMed]<br />
# Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D, Wade J, Sleckman B, Lenz HJ, Stiff P, Kumar P, Xu P, Henderson L, Takebe N, Salgia R, Wang X, Stadler WM, de Sauvage FJ, Kindler HL. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015 Dec 20;33(36):4284-92. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/36/4284.long link to original article] '''contains protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527777 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
# '''ViP:''' Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr;18(4):486-499. Epub 2017 Mar 2. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28259610 PubMed]<br />
<br />
==GemOx {{#subobject:520af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:9d3266|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine, FDR]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
<br />
==Gemcitabine & nab-Paclitaxel {{#subobject:fbd698|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:63ba04|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] as follows, '''given first''':<br />
**Cycle 1: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15<br />
<br />
'''8-week cycle followed by 28-day cycles until disease progression or intolerance'''<br />
<br />
===Variant #2 {{#subobject:ecc1c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ Von Hoff et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 or 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/34/4548.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969517 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
<br />
==GTX {{#subobject:f0d62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
GTX: '''<u>G</u>'''emcitabine, '''<u>T</u>'''axotere (Docetaxel), '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:fc0e50|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.springerlink.com/content/75m422843l3461m0/ Fine et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: De Jesus-Acosta et al. 2012 lists the capecitabine dose as "750 mg/m<sup>2</sup>/day orally divided into two doses," but this is believed to be a typographical error since the original reference that it cites, Fine et al. 2007, uses capecitabine at 750 mg/m<sup>2</sup> PO BID. The 2009 ASCO abstract by Fine also lists this 750 mg/m<sup>2</sup> PO BID (1500 mg/m<sup>2</sup>/day) dose.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 75 minutes once per day on days 4 & 11<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 11<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75. Epub 2007 Apr 18. [http://www.springerlink.com/content/75m422843l3461m0/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17440727 PubMed]<br />
# '''Abstract:''' R. L. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. 2009 ASCO Annual Meeting abstract 4623. [http://ascopubs.org/doi/full/10.1200/jco.2009.27.15s.4623 link to abstract] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012 Feb;69(2):415-24. Epub 2011 Jul 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723 link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21800112 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:759f1a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:94d490|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<br />
=Metastatic disease, refractory=<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#OFF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Best supportive care. Placed here because one or more randomized clinical trials included a best supportive care arm in this disease context.''<br />
<br />
===References===<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<br />
==Capecitabine & Erlotinib {{#subobject:4655b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d5c799|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4787.full Kulke et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> (rounded to the nearest 150 mg tablet) PO BID on days 1 to 14<br />
*[[Erlotinib (Tarceva)]] 150 mg PO on days 1 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak EL, Muzikansky A, Lawrence C, Fuchs CS. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007 Oct 20;25(30):4787-92. [http://jco.ascopubs.org/content/25/30/4787.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947726 PubMed]<br />
<br />
==CapeOx {{#subobject:d09d5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:57ad5f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full Xiong et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 1000 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 110 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008 Oct 15;113(8):2046-52. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18756532 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, nanoliposomal Irinotecan {{#subobject:72308d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a81310|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''started on day 1 after folinic acid'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given prior to fluorouracil'''<br />
*[[Irinotecan liposome (Onivyde)]] 70 mg/m<sup>2</sup> (irinotecan free base) IV over 90 minutes once on day 1, '''given first'''<br />
**Per Wang-Gillam et al. 2015 (NAPOLI-01), 70 mg/m<sup>2</sup> irinotecan free base is equivalent to 80 mg/m<sup>2</sup> nanoliposomal irinotecan. According to the trial's ClinicalTrials.gov page: "The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m<sup>2</sup> dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/ m2 of irinotecan free base."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
<br />
==FOLFIRI {{#subobject:6fd426|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br />
===Variant #1 {{#subobject:6a9cae|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 Zaniboni et al. 2012 (GISCAD)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, and 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, modified FOLFIRI.3 {{#subobject:4758e8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFOX|mFOLFOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Irinotecan (Camptosar)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 3<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
# Zaniboni A, Aitini E, Barni S, Ferrari D, Cascinu S, Catalano V, Valmadre G, Ferrara D, Veltri E, Codignola C, Labianca R. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jun;69(6):1641-5. Epub 2012 May 11. [http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22576338 PubMed]<br />
<br />
==FOLFOX {{#subobject:377e80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:33ef68|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFIRI|mFOLFIRI.3]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
<br />
==OFF {{#subobject:8b32c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OFF: '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil, '''<u>F</u>'''olinic acid <br />
===Regimen {{#subobject:ae57d5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
<br />
''Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m<sup>2</sup>," or 850 mg/m<sup>2</sup>.''<br />
====Chemotherapy====<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once per day on days 8 & 22, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous 24-hour infusion on days 1, 8, 15, 22, '''started after folinic acid bolus'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, '''given prior to fluorouracil'''<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
# Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
<br />
==Olaparib monotherapy {{#subobject:0c2eb3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:21eb78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/3/244.long Kaufman et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients had germline BRCA1/2 mutations and had previously received gemcitabine.''<br />
====Chemotherapy====<br />
*[[Olaparib (Lynparza)]] 400 mg PO BID<br />
<br />
'''Continued until progression'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
# Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/33/3/244.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed]<br />
<br />
==Paclitaxel, nanoparticle albumin-bound monotherapy {{#subobject:ab9fc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8d38d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract Hosein et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Hosein PJ, de Lima Lopes G Jr, Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013 Apr;36(2):151-6. Epub 2012 Feb 2. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22307213 PubMed]<br />
<br />
[[Category:Pancreatic cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdheryhttps://hemonc.org/w/index.php?title=Pancreatic_cancer&diff=27243Pancreatic cancer2018-06-07T16:12:11Z<p>Rozinachowdhery: /* Fluorouracil & RT */</p>
<hr />
<div><!--'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]]. If this is your first time visiting, we suggest you read the [[tutorial]].'''--><br />
<!--Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are [[How_to_contribute|invited to contribute to the site]].-->{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>Chicago, IL</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2017:''' [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.4948 Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/28398845 PubMed]<br />
*'''2016:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019760/ Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2016:''' [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.5561 Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/27247216 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2015:''' [http://annonc.oxfordjournals.org/content/26/suppl_5/v56.full.pdf+html Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015)] [https://www.ncbi.nlm.nih.gov/pubmed/26314780 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf NCCN Guidelines - Pancreatic Adenocarcinoma]<br />
<br />
=Adjuvant therapy=<br />
==Capecitabine & Gemcitabine {{#subobject:17f9f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Regimen {{#subobject:e6a3e3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Treatment starts within 12 weeks of surgery.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week on weeks 1 to 3<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# '''ESPAC-4:''' Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:29266e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:242770|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
<br />
==Fluorouracil, then Fluorouracil & RT {{#subobject:331d4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:89426a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br> [[#Observation|Observation]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine.2C_then_Fluorouracil_.26_RT.2C_then_Gemcitabine|Gemcitabine, then Fluorouracil & RT, then Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 21<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 28<br />
<br />
'''6-week cycle for 2 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:34e70d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a756a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|Fluorouracil & Leucovorin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine|Capecitabine & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
<br />
''Note: efficacy for CONKO-001 is based on the 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
# Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Gemcitabine, then Fluorouracil & RT, then Gemcitabine {{#subobject:f8c8d9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:3fef3f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|Fluorouracil & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Efficacy for ESPAC-1 is based on the 2004 update and efficacy for CONKO-001 is based on 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cdcc15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, potentially resectable=<br />
<br />
==Docetaxel, Gemcitabine, RT {{#subobject:49a407|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:78b0ba|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1245%2FASO.2005.04.503 Pipas et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 65 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Gemcitabine (Gemzar)]] 4000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29<br />
<br />
'''6-week course, followed immediately (day 43) by:'''<br />
<br />
====Chemoradiation====<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy to primary target volume. Then 5.4 Gy boost to secondary target volume of 1- to 1.5-cm margin on all sides, including proven nodal involvement. Total 50.4 Gy in 28 fractions.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
# Pipas JM, Barth RJ Jr, Zaki B, Tsapakos MJ, Suriawinata AA, Bettmann MA, Cates JM, Ripple GH, Sutton JE, Gordon SR, McDonnell CE, Perez RP, Redfield N, Meyer LP, Marshall JF, Cole BF, Colacchio TA. Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2005 Dec;12(12):995-1004. Epub 2005 Nov 1. [http://link.springer.com/article/10.1245%2FASO.2005.04.503 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16252135 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:55e32d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen 1 {{#subobject:6ce551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract Takahashi et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*Concurrent radiation therapy, 2 Gy per fraction, 5 days per week, 25 fractions, total dose of 50 Gy over 5 weeks.<br />
<br />
'''28-day cycle for 3 cycles''' ''(Radiation given over weeks 1-5 only)''<br />
<br />
''Restaging is performed 8 weeks after radiation complete (2 weeks after chemotherapy complete). Resection immediately thereafter, if feasible.''<br />
<br />
===Regimen 2 {{#subobject:dc32dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 500 mg/m<sup>2</sup> IV over 50 minutes once per week for 6 weeks<br />
*Concurrent radiation therapy, 180 cGy x 22 with 3 cm margin to GTV then 180 cGy x 6 with 2 cm margin to GTV, total 50.4 Gy over 6 weeks<br />
<br />
''Restaging after radiation complete. 4 to 6 week break, followed by surgery, followed by 4 to 8 week break. Then adjuvant chemotherapy:''<br />
<br />
====Adjuvant chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 5 cycles'''<br />
<br />
===References===<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [https://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, Ioka T, Uehara H, Yano M, Ishikawa O. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013 Dec;258(6):1040-50.[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23799421 PubMed]<br />
<br />
==Gemcitabine, Cetuximab, RT {{#subobject:aea7b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c38534|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ Pipas et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**6 to 8 days prior radiation: 400 mg/m<sup>2</sup> IV over 2 hours once<br />
**During radiation: 250 mg/m<sup>2</sup> over 60 minutes once per week for 6 doses<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, delivered using IMRT. Gross tumor volume (GTV) was all known disease including imaging proven nodal disease. The primary planning target volume (PTV1) included the GTV with 2- to 3-cm margins in all directions as well as potential nodal involvement. Secondary planning target volume (PTV2) included the GTV with 1- to 1.5-cm margins on all sides including proven nodal involvement. Tertiary planning treatment volume (PTV3) included the area of the GTV adjacent to the vascular structures specifically the mesenteric and portal vessels with a 0.5-cm margin. The prescription dose delivered to PTV3 was 54 Gy in 28 fractions. Synchronously, PTV1 and PTV2 received 45 and 50.4 Gy, respectively. All fields were treated daily at five fractions per week.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
''One month following therapy, patients were restaged with CT scan of chest/abdomen/pelvis. Patients deemed to be candidates for surgical resection were offered laparotomy ∼6 to 10 weeks after completion of neoadjuvant therapy.''<br />
<br />
===References===<br />
# Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, Tsongalis GJ, Colacchio TA, Gordon SR, Sutton JE, Srivastava A, Smith KD, Gardner TB, Korc M, Davis TH, Preis M, Tarczewski SM, Mackenzie TA, Barth RJ Jr. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. 2012 Nov;23(11):2820-7. Epub 2012 May 9. [http://annonc.oxfordjournals.org/content/23/11/2820.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571859 PubMed]<br />
<br />
==mFOLFIRINOX, Gemcitabine, RT {{#subobject:b71003|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFIRINOX, Gemcitabine, RT: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin, Gemcitabine, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:d87ec0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ Blazer et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion for 46 h on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once on day 1<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 4<br />
<br />
'''14-day cycle for 4 to 8 cycles'''<br />
<br />
''Followed by complete restaging. If tumor localized but still not resectable, chemoradiotherapy was administered:''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup>/week concurrent with radiation<br />
*Radiation was 36 Gy in 15 daily fractions<br />
<br />
===Variant #2 {{#subobject:7bb0e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ Hosein et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion for 46 hours on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles. Protocol followed "per ACCORD-11 trial." Filgrastim was given at the discretion of the treating physician.'''<br />
<br />
''Treatment stopped at maximum response or tolerability. Resectable patients by imaging criteria were offered surgery, followed by postoperative chemoradiotherapy. Unresectable patients were offered chemoradiotherapy, followed by surgery (if they became resectable):''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup>/week<br />
*Radiation at 50.4 Gy in 28 fractions.<br />
<br />
===References===<br />
# '''Retrospective:''' Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, Narayanan G, Ribeiro A, Portelance L, Merchan JR, Levi JU, Rocha-Lima CM. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012 May 29;12:199. [http://www.biomedcentral.com/1471-2407/12/199 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22642850 PubMed]<br />
# '''Retrospective:''' Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, Wuthrick E, Williams TM, Reardon J, Christopher Ellison E, Bloomston M, Bekaii-Saab T. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015 Apr;22(4):1153-9. [http://link.springer.com/article/10.1245%2Fs10434-014-4225-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25358667 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, unresectable=<br />
<br />
==Capecitabine monotherapy {{#subobject:dbd841|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dc4779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:6d97a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, Gem 3 out of 4 weeks x 4 {{#subobject:87edde|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Erlotinib & Gemcitabine x 2 more cycles (6 total) versus Capecitabine, Erlotinib, RT<br />
<br />
===Variant #2, Gem 3 out of 4 weeks x 6 {{#subobject:5a5e14|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
''Note: it is not clear from the protocol whether erlotinib is continued beyond the end of chemotherapy.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] as follows:<br />
**Cycles 1 to 4: 100 mg PO once per day<br />
**Cycles 5 & 6: 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:b4258e|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #4, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:b7a41f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''GERCOR LAP07:''' Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Fluorouracil & RT {{#subobject:26f1c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:29784e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ Herman et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Fluorouracil & RT with TNFerade<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion once per day on radiation days (total dose per week: 1000 mg/m<sup>2</sup>)<br />
*Concurrent radiation therapy, 50.4 Gy total: 1.80 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy, followed by 1.80 Gy x 3 fractions boost to the tumor bed.<br />
<br />
'''One course'''<br />
====Subsequent treatment until progression or toxicity (starting four weeks after chemoradiotherapy)====<br />
*Gemcitabine or Erlotinib & Gemcitabine maintenance<br />
<br />
===References===<br />
# Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, Donehower RC, Pawlik TM, Ziegler MA, Cai H, Savage DT, Canto MI, Klapman J, Reid T, Shah RJ, Hoffe SE, Rosemurgy A, Wolfgang CL, Laheru DA. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013 Mar 1;31(7):886-94. Epub 2013 Jan 22. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.7516 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23341531 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:4f0be9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 3 out of 4 weeks x 4 {{#subobject:c511a7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Gemcitabine x 2 more cycles (6 total) versus Capecitabine & RT<br />
<br />
===Variant #2, 3 out of 4 weeks x 6 {{#subobject:cf89f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in {{#subobject:82f8b2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#GemOx|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_.26_RT_2|Gemcitabine & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent 4-week cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''Continued for at least 3 months'''<br />
<br />
''Per '''Louvet et al. 2005''', subsequent chemoradiotherapy was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:a6e6fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 (600 mg/m<sup>2</sup>) {{#subobject:a6de29|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract Cardenes et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV over 30 to 60 minutes once per week during radiation<br />
*Concurrent radiation therapy, 1.8 Gy per fraction, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks.<br />
<br />
'''One course, followed in 4 weeks by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycle for 5 cycles or until disease progression'''<br />
<br />
===Variant #2 (400 mg/m<sup>2</sup>) {{#subobject:c1ac3c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract Epelbaum et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week for 7 weeks<br />
<br />
'''Radiation planning during this phase, followed by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 400 mg/m<sup>2</sup> IV over 30 minutes once per week (days 1, 8, 15)<br />
*Concurrent radiation therapy, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks<br />
<br />
'''28 day cycle for 2 cycles (completion of radiation), followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycles until disease progression'''<br />
<br />
===References===<br />
# Epelbaum R, Rosenblatt E, Nasrallah S, Faraggi D, Gaitini D, Mizrahi S, Kuten A. Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J Surg Oncol. 2002 Nov;81(3):138-43. [https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12407726 PubMed]<br />
# Cardenes HR, Moore AM, Johnson CS, Yu M, Helft P, Chiorean EG, Vinson J, Howard TJ, Stephens AW, Tai DF, Loehrer PJ Sr. A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study. Am J Clin Oncol. 2011 Oct;34(5):460-5.[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20881474 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
<br />
==GemOx {{#subobject:19d87f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:5a25e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_2|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycle for at least 3 months'''<br />
<br />
''Subsequent chemoradiotherapy was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
<br />
=Metastatic disease, first-line=<br />
<br />
==Capecitabine monotherapy {{#subobject:4f5f03|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b31bbb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Capecitabine & Gemcitabine {{#subobject:2f0431|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Variant #1 {{#subobject:fcd708|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Note: this is essentially identical to the maintenance phase of Cunningham et al. 2009, below.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:e8f0bf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21, 29 to 49<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:a7e551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 650 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 24 weeks'''<br />
<br />
===References===<br />
# Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:c30d8f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, weekly dosing {{#subobject:20a0f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note that cisplatin is not given on day 22 of the first 8 weeks; otherwise, the schedule is identical to the schedule for gemcitabine.''<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] as follows, '''given 60 minutes prior to gemcitabine''':<br />
**First 8 weeks: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Subsequent cycles: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, bi-weekly dosing {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract Cascinu et al. 2008 (GISCAD)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Cisplatin, Gemcitabine, Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 Jan;9(1):39-44. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18077217 PubMed]<br />
# Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:bf797a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, no gemcitabine lead-in {{#subobject:43fe43|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext Kordes et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Erlotinib, Gemcitabine, Metformin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:fc43f2|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:d49fb0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47. Epub 2015 Jun 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext link to original article]'''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26067687 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:c6c509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:3ca01f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Inferior to gemcitabine. Here for historical reference purposes, only.''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
<br />
==FOLFIRINOX {{#subobject:aaa3c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e140cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior QoL by [http://groups.eortc.be/qol/eortc-qlq-c30 EORTC QLQ-C30]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 1200 mg/m<sup>2</sup>/day IV continuous 46-hour infusion on days 1 to 2; '''given last''' (total dose per cycle: 2400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1; '''given third together with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:3a0f4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 8-week lead-in {{#subobject:5d6dd0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx_2|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract Reni et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PEFG<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|GEM FDR<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GEM-CAP]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ Philip et al. 2010 (SWOG S0205)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_nab-Paclitaxel|Gemcitabine & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext Middleton et al. 2017 (ViP)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Vandetanib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
***In Burris et al. 1997, patients with grade 2 or lower toxicities could have had doses increased to 1250 mg/m<sup>2</sup><br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 4 week cycles {{#subobject:c6349|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract Kindler et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ Fuchs et al. 2015 (GAMMA)]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & [[Ganitumab (AMG 479)|Ganitumab]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ Catenacci et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & Vismodegib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 3 week cycles {{#subobject:8bae67|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 Hong et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|Gemcitabine & Simvastatin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, fixed-dose rate (FDR) {{#subobject:5114cc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 150 minutes (10 mg/m<sup>2</sup>/min) once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15925814 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
# '''SWOG S0205:''' Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 1;28(22):3605-10. Epub 2010 Jul 6. [http://jco.ascopubs.org/content/28/22/3605.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20606093 PubMed]<br />
# Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306953 PubMed]<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
# Hong JY, Nam EM, Lee J, Park JO, Lee SC, Song SY, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol. 2014 Jan;73(1):125-30. Epub 2013 Oct 27. [https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24162380 PubMed]<br />
# '''GAMMA:''' Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921-7. Epub 2015 Jan 21. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25609246 PubMed]<br />
# Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D, Wade J, Sleckman B, Lenz HJ, Stiff P, Kumar P, Xu P, Henderson L, Takebe N, Salgia R, Wang X, Stadler WM, de Sauvage FJ, Kindler HL. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015 Dec 20;33(36):4284-92. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/36/4284.long link to original article] '''contains protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527777 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
# '''ViP:''' Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr;18(4):486-499. Epub 2017 Mar 2. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28259610 PubMed]<br />
<br />
==GemOx {{#subobject:520af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:9d3266|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine, FDR]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
<br />
==Gemcitabine & nab-Paclitaxel {{#subobject:fbd698|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:63ba04|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] as follows, '''given first''':<br />
**Cycle 1: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15<br />
<br />
'''8-week cycle followed by 28-day cycles until disease progression or intolerance'''<br />
<br />
===Variant #2 {{#subobject:ecc1c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ Von Hoff et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 or 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/34/4548.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969517 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
<br />
==GTX {{#subobject:f0d62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
GTX: '''<u>G</u>'''emcitabine, '''<u>T</u>'''axotere (Docetaxel), '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:fc0e50|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.springerlink.com/content/75m422843l3461m0/ Fine et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: De Jesus-Acosta et al. 2012 lists the capecitabine dose as "750 mg/m<sup>2</sup>/day orally divided into two doses," but this is believed to be a typographical error since the original reference that it cites, Fine et al. 2007, uses capecitabine at 750 mg/m<sup>2</sup> PO BID. The 2009 ASCO abstract by Fine also lists this 750 mg/m<sup>2</sup> PO BID (1500 mg/m<sup>2</sup>/day) dose.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 75 minutes once per day on days 4 & 11<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 11<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75. Epub 2007 Apr 18. [http://www.springerlink.com/content/75m422843l3461m0/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17440727 PubMed]<br />
# '''Abstract:''' R. L. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. 2009 ASCO Annual Meeting abstract 4623. [http://ascopubs.org/doi/full/10.1200/jco.2009.27.15s.4623 link to abstract] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012 Feb;69(2):415-24. Epub 2011 Jul 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723 link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21800112 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:759f1a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:94d490|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<br />
=Metastatic disease, refractory=<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#OFF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Best supportive care. Placed here because one or more randomized clinical trials included a best supportive care arm in this disease context.''<br />
<br />
===References===<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<br />
==Capecitabine & Erlotinib {{#subobject:4655b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d5c799|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4787.full Kulke et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> (rounded to the nearest 150 mg tablet) PO BID on days 1 to 14<br />
*[[Erlotinib (Tarceva)]] 150 mg PO on days 1 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak EL, Muzikansky A, Lawrence C, Fuchs CS. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007 Oct 20;25(30):4787-92. [http://jco.ascopubs.org/content/25/30/4787.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947726 PubMed]<br />
<br />
==CapeOx {{#subobject:d09d5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:57ad5f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full Xiong et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 1000 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 110 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008 Oct 15;113(8):2046-52. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18756532 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, nanoliposomal Irinotecan {{#subobject:72308d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a81310|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''started on day 1 after folinic acid'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given prior to fluorouracil'''<br />
*[[Irinotecan liposome (Onivyde)]] 70 mg/m<sup>2</sup> (irinotecan free base) IV over 90 minutes once on day 1, '''given first'''<br />
**Per Wang-Gillam et al. 2015 (NAPOLI-01), 70 mg/m<sup>2</sup> irinotecan free base is equivalent to 80 mg/m<sup>2</sup> nanoliposomal irinotecan. According to the trial's ClinicalTrials.gov page: "The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m<sup>2</sup> dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/ m2 of irinotecan free base."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
<br />
==FOLFIRI {{#subobject:6fd426|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br />
===Variant #1 {{#subobject:6a9cae|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 Zaniboni et al. 2012 (GISCAD)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, and 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, modified FOLFIRI.3 {{#subobject:4758e8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFOX|mFOLFOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Irinotecan (Camptosar)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 3<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
# Zaniboni A, Aitini E, Barni S, Ferrari D, Cascinu S, Catalano V, Valmadre G, Ferrara D, Veltri E, Codignola C, Labianca R. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jun;69(6):1641-5. Epub 2012 May 11. [http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22576338 PubMed]<br />
<br />
==FOLFOX {{#subobject:377e80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:33ef68|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFIRI|mFOLFIRI.3]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
<br />
==OFF {{#subobject:8b32c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OFF: '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil, '''<u>F</u>'''olinic acid <br />
===Regimen {{#subobject:ae57d5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
<br />
''Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m<sup>2</sup>," or 850 mg/m<sup>2</sup>.''<br />
====Chemotherapy====<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once per day on days 8 & 22, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous 24-hour infusion on days 1, 8, 15, 22, '''started after folinic acid bolus'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, '''given prior to fluorouracil'''<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
# Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
<br />
==Olaparib monotherapy {{#subobject:0c2eb3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:21eb78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/3/244.long Kaufman et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients had germline BRCA1/2 mutations and had previously received gemcitabine.''<br />
====Chemotherapy====<br />
*[[Olaparib (Lynparza)]] 400 mg PO BID<br />
<br />
'''Continued until progression'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
# Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/33/3/244.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed]<br />
<br />
==Paclitaxel, nanoparticle albumin-bound monotherapy {{#subobject:ab9fc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8d38d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract Hosein et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Hosein PJ, de Lima Lopes G Jr, Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013 Apr;36(2):151-6. Epub 2012 Feb 2. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22307213 PubMed]<br />
<br />
[[Category:Pancreatic cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdheryhttps://hemonc.org/w/index.php?title=Pancreatic_cancer&diff=27242Pancreatic cancer2018-06-07T15:47:16Z<p>Rozinachowdhery: /* Chemotherapy, mFOLFIRINOX portion */</p>
<hr />
<div><!--'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]]. If this is your first time visiting, we suggest you read the [[tutorial]].'''--><br />
<!--Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are [[How_to_contribute|invited to contribute to the site]].-->{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>Chicago, IL</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2017:''' [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.4948 Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/28398845 PubMed]<br />
*'''2016:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019760/ Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2016:''' [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.5561 Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/27247216 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2015:''' [http://annonc.oxfordjournals.org/content/26/suppl_5/v56.full.pdf+html Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015)] [https://www.ncbi.nlm.nih.gov/pubmed/26314780 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf NCCN Guidelines - Pancreatic Adenocarcinoma]<br />
<br />
=Adjuvant therapy=<br />
==Capecitabine & Gemcitabine {{#subobject:17f9f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Regimen {{#subobject:e6a3e3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Treatment starts within 12 weeks of surgery.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week on weeks 1 to 3<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# '''ESPAC-4:''' Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:29266e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:242770|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
<br />
==Fluorouracil, then Fluorouracil & RT {{#subobject:331d4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:89426a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br> [[#Observation|Observation]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine.2C_then_Fluorouracil_.26_RT.2C_then_Gemcitabine|Gemcitabine, then Fluorouracil & RT, then Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 21<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 28<br />
<br />
'''6-week cycle for 2 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:34e70d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a756a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|Fluorouracil & Leucovorin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine|Capecitabine & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
<br />
''Note: efficacy for CONKO-001 is based on the 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
# Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Gemcitabine, then Fluorouracil & RT, then Gemcitabine {{#subobject:f8c8d9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:3fef3f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|Fluorouracil & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Efficacy for ESPAC-1 is based on the 2004 update and efficacy for CONKO-001 is based on 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cdcc15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, potentially resectable=<br />
<br />
==Docetaxel, Gemcitabine, RT {{#subobject:49a407|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:78b0ba|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1245%2FASO.2005.04.503 Pipas et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 65 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Gemcitabine (Gemzar)]] 4000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29<br />
<br />
'''6-week course, followed immediately (day 43) by:'''<br />
<br />
====Chemoradiation====<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy to primary target volume. Then 5.4 Gy boost to secondary target volume of 1- to 1.5-cm margin on all sides, including proven nodal involvement. Total 50.4 Gy in 28 fractions.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
# Pipas JM, Barth RJ Jr, Zaki B, Tsapakos MJ, Suriawinata AA, Bettmann MA, Cates JM, Ripple GH, Sutton JE, Gordon SR, McDonnell CE, Perez RP, Redfield N, Meyer LP, Marshall JF, Cole BF, Colacchio TA. Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2005 Dec;12(12):995-1004. Epub 2005 Nov 1. [http://link.springer.com/article/10.1245%2FASO.2005.04.503 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16252135 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:55e32d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen 1 {{#subobject:6ce551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract Takahashi et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*Concurrent radiation therapy, 2 Gy per fraction, 5 days per week, 25 fractions, total dose of 50 Gy over 5 weeks.<br />
<br />
'''28-day cycle for 3 cycles''' ''(Radiation given over weeks 1-5 only)''<br />
<br />
''Restaging is performed 8 weeks after radiation complete (2 weeks after chemotherapy complete). Resection immediately thereafter, if feasible.''<br />
<br />
===Regimen 2 {{#subobject:dc32dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 500 mg/m<sup>2</sup> IV over 50 minutes once per week for 6 weeks<br />
*Concurrent radiation therapy, 180 cGy x 22 with 3 cm margin to GTV then 180 cGy x 6 with 2 cm margin to GTV, total 50.4 Gy over 6 weeks<br />
<br />
''Restaging after radiation complete. 4 to 6 week break, followed by surgery, followed by 4 to 8 week break. Then adjuvant chemotherapy:''<br />
<br />
====Adjuvant chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 5 cycles'''<br />
<br />
===References===<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [https://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, Ioka T, Uehara H, Yano M, Ishikawa O. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013 Dec;258(6):1040-50.[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23799421 PubMed]<br />
<br />
==Gemcitabine, Cetuximab, RT {{#subobject:aea7b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c38534|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ Pipas et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**6 to 8 days prior radiation: 400 mg/m<sup>2</sup> IV over 2 hours once<br />
**During radiation: 250 mg/m<sup>2</sup> over 60 minutes once per week for 6 doses<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, delivered using IMRT. Gross tumor volume (GTV) was all known disease including imaging proven nodal disease. The primary planning target volume (PTV1) included the GTV with 2- to 3-cm margins in all directions as well as potential nodal involvement. Secondary planning target volume (PTV2) included the GTV with 1- to 1.5-cm margins on all sides including proven nodal involvement. Tertiary planning treatment volume (PTV3) included the area of the GTV adjacent to the vascular structures specifically the mesenteric and portal vessels with a 0.5-cm margin. The prescription dose delivered to PTV3 was 54 Gy in 28 fractions. Synchronously, PTV1 and PTV2 received 45 and 50.4 Gy, respectively. All fields were treated daily at five fractions per week.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
''One month following therapy, patients were restaged with CT scan of chest/abdomen/pelvis. Patients deemed to be candidates for surgical resection were offered laparotomy ∼6 to 10 weeks after completion of neoadjuvant therapy.''<br />
<br />
===References===<br />
# Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, Tsongalis GJ, Colacchio TA, Gordon SR, Sutton JE, Srivastava A, Smith KD, Gardner TB, Korc M, Davis TH, Preis M, Tarczewski SM, Mackenzie TA, Barth RJ Jr. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. 2012 Nov;23(11):2820-7. Epub 2012 May 9. [http://annonc.oxfordjournals.org/content/23/11/2820.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571859 PubMed]<br />
<br />
==mFOLFIRINOX, Gemcitabine, RT {{#subobject:b71003|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFIRINOX, Gemcitabine, RT: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin, Gemcitabine, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:d87ec0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ Blazer et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion for 46 h on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once on day 1<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 4<br />
<br />
'''14-day cycle for 4 to 8 cycles'''<br />
<br />
''Followed by complete restaging. If tumor localized but still not resectable, chemoradiotherapy was administered:''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup>/week concurrent with radiation<br />
*Radiation was 36 Gy in 15 daily fractions<br />
<br />
===Variant #2 {{#subobject:7bb0e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ Hosein et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion for 46 hours on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles. Protocol followed "per ACCORD-11 trial." Filgrastim was given at the discretion of the treating physician.'''<br />
<br />
''Treatment stopped at maximum response or tolerability. Resectable patients by imaging criteria were offered surgery, followed by postoperative chemoradiotherapy. Unresectable patients were offered chemoradiotherapy, followed by surgery (if they became resectable):''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup>/week<br />
*Radiation at 50.4 Gy in 28 fractions.<br />
<br />
===References===<br />
# '''Retrospective:''' Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, Narayanan G, Ribeiro A, Portelance L, Merchan JR, Levi JU, Rocha-Lima CM. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012 May 29;12:199. [http://www.biomedcentral.com/1471-2407/12/199 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22642850 PubMed]<br />
# '''Retrospective:''' Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, Wuthrick E, Williams TM, Reardon J, Christopher Ellison E, Bloomston M, Bekaii-Saab T. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015 Apr;22(4):1153-9. [http://link.springer.com/article/10.1245%2Fs10434-014-4225-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25358667 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, unresectable=<br />
<br />
==Capecitabine monotherapy {{#subobject:dbd841|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dc4779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:6d97a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, Gem 3 out of 4 weeks x 4 {{#subobject:87edde|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Erlotinib & Gemcitabine x 2 more cycles (6 total) versus Capecitabine, Erlotinib, RT<br />
<br />
===Variant #2, Gem 3 out of 4 weeks x 6 {{#subobject:5a5e14|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
''Note: it is not clear from the protocol whether erlotinib is continued beyond the end of chemotherapy.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] as follows:<br />
**Cycles 1 to 4: 100 mg PO once per day<br />
**Cycles 5 & 6: 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:b4258e|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #4, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:b7a41f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''GERCOR LAP07:''' Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Fluorouracil & RT {{#subobject:26f1c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:29784e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ Herman et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Fluorouracil & RT with TNFerade<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion once per day on radiation days (total dose per week: 1000 mg/m<sup>2</sup>)<br />
*Concurrent radiation therapy, 50.4 Gy total: 1.80 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy, followed by 1.80 Gy x 3 fractions boost to the tumor bed.<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
*Gemcitabine or Erlotinib & Gemcitabine maintenance<br />
<br />
===References===<br />
# Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, Donehower RC, Pawlik TM, Ziegler MA, Cai H, Savage DT, Canto MI, Klapman J, Reid T, Shah RJ, Hoffe SE, Rosemurgy A, Wolfgang CL, Laheru DA. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013 Mar 1;31(7):886-94. Epub 2013 Jan 22. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.7516 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23341531 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:4f0be9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 3 out of 4 weeks x 4 {{#subobject:c511a7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Gemcitabine x 2 more cycles (6 total) versus Capecitabine & RT<br />
<br />
===Variant #2, 3 out of 4 weeks x 6 {{#subobject:cf89f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in {{#subobject:82f8b2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#GemOx|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_.26_RT_2|Gemcitabine & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent 4-week cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''Continued for at least 3 months'''<br />
<br />
''Per '''Louvet et al. 2005''', subsequent chemoradiotherapy was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:a6e6fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 (600 mg/m<sup>2</sup>) {{#subobject:a6de29|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract Cardenes et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV over 30 to 60 minutes once per week during radiation<br />
*Concurrent radiation therapy, 1.8 Gy per fraction, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks.<br />
<br />
'''One course, followed in 4 weeks by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycle for 5 cycles or until disease progression'''<br />
<br />
===Variant #2 (400 mg/m<sup>2</sup>) {{#subobject:c1ac3c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract Epelbaum et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week for 7 weeks<br />
<br />
'''Radiation planning during this phase, followed by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 400 mg/m<sup>2</sup> IV over 30 minutes once per week (days 1, 8, 15)<br />
*Concurrent radiation therapy, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks<br />
<br />
'''28 day cycle for 2 cycles (completion of radiation), followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycles until disease progression'''<br />
<br />
===References===<br />
# Epelbaum R, Rosenblatt E, Nasrallah S, Faraggi D, Gaitini D, Mizrahi S, Kuten A. Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J Surg Oncol. 2002 Nov;81(3):138-43. [https://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12407726 PubMed]<br />
# Cardenes HR, Moore AM, Johnson CS, Yu M, Helft P, Chiorean EG, Vinson J, Howard TJ, Stephens AW, Tai DF, Loehrer PJ Sr. A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study. Am J Clin Oncol. 2011 Oct;34(5):460-5.[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20881474 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
<br />
==GemOx {{#subobject:19d87f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:5a25e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_2|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycle for at least 3 months'''<br />
<br />
''Subsequent chemoradiotherapy was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
<br />
=Metastatic disease, first-line=<br />
<br />
==Capecitabine monotherapy {{#subobject:4f5f03|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b31bbb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Capecitabine & Gemcitabine {{#subobject:2f0431|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Variant #1 {{#subobject:fcd708|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Note: this is essentially identical to the maintenance phase of Cunningham et al. 2009, below.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:e8f0bf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21, 29 to 49<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:a7e551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 650 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 24 weeks'''<br />
<br />
===References===<br />
# Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:c30d8f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, weekly dosing {{#subobject:20a0f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note that cisplatin is not given on day 22 of the first 8 weeks; otherwise, the schedule is identical to the schedule for gemcitabine.''<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] as follows, '''given 60 minutes prior to gemcitabine''':<br />
**First 8 weeks: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Subsequent cycles: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, bi-weekly dosing {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract Cascinu et al. 2008 (GISCAD)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Cisplatin, Gemcitabine, Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 Jan;9(1):39-44. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18077217 PubMed]<br />
# Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:bf797a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, no gemcitabine lead-in {{#subobject:43fe43|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext Kordes et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Erlotinib, Gemcitabine, Metformin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:fc43f2|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:d49fb0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47. Epub 2015 Jun 8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext link to original article]'''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26067687 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:c6c509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:3ca01f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Inferior to gemcitabine. Here for historical reference purposes, only.''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
<br />
==FOLFIRINOX {{#subobject:aaa3c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e140cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior QoL by [http://groups.eortc.be/qol/eortc-qlq-c30 EORTC QLQ-C30]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 1200 mg/m<sup>2</sup>/day IV continuous 46-hour infusion on days 1 to 2; '''given last''' (total dose per cycle: 2400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1; '''given third together with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:3a0f4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 8-week lead-in {{#subobject:5d6dd0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx_2|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract Reni et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PEFG<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|GEM FDR<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GEM-CAP]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ Philip et al. 2010 (SWOG S0205)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_nab-Paclitaxel|Gemcitabine & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext Middleton et al. 2017 (ViP)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Vandetanib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
***In Burris et al. 1997, patients with grade 2 or lower toxicities could have had doses increased to 1250 mg/m<sup>2</sup><br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 4 week cycles {{#subobject:c6349|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract Kindler et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ Fuchs et al. 2015 (GAMMA)]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & [[Ganitumab (AMG 479)|Ganitumab]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ Catenacci et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & Vismodegib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 3 week cycles {{#subobject:8bae67|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 Hong et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|Gemcitabine & Simvastatin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, fixed-dose rate (FDR) {{#subobject:5114cc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 150 minutes (10 mg/m<sup>2</sup>/min) once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15925814 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
# '''SWOG S0205:''' Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 1;28(22):3605-10. Epub 2010 Jul 6. [http://jco.ascopubs.org/content/28/22/3605.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20606093 PubMed]<br />
# Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306953 PubMed]<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
# Hong JY, Nam EM, Lee J, Park JO, Lee SC, Song SY, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol. 2014 Jan;73(1):125-30. Epub 2013 Oct 27. [https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24162380 PubMed]<br />
# '''GAMMA:''' Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921-7. Epub 2015 Jan 21. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25609246 PubMed]<br />
# Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D, Wade J, Sleckman B, Lenz HJ, Stiff P, Kumar P, Xu P, Henderson L, Takebe N, Salgia R, Wang X, Stadler WM, de Sauvage FJ, Kindler HL. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015 Dec 20;33(36):4284-92. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/36/4284.long link to original article] '''contains protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527777 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
# '''ViP:''' Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr;18(4):486-499. Epub 2017 Mar 2. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28259610 PubMed]<br />
<br />
==GemOx {{#subobject:520af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:9d3266|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine, FDR]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
<br />
==Gemcitabine & nab-Paclitaxel {{#subobject:fbd698|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:63ba04|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] as follows, '''given first''':<br />
**Cycle 1: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15<br />
<br />
'''8-week cycle followed by 28-day cycles until disease progression or intolerance'''<br />
<br />
===Variant #2 {{#subobject:ecc1c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ Von Hoff et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 or 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/34/4548.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969517 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
<br />
==GTX {{#subobject:f0d62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
GTX: '''<u>G</u>'''emcitabine, '''<u>T</u>'''axotere (Docetaxel), '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:fc0e50|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.springerlink.com/content/75m422843l3461m0/ Fine et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: De Jesus-Acosta et al. 2012 lists the capecitabine dose as "750 mg/m<sup>2</sup>/day orally divided into two doses," but this is believed to be a typographical error since the original reference that it cites, Fine et al. 2007, uses capecitabine at 750 mg/m<sup>2</sup> PO BID. The 2009 ASCO abstract by Fine also lists this 750 mg/m<sup>2</sup> PO BID (1500 mg/m<sup>2</sup>/day) dose.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 75 minutes once per day on days 4 & 11<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 11<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75. Epub 2007 Apr 18. [http://www.springerlink.com/content/75m422843l3461m0/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17440727 PubMed]<br />
# '''Abstract:''' R. L. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. 2009 ASCO Annual Meeting abstract 4623. [http://ascopubs.org/doi/full/10.1200/jco.2009.27.15s.4623 link to abstract] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012 Feb;69(2):415-24. Epub 2011 Jul 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723 link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21800112 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:759f1a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:94d490|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<br />
=Metastatic disease, refractory=<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#OFF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Best supportive care. Placed here because one or more randomized clinical trials included a best supportive care arm in this disease context.''<br />
<br />
===References===<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<br />
==Capecitabine & Erlotinib {{#subobject:4655b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d5c799|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4787.full Kulke et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> (rounded to the nearest 150 mg tablet) PO BID on days 1 to 14<br />
*[[Erlotinib (Tarceva)]] 150 mg PO on days 1 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak EL, Muzikansky A, Lawrence C, Fuchs CS. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007 Oct 20;25(30):4787-92. [http://jco.ascopubs.org/content/25/30/4787.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947726 PubMed]<br />
<br />
==CapeOx {{#subobject:d09d5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:57ad5f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full Xiong et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 1000 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 110 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008 Oct 15;113(8):2046-52. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18756532 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, nanoliposomal Irinotecan {{#subobject:72308d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a81310|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''started on day 1 after folinic acid'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given prior to fluorouracil'''<br />
*[[Irinotecan liposome (Onivyde)]] 70 mg/m<sup>2</sup> (irinotecan free base) IV over 90 minutes once on day 1, '''given first'''<br />
**Per Wang-Gillam et al. 2015 (NAPOLI-01), 70 mg/m<sup>2</sup> irinotecan free base is equivalent to 80 mg/m<sup>2</sup> nanoliposomal irinotecan. According to the trial's ClinicalTrials.gov page: "The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m<sup>2</sup> dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/ m2 of irinotecan free base."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
<br />
==FOLFIRI {{#subobject:6fd426|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br />
===Variant #1 {{#subobject:6a9cae|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 Zaniboni et al. 2012 (GISCAD)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, and 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, modified FOLFIRI.3 {{#subobject:4758e8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFOX|mFOLFOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Irinotecan (Camptosar)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 3<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
# Zaniboni A, Aitini E, Barni S, Ferrari D, Cascinu S, Catalano V, Valmadre G, Ferrara D, Veltri E, Codignola C, Labianca R. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jun;69(6):1641-5. Epub 2012 May 11. [http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22576338 PubMed]<br />
<br />
==FOLFOX {{#subobject:377e80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:33ef68|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFIRI|mFOLFIRI.3]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [https://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
<br />
==OFF {{#subobject:8b32c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OFF: '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil, '''<u>F</u>'''olinic acid <br />
===Regimen {{#subobject:ae57d5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
<br />
''Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m<sup>2</sup>," or 850 mg/m<sup>2</sup>.''<br />
====Chemotherapy====<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once per day on days 8 & 22, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous 24-hour infusion on days 1, 8, 15, 22, '''started after folinic acid bolus'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, '''given prior to fluorouracil'''<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [https://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
# Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
<br />
==Olaparib monotherapy {{#subobject:0c2eb3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:21eb78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/3/244.long Kaufman et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients had germline BRCA1/2 mutations and had previously received gemcitabine.''<br />
====Chemotherapy====<br />
*[[Olaparib (Lynparza)]] 400 mg PO BID<br />
<br />
'''Continued until progression'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
# Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/33/3/244.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed]<br />
<br />
==Paclitaxel, nanoparticle albumin-bound monotherapy {{#subobject:ab9fc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8d38d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract Hosein et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Hosein PJ, de Lima Lopes G Jr, Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013 Apr;36(2):151-6. Epub 2012 Feb 2. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22307213 PubMed]<br />
<br />
[[Category:Pancreatic cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdheryhttps://hemonc.org/w/index.php?title=Pancreatic_cancer&diff=26630Pancreatic cancer2018-05-18T18:35:03Z<p>Rozinachowdhery: /* Gemcitabine, Cetuximab, RT */</p>
<hr />
<div><!--'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]]. If this is your first time visiting, we suggest you read the [[tutorial]].'''--><br />
<!--Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are [[How_to_contribute|invited to contribute to the site]].-->{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>Chicago, IL</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2017:''' [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.4948 Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/28398845 PubMed]<br />
*'''2016:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019760/ Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2016:''' [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.5561 Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/27247216 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2015:''' [http://annonc.oxfordjournals.org/content/26/suppl_5/v56.full.pdf+html Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015)] [https://www.ncbi.nlm.nih.gov/pubmed/26314780 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf NCCN Guidelines - Pancreatic Adenocarcinoma]<br />
<br />
=Adjuvant therapy=<br />
==Capecitabine & Gemcitabine {{#subobject:17f9f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Regimen {{#subobject:e6a3e3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Treatment starts within 12 weeks of surgery.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week on weeks 1 to 3<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# '''ESPAC-4:''' Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:29266e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:242770|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
<br />
==Fluorouracil, then Fluorouracil & RT {{#subobject:331d4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:89426a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br> [[#Observation|Observation]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine.2C_then_Fluorouracil_.26_RT.2C_then_Gemcitabine|Gemcitabine, then Fluorouracil & RT, then Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 21<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 28<br />
<br />
'''6-week cycle for 2 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:34e70d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a756a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|Fluorouracil & Leucovorin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine|Capecitabine & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
<br />
''Note: efficacy for CONKO-001 is based on the 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
# Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Gemcitabine, then Fluorouracil & RT, then Gemcitabine {{#subobject:f8c8d9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:3fef3f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|Fluorouracil & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Efficacy for ESPAC-1 is based on the 2004 update and efficacy for CONKO-001 is based on 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cdcc15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, potentially resectable=<br />
<br />
==Docetaxel, Gemcitabine, RT {{#subobject:49a407|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:78b0ba|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1245%2FASO.2005.04.503 Pipas et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 65 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Gemcitabine (Gemzar)]] 4000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29<br />
<br />
'''6-week course, followed immediately (day 43) by:'''<br />
<br />
====Chemoradiation====<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy to primary target volume. Then 5.4 Gy boost to secondary target volume of 1- to 1.5-cm margin on all sides, including proven nodal involvement. Total 50.4 Gy in 28 fractions.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
# Pipas JM, Barth RJ Jr, Zaki B, Tsapakos MJ, Suriawinata AA, Bettmann MA, Cates JM, Ripple GH, Sutton JE, Gordon SR, McDonnell CE, Perez RP, Redfield N, Meyer LP, Marshall JF, Cole BF, Colacchio TA. Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2005 Dec;12(12):995-1004. Epub 2005 Nov 1. [http://link.springer.com/article/10.1245%2FASO.2005.04.503 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16252135 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:55e32d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen 1 {{#subobject:6ce551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract Takahashi et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*Concurrent radiation therapy, 2 Gy per fraction, 5 days per week, 25 fractions, total dose of 50 Gy over 5 weeks.<br />
<br />
'''28-day cycle for 3 cycles''' ''(Radiation given over weeks 1-5 only)''<br />
<br />
''Restaging is performed 8 weeks after radiation complete (2 weeks after chemotherapy complete). Resection immediately thereafter, if feasible.''<br />
<br />
===Regimen 2 {{#subobject:dc32dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 500 mg/m<sup>2</sup> IV over 50 minutes once per week for 6 weeks<br />
*Concurrent radiation therapy, 180 cGy x 22 with 3 cm margin to GTV then 180 cGy x 6 with 2 cm margin to GTV, total 50.4 Gy over 6 weeks<br />
<br />
''Restaging after radiation complete. 4 to 6 week break, followed by surgery, followed by 4 to 8 week break. Then adjuvant chemotherapy:''<br />
<br />
====Adjuvant chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 5 cycles'''<br />
<br />
===References===<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [http://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, Ioka T, Uehara H, Yano M, Ishikawa O. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013 Dec;258(6):1040-50.[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23799421 PubMed]<br />
<br />
==Gemcitabine, Cetuximab, RT {{#subobject:aea7b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c38534|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ Pipas et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**6 to 8 days prior radiation: 400 mg/m<sup>2</sup> IV over 2 hours once<br />
**During radiation: 250 mg/m<sup>2</sup> over 60 minutes once per week for 6 doses<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, delivered using IMRT. Gross tumor volume (GTV) was all known disease including imaging proven nodal disease. The primary planning target volume (PTV1) included the GTV with 2- to 3-cm margins in all directions as well as potential nodal involvement. Secondary planning target volume (PTV2) included the GTV with 1- to 1.5-cm margins on all sides including proven nodal involvement. Tertiary planning treatment volume (PTV3) included the area of the GTV adjacent to the vascular structures specifically the mesenteric and portal vessels with a 0.5-cm margin. The prescription dose delivered to PTV3 was 54 Gy in 28 fractions. Synchronously, PTV1 and PTV2 received 45 and 50.4 Gy, respectively. All fields were treated daily at five fractions per week.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
''One month following therapy, patients were restaged with CT scan of chest/abdomen/pelvis. Patients deemed to be candidates for surgical resection were offered laparotomy ∼6 to 10 weeks after completion of neoadjuvant therapy.''<br />
<br />
===References===<br />
# Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, Tsongalis GJ, Colacchio TA, Gordon SR, Sutton JE, Srivastava A, Smith KD, Gardner TB, Korc M, Davis TH, Preis M, Tarczewski SM, Mackenzie TA, Barth RJ Jr. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. 2012 Nov;23(11):2820-7. Epub 2012 May 9. [http://annonc.oxfordjournals.org/content/23/11/2820.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571859 PubMed]<br />
<br />
==mFOLFIRINOX, Gemcitabine, RT {{#subobject:b71003|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFIRINOX, Gemcitabine, RT: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin, Gemcitabine, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:d87ec0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ Blazer et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion for 46 h on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once on day 1<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 4<br />
<br />
'''14-day cycle for 4 to 8 cycles'''<br />
<br />
''Followed by complete restaging. If tumor localized but still not resectable, chemoradiotherapy was administered:''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup>/week concurrent with radiation<br />
*Radiation was 36 Gy in 15 daily fractions<br />
<br />
===Variant #2 {{#subobject:7bb0e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ Hosein et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion for 46 hours on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles. Protocol followed "per ACCORD-11 trial"'''<br />
<br />
''Treatment stopped at maximum response or tolerability. Resectable patients by imaging criteria were offered surgery, followed by postoperative chemoradiotherapy. Unresectable patients were offered chemoradiotherapy, followed by surgery (if they became resectable):''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup>/week<br />
*Radiation at 50.4 Gy in 28 fractions.<br />
<br />
===References===<br />
# '''Retrospective:''' Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, Narayanan G, Ribeiro A, Portelance L, Merchan JR, Levi JU, Rocha-Lima CM. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012 May 29;12:199. [http://www.biomedcentral.com/1471-2407/12/199 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22642850 PubMed]<br />
# '''Retrospective:''' Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, Wuthrick E, Williams TM, Reardon J, Christopher Ellison E, Bloomston M, Bekaii-Saab T. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015 Apr;22(4):1153-9. [http://link.springer.com/article/10.1245%2Fs10434-014-4225-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25358667 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, unresectable=<br />
<br />
==Capecitabine monotherapy {{#subobject:dbd841|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dc4779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:6d97a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, Gem 3 out of 4 weeks x 4 {{#subobject:87edde|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Erlotinib & Gemcitabine x 2 more cycles (6 total) versus Capecitabine, Erlotinib, RT<br />
<br />
===Variant #2, Gem 3 out of 4 weeks x 6 {{#subobject:5a5e14|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
''Note: it is not clear from the protocol whether erlotinib is continued beyond the end of chemotherapy.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] as follows:<br />
**Cycles 1 to 4: 100 mg PO once per day<br />
**Cycles 5 & 6: 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:b4258e|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #4, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:b7a41f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''GERCOR LAP07:''' Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Fluorouracil & RT {{#subobject:26f1c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:29784e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ Herman et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Fluorouracil & RT with TNFerade<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion once per day on radiation days (total dose per week: 1000 mg/m<sup>2</sup>)<br />
*Concurrent radiation therapy, 50.4 Gy total: 1.80 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy, followed by 1.80 Gy x 3 fractions boost to the tumor bed.<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
*Gemcitabine or Erlotinib & Gemcitabine maintenance<br />
<br />
===References===<br />
# Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, Donehower RC, Pawlik TM, Ziegler MA, Cai H, Savage DT, Canto MI, Klapman J, Reid T, Shah RJ, Hoffe SE, Rosemurgy A, Wolfgang CL, Laheru DA. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013 Mar 1;31(7):886-94. Epub 2013 Jan 22. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.7516 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23341531 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:4f0be9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 3 out of 4 weeks x 4 {{#subobject:c511a7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Gemcitabine x 2 more cycles (6 total) versus Capecitabine & RT<br />
<br />
===Variant #2, 3 out of 4 weeks x 6 {{#subobject:cf89f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in {{#subobject:82f8b2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#GemOx|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_.26_RT_2|Gemcitabine & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent 4-week cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''Continued for at least 3 months'''<br />
<br />
''Per '''Louvet et al. 2005''', subsequent chemoradiotherapy was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:a6e6fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 (600 mg/m<sup>2</sup>) {{#subobject:a6de29|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract Cardenes et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV over 30 to 60 minutes once per week during radiation<br />
*Concurrent radiation therapy, 1.8 Gy per fraction, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks.<br />
<br />
'''One course, followed in 4 weeks by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycle for 5 cycles or until disease progression'''<br />
<br />
===Variant #2 (400 mg/m<sup>2</sup>) {{#subobject:c1ac3c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract Epelbaum et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week for 7 weeks<br />
<br />
'''Radiation planning during this phase, followed by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 400 mg/m<sup>2</sup> IV over 30 minutes once per week (days 1, 8, 15)<br />
*Concurrent radiation therapy, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks<br />
<br />
'''28 day cycle for 2 cycles (completion of radiation), followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycles until disease progression'''<br />
<br />
===References===<br />
# Epelbaum R, Rosenblatt E, Nasrallah S, Faraggi D, Gaitini D, Mizrahi S, Kuten A. Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J Surg Oncol. 2002 Nov;81(3):138-43. [http://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12407726 PubMed]<br />
# Cardenes HR, Moore AM, Johnson CS, Yu M, Helft P, Chiorean EG, Vinson J, Howard TJ, Stephens AW, Tai DF, Loehrer PJ Sr. A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study. Am J Clin Oncol. 2011 Oct;34(5):460-5.[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20881474 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
<br />
==GemOx {{#subobject:19d87f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:5a25e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_2|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycle for at least 3 months'''<br />
<br />
''Subsequent chemoradiotherapy was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
<br />
=Metastatic disease, first-line=<br />
<br />
==Capecitabine monotherapy {{#subobject:4f5f03|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b31bbb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Capecitabine & Gemcitabine {{#subobject:2f0431|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Variant #1 {{#subobject:fcd708|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Note: this is essentially identical to the maintenance phase of Cunningham et al. 2009, below.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:e8f0bf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21, 29 to 49<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:a7e551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 650 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 24 weeks'''<br />
<br />
===References===<br />
# Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:c30d8f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, weekly dosing {{#subobject:20a0f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note that cisplatin is not given on day 22 of the first 8 weeks; otherwise, the schedule is identical to the schedule for gemcitabine.''<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] as follows, '''given 60 minutes prior to gemcitabine''':<br />
**First 8 weeks: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Subsequent cycles: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, bi-weekly dosing {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract Cascinu et al. 2008 (GISCAD)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Cisplatin, Gemcitabine, Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 Jan;9(1):39-44. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18077217 PubMed]<br />
# Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:bf797a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, no gemcitabine lead-in {{#subobject:43fe43|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext Kordes et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Erlotinib, Gemcitabine, Metformin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:fc43f2|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:d49fb0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47. Epub 2015 Jun 8. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext link to original article]'''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26067687 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:c6c509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:3ca01f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Inferior to gemcitabine. Here for historical reference purposes, only.''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
<br />
==FOLFIRINOX {{#subobject:aaa3c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e140cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior QoL by [http://groups.eortc.be/qol/eortc-qlq-c30 EORTC QLQ-C30]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 1200 mg/m<sup>2</sup>/day IV continuous 46-hour infusion on days 1 to 2; '''given last''' (total dose per cycle: 2400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1; '''given third together with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:3a0f4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 8-week lead-in {{#subobject:5d6dd0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx_2|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract Reni et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PEFG<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|GEM FDR<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GEM-CAP]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ Philip et al. 2010 (SWOG S0205)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_nab-Paclitaxel|Gemcitabine & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext Middleton et al. 2017 (ViP)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Vandetanib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
***In Burris et al. 1997, patients with grade 2 or lower toxicities could have had doses increased to 1250 mg/m<sup>2</sup><br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 4 week cycles {{#subobject:c6349|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract Kindler et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ Fuchs et al. 2015 (GAMMA)]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & [[Ganitumab (AMG 479)|Ganitumab]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ Catenacci et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & Vismodegib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 3 week cycles {{#subobject:8bae67|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 Hong et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|Gemcitabine & Simvastatin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, fixed-dose rate (FDR) {{#subobject:5114cc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 150 minutes (10 mg/m<sup>2</sup>/min) once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15925814 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
# '''SWOG S0205:''' Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 1;28(22):3605-10. Epub 2010 Jul 6. [http://jco.ascopubs.org/content/28/22/3605.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20606093 PubMed]<br />
# Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306953 PubMed]<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
# Hong JY, Nam EM, Lee J, Park JO, Lee SC, Song SY, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol. 2014 Jan;73(1):125-30. Epub 2013 Oct 27. [https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24162380 PubMed]<br />
# '''GAMMA:''' Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921-7. Epub 2015 Jan 21. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25609246 PubMed]<br />
# Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D, Wade J, Sleckman B, Lenz HJ, Stiff P, Kumar P, Xu P, Henderson L, Takebe N, Salgia R, Wang X, Stadler WM, de Sauvage FJ, Kindler HL. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015 Dec 20;33(36):4284-92. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/36/4284.long link to original article] '''contains protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527777 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
# '''ViP:''' Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr;18(4):486-499. Epub 2017 Mar 2. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28259610 PubMed]<br />
<br />
==GemOx {{#subobject:520af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:9d3266|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine, FDR]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
<br />
==Gemcitabine & nab-Paclitaxel {{#subobject:fbd698|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:63ba04|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] as follows, '''given first''':<br />
**Cycle 1: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15<br />
<br />
'''8-week cycle followed by 28-day cycles until disease progression or intolerance'''<br />
<br />
===Variant #2 {{#subobject:ecc1c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ Von Hoff et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 or 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/34/4548.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969517 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
<br />
==GTX {{#subobject:f0d62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
GTX: '''<u>G</u>'''emcitabine, '''<u>T</u>'''axotere (Docetaxel), '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:fc0e50|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.springerlink.com/content/75m422843l3461m0/ Fine et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: De Jesus-Acosta et al. 2012 lists the capecitabine dose as "750 mg/m<sup>2</sup>/day orally divided into two doses," but this is believed to be a typographical error since the original reference that it cites, Fine et al. 2007, uses capecitabine at 750 mg/m<sup>2</sup> PO BID. The 2009 ASCO abstract by Fine also lists this 750 mg/m<sup>2</sup> PO BID (1500 mg/m<sup>2</sup>/day) dose.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 75 minutes once per day on days 4 & 11<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 11<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75. Epub 2007 Apr 18. [http://www.springerlink.com/content/75m422843l3461m0/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17440727 PubMed]<br />
# '''Abstract:''' R. L. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. 2009 ASCO Annual Meeting abstract 4623. [http://ascopubs.org/doi/full/10.1200/jco.2009.27.15s.4623 link to abstract] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012 Feb;69(2):415-24. Epub 2011 Jul 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723 link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21800112 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:759f1a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:94d490|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<br />
=Metastatic disease, refractory=<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#OFF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Best supportive care. Placed here because one or more randomized clinical trials included a best supportive care arm in this disease context.''<br />
<br />
===References===<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<br />
==Capecitabine & Erlotinib {{#subobject:4655b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d5c799|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4787.full Kulke et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> (rounded to the nearest 150 mg tablet) PO BID on days 1 to 14<br />
*[[Erlotinib (Tarceva)]] 150 mg PO on days 1 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak EL, Muzikansky A, Lawrence C, Fuchs CS. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007 Oct 20;25(30):4787-92. [http://jco.ascopubs.org/content/25/30/4787.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947726 PubMed]<br />
<br />
==CapeOx {{#subobject:d09d5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:57ad5f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full Xiong et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 1000 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 110 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008 Oct 15;113(8):2046-52. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18756532 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, nanoliposomal Irinotecan {{#subobject:72308d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a81310|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''started on day 1 after folinic acid'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given prior to fluorouracil'''<br />
*[[Irinotecan liposome (Onivyde)]] 70 mg/m<sup>2</sup> (irinotecan free base) IV over 90 minutes once on day 1, '''given first'''<br />
**Per Wang-Gillam et al. 2015 (NAPOLI-01), 70 mg/m<sup>2</sup> irinotecan free base is equivalent to 80 mg/m<sup>2</sup> nanoliposomal irinotecan. According to the trial's ClinicalTrials.gov page: "The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m<sup>2</sup> dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/ m2 of irinotecan free base."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
<br />
==FOLFIRI {{#subobject:6fd426|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br />
===Variant #1 {{#subobject:6a9cae|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 Zaniboni et al. 2012 (GISCAD)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, and 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, modified FOLFIRI.3 {{#subobject:4758e8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFOX|mFOLFOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Irinotecan (Camptosar)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 3<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [http://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
# Zaniboni A, Aitini E, Barni S, Ferrari D, Cascinu S, Catalano V, Valmadre G, Ferrara D, Veltri E, Codignola C, Labianca R. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jun;69(6):1641-5. Epub 2012 May 11. [http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22576338 PubMed]<br />
<br />
==FOLFOX {{#subobject:377e80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:33ef68|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFIRI|mFOLFIRI.3]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [http://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
<br />
==OFF {{#subobject:8b32c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OFF: '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil, '''<u>F</u>'''olinic acid <br />
===Regimen {{#subobject:ae57d5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
<br />
''Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m<sup>2</sup>," or 850 mg/m<sup>2</sup>.''<br />
====Chemotherapy====<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once per day on days 8 & 22, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous 24-hour infusion on days 1, 8, 15, 22, '''started after folinic acid bolus'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, '''given prior to fluorouracil'''<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
# Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
<br />
==Olaparib monotherapy {{#subobject:0c2eb3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:21eb78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/3/244.long Kaufman et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients had germline BRCA1/2 mutations and had previously received gemcitabine.''<br />
====Chemotherapy====<br />
*[[Olaparib (Lynparza)]] 400 mg PO BID<br />
<br />
'''Continued until progression'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
# Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/33/3/244.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed]<br />
<br />
==Paclitaxel, nanoparticle albumin-bound monotherapy {{#subobject:ab9fc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8d38d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract Hosein et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Hosein PJ, de Lima Lopes G Jr, Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013 Apr;36(2):151-6. Epub 2012 Feb 2. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22307213 PubMed]<br />
<br />
[[Category:Pancreatic cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdheryhttps://hemonc.org/w/index.php?title=Pancreatic_cancer&diff=26629Pancreatic cancer2018-05-18T18:20:07Z<p>Rozinachowdhery: /* Regimen 1 */</p>
<hr />
<div><!--'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]]. If this is your first time visiting, we suggest you read the [[tutorial]].'''--><br />
<!--Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are [[How_to_contribute|invited to contribute to the site]].-->{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>Chicago, IL</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2017:''' [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.4948 Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/28398845 PubMed]<br />
*'''2016:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019760/ Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2016:''' [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.5561 Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/27247216 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2015:''' [http://annonc.oxfordjournals.org/content/26/suppl_5/v56.full.pdf+html Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015)] [https://www.ncbi.nlm.nih.gov/pubmed/26314780 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf NCCN Guidelines - Pancreatic Adenocarcinoma]<br />
<br />
=Adjuvant therapy=<br />
==Capecitabine & Gemcitabine {{#subobject:17f9f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Regimen {{#subobject:e6a3e3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Treatment starts within 12 weeks of surgery.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week on weeks 1 to 3<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# '''ESPAC-4:''' Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Fluorouracil & Folinic acid {{#subobject:29266e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:242770|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
<br />
==Fluorouracil, then Fluorouracil & RT {{#subobject:331d4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:89426a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br> [[#Observation|Observation]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine.2C_then_Fluorouracil_.26_RT.2C_then_Gemcitabine|Gemcitabine, then Fluorouracil & RT, then Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 21<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 28<br />
<br />
'''6-week cycle for 2 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:34e70d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a756a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Folinic_acid|Fluorouracil & Leucovorin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine|Capecitabine & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
<br />
''Note: efficacy for CONKO-001 is based on the 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
# Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Gemcitabine, then Fluorouracil & RT, then Gemcitabine {{#subobject:f8c8d9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:3fef3f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_RT|Fluorouracil & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy, part 1====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy, part 2====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[[#Fluorouracil_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No active antineoplastic treatment. Efficacy for ESPAC-1 is based on the 2004 update and efficacy for CONKO-001 is based on 2013 update.''<br />
====Preceding treatment====<br />
*Surgery<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cdcc15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
====Preceding treatment====<br />
*Surgery<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, potentially resectable=<br />
<br />
==Docetaxel, Gemcitabine, RT {{#subobject:49a407|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:78b0ba|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1245%2FASO.2005.04.503 Pipas et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 65 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Gemcitabine (Gemzar)]] 4000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29<br />
<br />
'''6-week course, followed immediately (day 43) by:'''<br />
<br />
====Chemoradiation====<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy to primary target volume. Then 5.4 Gy boost to secondary target volume of 1- to 1.5-cm margin on all sides, including proven nodal involvement. Total 50.4 Gy in 28 fractions.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
# Pipas JM, Barth RJ Jr, Zaki B, Tsapakos MJ, Suriawinata AA, Bettmann MA, Cates JM, Ripple GH, Sutton JE, Gordon SR, McDonnell CE, Perez RP, Redfield N, Meyer LP, Marshall JF, Cole BF, Colacchio TA. Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2005 Dec;12(12):995-1004. Epub 2005 Nov 1. [http://link.springer.com/article/10.1245%2FASO.2005.04.503 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16252135 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:55e32d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen 1 {{#subobject:6ce551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract Takahashi et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*Concurrent radiation therapy, 2 Gy per fraction, 5 days per week, 25 fractions, total dose of 50 Gy over 5 weeks.<br />
<br />
'''28-day cycle for 3 cycles''' ''(Radiation given over weeks 1-5 only)''<br />
<br />
''Restaging is performed 8 weeks after radiation complete (2 weeks after chemotherapy complete). Resection immediately thereafter, if feasible.''<br />
<br />
===Regimen 2 {{#subobject:dc32dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 500 mg/m<sup>2</sup> IV over 50 minutes once per week for 6 weeks<br />
*Concurrent radiation therapy, 180 cGy x 22 with 3 cm margin to GTV then 180 cGy x 6 with 2 cm margin to GTV, total 50.4 Gy over 6 weeks<br />
<br />
''Restaging after radiation complete. 4 to 6 week break, followed by surgery, followed by 4 to 8 week break. Then adjuvant chemotherapy:''<br />
<br />
====Adjuvant chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 5 cycles'''<br />
<br />
===References===<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [http://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, Ioka T, Uehara H, Yano M, Ishikawa O. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013 Dec;258(6):1040-50.[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23799421 PubMed]<br />
<br />
==Gemcitabine, Cetuximab, RT {{#subobject:aea7b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c38534|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ Pipas et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**6 to 8 days prior radiation: 400 mg/m<sup>2</sup> IV over 2 hours once<br />
**During radiation: 250 mg/m<sup>2</sup> over 60 minutes once per week for 6 doses<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, delivered using IMRT. Gross tumor volume (GTV) was all known disease including imaging proven nodal disease. The primary planning target volume (PTV1) included the GTV with 2- to 3-cm margins in all directions as well as potential nodal involvement. Secondary planning target volume (PTV2) included the GTV with 1- to 1.5-cm margins on all sides including proven nodal involvement. Tertiary planning treatment volume (PTV3) included the area of the GTV adjacent to the vascular structures specifically the mesenteric and portal vessels with a 0.5-cm margin. The prescription dose delivered to PTV3 was 54 Gy in 28 fractions. Synchronously, PTV1 and PTV2 received 45 and 50.4 Gy, respectively. All fields were treated daily at five fractions per week.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
''One month following therapy, patients were restaged with CT scan of chest/abdomen/pelvis. Patients deemed to be candidates for surgical resection were offered laparotomy ∼6to 10 weeks after completion of neoadjuvant therapy.''<br />
<br />
===References===<br />
# Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, Tsongalis GJ, Colacchio TA, Gordon SR, Sutton JE, Srivastava A, Smith KD, Gardner TB, Korc M, Davis TH, Preis M, Tarczewski SM, Mackenzie TA, Barth RJ Jr. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. 2012 Nov;23(11):2820-7. Epub 2012 May 9. [http://annonc.oxfordjournals.org/content/23/11/2820.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571859 PubMed]<br />
<br />
==mFOLFIRINOX, Gemcitabine, RT {{#subobject:b71003|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFIRINOX, Gemcitabine, RT: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin, Gemcitabine, '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:d87ec0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ Blazer et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion for 46 h on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once on day 1<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 4<br />
<br />
'''14-day cycle for 4 to 8 cycles'''<br />
<br />
''Followed by complete restaging. If tumor localized but still not resectable, chemoradiotherapy was administered:''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup>/week concurrent with radiation<br />
*Radiation was 36 Gy in 15 daily fractions<br />
<br />
===Variant #2 {{#subobject:7bb0e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ Hosein et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Chemotherapy, mFOLFIRINOX portion====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion for 46 hours on days 1 to 3<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles. Protocol followed "per ACCORD-11 trial"'''<br />
<br />
''Treatment stopped at maximum response or tolerability. Resectable patients by imaging criteria were offered surgery, followed by postoperative chemoradiotherapy. Unresectable patients were offered chemoradiotherapy, followed by surgery (if they became resectable):''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup>/week<br />
*Radiation at 50.4 Gy in 28 fractions.<br />
<br />
===References===<br />
# '''Retrospective:''' Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, Narayanan G, Ribeiro A, Portelance L, Merchan JR, Levi JU, Rocha-Lima CM. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012 May 29;12:199. [http://www.biomedcentral.com/1471-2407/12/199 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22642850 PubMed]<br />
# '''Retrospective:''' Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, Wuthrick E, Williams TM, Reardon J, Christopher Ellison E, Bloomston M, Bekaii-Saab T. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015 Apr;22(4):1153-9. [http://link.springer.com/article/10.1245%2Fs10434-014-4225-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25358667 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, unresectable=<br />
<br />
==Capecitabine monotherapy {{#subobject:dbd841|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dc4779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:6d97a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, Gem 3 out of 4 weeks x 4 {{#subobject:87edde|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Erlotinib & Gemcitabine x 2 more cycles (6 total) versus Capecitabine, Erlotinib, RT<br />
<br />
===Variant #2, Gem 3 out of 4 weeks x 6 {{#subobject:5a5e14|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
''Note: it is not clear from the protocol whether erlotinib is continued beyond the end of chemotherapy.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] as follows:<br />
**Cycles 1 to 4: 100 mg PO once per day<br />
**Cycles 5 & 6: 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:b4258e|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #4, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:b7a41f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''GERCOR LAP07:''' Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Fluorouracil & RT {{#subobject:26f1c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:29784e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ Herman et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Fluorouracil & RT with TNFerade<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion once per day on radiation days (total dose per week: 1000 mg/m<sup>2</sup>)<br />
*Concurrent radiation therapy, 50.4 Gy total: 1.80 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy, followed by 1.80 Gy x 3 fractions boost to the tumor bed.<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
*Gemcitabine or Erlotinib & Gemcitabine maintenance<br />
<br />
===References===<br />
# Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, Donehower RC, Pawlik TM, Ziegler MA, Cai H, Savage DT, Canto MI, Klapman J, Reid T, Shah RJ, Hoffe SE, Rosemurgy A, Wolfgang CL, Laheru DA. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013 Mar 1;31(7):886-94. Epub 2013 Jan 22. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.7516 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23341531 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:4f0be9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 3 out of 4 weeks x 4 {{#subobject:c511a7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Gemcitabine x 2 more cycles (6 total) versus Capecitabine & RT<br />
<br />
===Variant #2, 3 out of 4 weeks x 6 {{#subobject:cf89f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in {{#subobject:82f8b2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#GemOx|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_.26_RT_2|Gemcitabine & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent 4-week cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''Continued for at least 3 months'''<br />
<br />
''Per '''Louvet et al. 2005''', subsequent chemoradiotherapy was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:a6e6fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 (600 mg/m<sup>2</sup>) {{#subobject:a6de29|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract Cardenes et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV over 30 to 60 minutes once per week during radiation<br />
*Concurrent radiation therapy, 1.8 Gy per fraction, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks.<br />
<br />
'''One course, followed in 4 weeks by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycle for 5 cycles or until disease progression'''<br />
<br />
===Variant #2 (400 mg/m<sup>2</sup>) {{#subobject:c1ac3c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract Epelbaum et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week for 7 weeks<br />
<br />
'''Radiation planning during this phase, followed by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 400 mg/m<sup>2</sup> IV over 30 minutes once per week (days 1, 8, 15)<br />
*Concurrent radiation therapy, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks<br />
<br />
'''28 day cycle for 2 cycles (completion of radiation), followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycles until disease progression'''<br />
<br />
===References===<br />
# Epelbaum R, Rosenblatt E, Nasrallah S, Faraggi D, Gaitini D, Mizrahi S, Kuten A. Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J Surg Oncol. 2002 Nov;81(3):138-43. [http://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12407726 PubMed]<br />
# Cardenes HR, Moore AM, Johnson CS, Yu M, Helft P, Chiorean EG, Vinson J, Howard TJ, Stephens AW, Tai DF, Loehrer PJ Sr. A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study. Am J Clin Oncol. 2011 Oct;34(5):460-5.[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20881474 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
<br />
==GemOx {{#subobject:19d87f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:5a25e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_2|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycle for at least 3 months'''<br />
<br />
''Subsequent chemoradiotherapy was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
<br />
=Metastatic disease, first-line=<br />
<br />
==Capecitabine monotherapy {{#subobject:4f5f03|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b31bbb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Capecitabine & Gemcitabine {{#subobject:2f0431|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Variant #1 {{#subobject:fcd708|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Note: this is essentially identical to the maintenance phase of Cunningham et al. 2009, below.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:e8f0bf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21, 29 to 49<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:a7e551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 650 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 24 weeks'''<br />
<br />
===References===<br />
# Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:c30d8f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, weekly dosing {{#subobject:20a0f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note that cisplatin is not given on day 22 of the first 8 weeks; otherwise, the schedule is identical to the schedule for gemcitabine.''<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] as follows, '''given 60 minutes prior to gemcitabine''':<br />
**First 8 weeks: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Subsequent cycles: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, bi-weekly dosing {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract Cascinu et al. 2008 (GISCAD)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Cisplatin, Gemcitabine, Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 Jan;9(1):39-44. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18077217 PubMed]<br />
# Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:bf797a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, no gemcitabine lead-in {{#subobject:43fe43|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext Kordes et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Erlotinib, Gemcitabine, Metformin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, gemcitabine lead-in, erlotinib 100 mg/d {{#subobject:fc43f2|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===Variant #3, gemcitabine lead-in, erlotinib 150 mg/d {{#subobject:d49fb0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007 (NCIC CTG PA.3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
''Note: due to low accrual, the efficacy of this arm could not be determined.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''One 8-week cycle, then 28-day cycles'''<br />
<br />
===References===<br />
# '''NCIC CTG PA.3:''' Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47. Epub 2015 Jun 8. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext link to original article]'''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26067687 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:c6c509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:3ca01f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Inferior to gemcitabine. Here for historical reference purposes, only.''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
<br />
==FOLFIRINOX {{#subobject:aaa3c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e140cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior QoL by [http://groups.eortc.be/qol/eortc-qlq-c30 EORTC QLQ-C30]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 1200 mg/m<sup>2</sup>/day IV continuous 46-hour infusion on days 1 to 2; '''given last''' (total dose per cycle: 2400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1; '''given third together with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:3a0f4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 8-week lead-in {{#subobject:5d6dd0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx_2|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract Reni et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PEFG<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|GEM FDR<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GEM-CAP]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ Philip et al. 2010 (SWOG S0205)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_nab-Paclitaxel|Gemcitabine & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext Middleton et al. 2017 (ViP)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Vandetanib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
***In Burris et al. 1997, patients with grade 2 or lower toxicities could have had doses increased to 1250 mg/m<sup>2</sup><br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 4 week cycles {{#subobject:c6349|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract Kindler et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ Fuchs et al. 2015 (GAMMA)]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & [[Ganitumab (AMG 479)|Ganitumab]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ Catenacci et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & Vismodegib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 3 week cycles {{#subobject:8bae67|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 Hong et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|Gemcitabine & Simvastatin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, fixed-dose rate (FDR) {{#subobject:5114cc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 150 minutes (10 mg/m<sup>2</sup>/min) once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15925814 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
# '''SWOG S0205:''' Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 1;28(22):3605-10. Epub 2010 Jul 6. [http://jco.ascopubs.org/content/28/22/3605.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20606093 PubMed]<br />
# Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306953 PubMed]<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
# Hong JY, Nam EM, Lee J, Park JO, Lee SC, Song SY, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol. 2014 Jan;73(1):125-30. Epub 2013 Oct 27. [https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24162380 PubMed]<br />
# '''GAMMA:''' Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921-7. Epub 2015 Jan 21. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25609246 PubMed]<br />
# Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D, Wade J, Sleckman B, Lenz HJ, Stiff P, Kumar P, Xu P, Henderson L, Takebe N, Salgia R, Wang X, Stadler WM, de Sauvage FJ, Kindler HL. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015 Dec 20;33(36):4284-92. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/36/4284.long link to original article] '''contains protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527777 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
# '''ViP:''' Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr;18(4):486-499. Epub 2017 Mar 2. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28259610 PubMed]<br />
<br />
==GemOx {{#subobject:520af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:9d3266|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine, FDR]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
<br />
==Gemcitabine & nab-Paclitaxel {{#subobject:fbd698|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:63ba04|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] as follows, '''given first''':<br />
**Cycle 1: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15<br />
<br />
'''8-week cycle followed by 28-day cycles until disease progression or intolerance'''<br />
<br />
===Variant #2 {{#subobject:ecc1c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ Von Hoff et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 or 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/34/4548.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969517 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
<br />
==GTX {{#subobject:f0d62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
GTX: '''<u>G</u>'''emcitabine, '''<u>T</u>'''axotere (Docetaxel), '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:fc0e50|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.springerlink.com/content/75m422843l3461m0/ Fine et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: De Jesus-Acosta et al. 2012 lists the capecitabine dose as "750 mg/m<sup>2</sup>/day orally divided into two doses," but this is believed to be a typographical error since the original reference that it cites, Fine et al. 2007, uses capecitabine at 750 mg/m<sup>2</sup> PO BID. The 2009 ASCO abstract by Fine also lists this 750 mg/m<sup>2</sup> PO BID (1500 mg/m<sup>2</sup>/day) dose.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 75 minutes once per day on days 4 & 11<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 11<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75. Epub 2007 Apr 18. [http://www.springerlink.com/content/75m422843l3461m0/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17440727 PubMed]<br />
# '''Abstract:''' R. L. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. 2009 ASCO Annual Meeting abstract 4623. [http://ascopubs.org/doi/full/10.1200/jco.2009.27.15s.4623 link to abstract] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012 Feb;69(2):415-24. Epub 2011 Jul 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723 link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21800112 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:759f1a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:94d490|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<br />
=Metastatic disease, refractory=<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#OFF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Best supportive care. Placed here because one or more randomized clinical trials included a best supportive care arm in this disease context.''<br />
<br />
===References===<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<br />
==Capecitabine & Erlotinib {{#subobject:4655b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d5c799|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4787.full Kulke et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> (rounded to the nearest 150 mg tablet) PO BID on days 1 to 14<br />
*[[Erlotinib (Tarceva)]] 150 mg PO on days 1 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak EL, Muzikansky A, Lawrence C, Fuchs CS. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007 Oct 20;25(30):4787-92. [http://jco.ascopubs.org/content/25/30/4787.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947726 PubMed]<br />
<br />
==CapeOx {{#subobject:d09d5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:57ad5f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full Xiong et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 1000 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 110 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008 Oct 15;113(8):2046-52. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18756532 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, nanoliposomal Irinotecan {{#subobject:72308d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a81310|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''started on day 1 after folinic acid'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given prior to fluorouracil'''<br />
*[[Irinotecan liposome (Onivyde)]] 70 mg/m<sup>2</sup> (irinotecan free base) IV over 90 minutes once on day 1, '''given first'''<br />
**Per Wang-Gillam et al. 2015 (NAPOLI-01), 70 mg/m<sup>2</sup> irinotecan free base is equivalent to 80 mg/m<sup>2</sup> nanoliposomal irinotecan. According to the trial's ClinicalTrials.gov page: "The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m<sup>2</sup> dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/ m2 of irinotecan free base."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
<br />
==FOLFIRI {{#subobject:6fd426|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br />
===Variant #1 {{#subobject:6a9cae|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 Zaniboni et al. 2012 (GISCAD)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, and 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, modified FOLFIRI.3 {{#subobject:4758e8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFOX|mFOLFOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Irinotecan (Camptosar)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 3<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [http://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
# Zaniboni A, Aitini E, Barni S, Ferrari D, Cascinu S, Catalano V, Valmadre G, Ferrara D, Veltri E, Codignola C, Labianca R. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jun;69(6):1641-5. Epub 2012 May 11. [http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22576338 PubMed]<br />
<br />
==FOLFOX {{#subobject:377e80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:33ef68|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFIRI|mFOLFIRI.3]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [http://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
<br />
==OFF {{#subobject:8b32c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OFF: '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil, '''<u>F</u>'''olinic acid <br />
===Regimen {{#subobject:ae57d5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
<br />
''Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m<sup>2</sup>," or 850 mg/m<sup>2</sup>.''<br />
====Chemotherapy====<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once per day on days 8 & 22, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous 24-hour infusion on days 1, 8, 15, 22, '''started after folinic acid bolus'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, '''given prior to fluorouracil'''<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
# Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
<br />
==Olaparib monotherapy {{#subobject:0c2eb3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:21eb78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/3/244.long Kaufman et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients had germline BRCA1/2 mutations and had previously received gemcitabine.''<br />
====Chemotherapy====<br />
*[[Olaparib (Lynparza)]] 400 mg PO BID<br />
<br />
'''Continued until progression'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
# Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/33/3/244.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed]<br />
<br />
==Paclitaxel, nanoparticle albumin-bound monotherapy {{#subobject:ab9fc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8d38d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract Hosein et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Hosein PJ, de Lima Lopes G Jr, Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013 Apr;36(2):151-6. Epub 2012 Feb 2. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22307213 PubMed]<br />
<br />
[[Category:Pancreatic cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdheryhttps://hemonc.org/w/index.php?title=Pancreatic_cancer&diff=25825Pancreatic cancer2018-03-22T21:32:49Z<p>Rozinachowdhery: /* Observation */</p>
<hr />
<div><!--'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]]. If this is your first time visiting, we suggest you read the [[tutorial]].'''--><br />
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! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>Chicago, IL</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2017:''' [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.4948 Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/28398845 PubMed]<br />
*'''2016:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019760/ Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2016:''' [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.5561 Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/27247216 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2015:''' [http://annonc.oxfordjournals.org/content/26/suppl_5/v56.full.pdf+html Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015)] [https://www.ncbi.nlm.nih.gov/pubmed/26314780 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf NCCN Guidelines - Pancreatic Adenocarcinoma]<br />
<br />
=Adjuvant therapy=<br />
==Capecitabine & Gemcitabine {{#subobject:17f9f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Regimen {{#subobject:e6a3e3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Treatment starts within 12 weeks of surgery.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week on weeks 1 to 3<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Fluorouracil & Leucovorin {{#subobject:29266e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:242770|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_monotherapy_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
<br />
==Fluorouracil, then Fluorouracil & RT {{#subobject:331d4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:89426a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Leucovorin|5-FU & Leucovorin]]<br> [[#Observation|Observation]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine.2C_then_Fluorouracil_.26_RT.2C_then_Gemcitabine|Gemcitabine, then Fluorouracil & RT, then Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Chemotherapy portion====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 21<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy portion====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 28<br />
<br />
'''6-week cycle for 2 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:34e70d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a756a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Leucovorin|Fluorouracil & Leucovorin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine|Capecitabine & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
<br />
''Note: efficacy for CONKO-001 is based on the 2013 update.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
# Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Gemcitabine, then Fluorouracil & RT, then Gemcitabine {{#subobject:f8c8d9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:3fef3f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_monotherapy_.26_RT|Fluorouracil & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy portion, part 1====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy portion====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy portion, part 2====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Leucovorin|5-FU & Leucovorin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[[#Fluorouracil_monotherapy_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
<br />
''No active antineoplastic treatment. Efficacy for ESPAC-1 is based on the 2004 update and efficacy for CONKO-001 is based on 2013 update.''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cdcc15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, potentially resectable=<br />
<br />
==Docetaxel, Gemcitabine, RT {{#subobject:49a407|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:78b0ba|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1245%2FASO.2005.04.503 Pipas et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 65 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Gemcitabine (Gemzar)]] 4000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29<br />
<br />
'''6-week course, followed immediately (day 43) by:'''<br />
<br />
====Chemoradiation====<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy to primary target volume. Then 5.4 Gy boost to secondary target volume of 1- to 1.5-cm margin on all sides, including proven nodal involvement. Total 50.4 Gy in 28 fractions.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
# Pipas JM, Barth RJ Jr, Zaki B, Tsapakos MJ, Suriawinata AA, Bettmann MA, Cates JM, Ripple GH, Sutton JE, Gordon SR, McDonnell CE, Perez RP, Redfield N, Meyer LP, Marshall JF, Cole BF, Colacchio TA. Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2005 Dec;12(12):995-1004. Epub 2005 Nov 1. [http://link.springer.com/article/10.1245%2FASO.2005.04.503 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16252135 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:55e32d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen 1 {{#subobject:6ce551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract Takahashi et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*Concurrent radiation therapy, 2 Gy per fraction, 5 days per week, 25 fractions, total dose of 50 Gy over 5 weeks.<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
''Restaging is performed 8 weeks after radiation complete (2 weeks after chemotherapy complete). Resection immediately thereafter, if feasible.''<br />
<br />
===Regimen 2 {{#subobject:dc32dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 500 mg/m<sup>2</sup> IV over 50 minutes once per week for 6 weeks<br />
*Concurrent radiation therapy, 180 cGy x 22 with 3 cm margin to GTV then 180 cGy x 6 with 2 cm margin to GTV, total 50.4 Gy over 6 weeks<br />
<br />
''Restaging after radiation complete. 4 to 6 week break, followed by surgery, followed by 4 to 8 week break. Then adjuvant chemotherapy:''<br />
<br />
====Adjuvant chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 5 cycles'''<br />
<br />
===References===<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [http://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, Ioka T, Uehara H, Yano M, Ishikawa O. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013 Dec;258(6):1040-50.[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23799421 PubMed]<br />
<br />
==Gemcitabine, Cetuximab, RT {{#subobject:aea7b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c38534|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ Pipas et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**6 to 8 days prior radiation: 400 mg/m<sup>2</sup> IV over 2 hours once<br />
**During radiation: 250 mg/m<sup>2</sup> over 60 minutes once per week for 6 doses<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, delivered using IMRT. Gross tumor volume (GTV) was all known disease including imaging proven nodal disease. The primary planning target volume (PTV1) included the GTV with 2- to 3-cm margins in all directions as well as potential nodal involvement. Secondary planning target volume (PTV2) included the GTV with 1- to 1.5-cm margins on all sides including proven nodal involvement. Tertiary planning treatment volume (PTV3) included the area of the GTV adjacent to the vascular structures specifically the mesenteric and portal vessels with a 0.5-cm margin. The prescription dose delivered to PTV3 was 54 Gy in 28 fractions. Synchronously, PTV1 and PTV2 received 45 and 50.4 Gy, respectively. All fields were treated daily at five fractions per week.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
''One month following therapy, patients were restaged with CT scan of chest/abdomen/pelvis. Patients deemed to be candidates for surgical resection were offered laparotomy ∼6to 10 weeks after completion of neoadjuvant therapy.''<br />
<br />
===References===<br />
# Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, Tsongalis GJ, Colacchio TA, Gordon SR, Sutton JE, Srivastava A, Smith KD, Gardner TB, Korc M, Davis TH, Preis M, Tarczewski SM, Mackenzie TA, Barth RJ Jr. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. 2012 Nov;23(11):2820-7. Epub 2012 May 9. [http://annonc.oxfordjournals.org/content/23/11/2820.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571859 PubMed]<br />
<br />
==mFOLFIRINOX, Gemcitabine, RT {{#subobject:b71003|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFIRINOX: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
<br>RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:d87ec0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ Blazer et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Modified FOLFIRINOX portion====<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion for 46 h on days 1 to 3<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 4<br />
<br />
'''14-day cycle for 4 to 8 cycles'''<br />
<br />
''Followed by complete restaging. If tumor localized but still not resectable, chemoradiotherapy was administered:''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup>/week concurrent with radiation<br />
*Radiation was 36 Gy in 15 daily fractions<br />
<br />
===Variant #2 {{#subobject:7bb0e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ Hosein et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====FOLFIRINOX portion====<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
*[[Folinic acid (Leucovorin)]] 400mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400mg/m<sup>2</sup> IV bolus on day 1<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion for 46 hours on days 1 to 3<br />
<br />
'''Cycles repeated every 2 weeks. Protocol followed "per ACCORD-11 trial"'''<br />
<br />
''Treatment stopped at maximum response or tolerability. Resectable patients by imaging criteria were offered surgery, followed by postoperative chemoradiotherapy. Unresectable patients were offered chemoradiotherapy, followed by surgery (if they became resectable):''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup>/week<br />
*Radiation at 50.4 Gy in 28 fractions.<br />
<br />
===References===<br />
# '''Retrospective:''' Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, Narayanan G, Ribeiro A, Portelance L, Merchan JR, Levi JU, Rocha-Lima CM. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012 May 29;12:199. [http://www.biomedcentral.com/1471-2407/12/199 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22642850 PubMed]<br />
# '''Retrospective:''' Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, Wuthrick E, Williams TM, Reardon J, Christopher Ellison E, Bloomston M, Bekaii-Saab T. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015 Apr;22(4):1153-9. [http://link.springer.com/article/10.1245%2Fs10434-014-4225-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25358667 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, unresectable=<br />
<br />
==Capecitabine monotherapy {{#subobject:dbd841|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dc4779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:6d97a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, Gem 3 out of 4 weeks x 4 {{#subobject:87edde|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Erlotinib & Gemcitabine x 2 more cycles (6 total) versus Capecitabine, Erlotinib, RT<br />
<br />
===Variant #2, Gem 3 out of 4 weeks x 6 {{#subobject:5a5e14|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
''Note: it is not clear from the protocol whether erlotinib is continued beyond the end of chemotherapy.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] as follows:<br />
**Cycles 1 to 4: 100 mg PO once per day<br />
**Cycles 5 & 6: 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in {{#subobject:b4258e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: although this is technically a superior arm, the effect size is considered to be not clinically meaningful.''<br />
====Initial chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 or 150 mg (100 mg dose recommended) PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 or 150 mg (100 mg dose recommended) PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Fluorouracil & RT {{#subobject:26f1c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:29784e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ Herman et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Fluorouracil & RT with TNFerade<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion once per day on radiation days (total dose per week: 1000 mg/m<sup>2</sup>)<br />
*Concurrent radiation therapy, 50.4 Gy total: 1.80 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy, followed by 1.80 Gy x 3 fractions boost to the tumor bed.<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
*Gemcitabine or Erlotinib & Gemcitabine maintenance<br />
<br />
===References===<br />
# Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, Donehower RC, Pawlik TM, Ziegler MA, Cai H, Savage DT, Canto MI, Klapman J, Reid T, Shah RJ, Hoffe SE, Rosemurgy A, Wolfgang CL, Laheru DA. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013 Mar 1;31(7):886-94. Epub 2013 Jan 22. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.7516 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23341531 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:4f0be9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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===Variant #1, 3 out of 4 weeks x 4 {{#subobject:c511a7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Gemcitabine x 2 more cycles (6 total) versus Capecitabine & RT<br />
<br />
===Variant #2, 3 out of 4 weeks x 6 {{#subobject:cf89f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in {{#subobject:82f8b2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#GemOx|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_.26_RT_2|Gemcitabine & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent 4-week cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''Continued for at least 3 months'''<br />
<br />
''Per '''Louvet et al. 2005''', subsequent chemoradiotherapy was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:a6e6fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 (600 mg/m<sup>2</sup>) {{#subobject:a6de29|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract Cardenes et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV over 30 to 60 minutes once per week during radiation<br />
*Concurrent radiation therapy, 1.8 Gy per fraction, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks.<br />
<br />
'''One course, followed in 4 weeks by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycle for 5 cycles or until disease progression'''<br />
<br />
===Variant #2 (400 mg/m<sup>2</sup>) {{#subobject:c1ac3c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract Epelbaum et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week for 7 weeks<br />
<br />
'''Radiation planning during this phase, followed by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 400 mg/m<sup>2</sup> IV over 30 minutes once per week (days 1, 8, 15)<br />
*Concurrent radiation therapy, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks<br />
<br />
'''28 day cycle for 2 cycles (completion of radiation), followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycles until disease progression'''<br />
<br />
===References===<br />
# Epelbaum R, Rosenblatt E, Nasrallah S, Faraggi D, Gaitini D, Mizrahi S, Kuten A. Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J Surg Oncol. 2002 Nov;81(3):138-43. [http://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12407726 PubMed]<br />
# Cardenes HR, Moore AM, Johnson CS, Yu M, Helft P, Chiorean EG, Vinson J, Howard TJ, Stephens AW, Tai DF, Loehrer PJ Sr. A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study. Am J Clin Oncol. 2011 Oct;34(5):460-5.[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20881474 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
<br />
==GemOx {{#subobject:19d87f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:5a25e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_2|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycle for at least 3 months'''<br />
<br />
''Subsequent chemoradiotherapy was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
<br />
=Metastatic disease, first-line=<br />
<br />
==Capecitabine monotherapy {{#subobject:4f5f03|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b31bbb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Capecitabine & Gemcitabine {{#subobject:2f0431|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Variant #1 {{#subobject:fcd708|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Note: this is essentially identical to the maintenance phase of Cunningham et al. 2009, below.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:e8f0bf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21, 29 to 49<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:a7e551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 650 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 24 weeks'''<br />
<br />
===References===<br />
# Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:c30d8f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, weekly dosing {{#subobject:20a0f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note that cisplatin is not given on day 22 of the first 8 weeks; otherwise, the schedule is identical to the schedule for gemcitabine.''<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] as follows, '''given 60 minutes prior to gemcitabine''':<br />
**First 8 weeks: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Subsequent cycles: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, bi-weekly dosing {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract Cascinu et al. 2008 (GISCAD)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Cisplatin, Gemcitabine, Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 Jan;9(1):39-44. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18077217 PubMed]<br />
# Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:bf797a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:43fe43|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext Kordes et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|Erlotinib, Gemcitabine, Metformin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:fc43f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 or 150 mg (100 mg dose recommended) PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 or 150 mg (100 mg dose recommended) PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47. Epub 2015 Jun 8. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext link to original article]'''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26067687 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:c6c509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:3ca01f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Inferior to gemcitabine. Here for historical reference purposes, only.''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
<br />
==FOLFIRINOX {{#subobject:aaa3c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e140cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior QoL by [http://groups.eortc.be/qol/eortc-qlq-c30 EORTC QLQ-C30]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 1200 mg/m<sup>2</sup>/day IV continuous 46-hour infusion on days 1 to 2; '''given last''' (total dose per cycle: 2400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1; '''given third together with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:3a0f4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 8-week lead-in {{#subobject:5d6dd0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx_2|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract Reni et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PEFG<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|GEM FDR<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GEM-CAP]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ Philip et al. 2010 (SWOG S0205)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_nab-Paclitaxel|Gemcitabine & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext Middleton et al. 2017 (ViP)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Vandetanib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
***In Burris et al. 1997, patients with grade 2 or lower toxicities could have had doses increased to 1250 mg/m<sup>2</sup><br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 4 week cycles {{#subobject:c6349|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract Kindler et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ Fuchs et al. 2015 (GAMMA)]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & [[Ganitumab (AMG 479)|Ganitumab]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ Catenacci et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & Vismodegib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 3 week cycles {{#subobject:8bae67|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 Hong et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|Gemcitabine & Simvastatin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, fixed-dose rate (FDR) {{#subobject:5114cc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 150 minutes (10 mg/m<sup>2</sup>/min) once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15925814 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
# '''SWOG S0205:''' Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 1;28(22):3605-10. Epub 2010 Jul 6. [http://jco.ascopubs.org/content/28/22/3605.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20606093 PubMed]<br />
# Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306953 PubMed]<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
# Hong JY, Nam EM, Lee J, Park JO, Lee SC, Song SY, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol. 2014 Jan;73(1):125-30. Epub 2013 Oct 27. [https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24162380 PubMed]<br />
# '''GAMMA:''' Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921-7. Epub 2015 Jan 21. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25609246 PubMed]<br />
# Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D, Wade J, Sleckman B, Lenz HJ, Stiff P, Kumar P, Xu P, Henderson L, Takebe N, Salgia R, Wang X, Stadler WM, de Sauvage FJ, Kindler HL. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015 Dec 20;33(36):4284-92. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/36/4284.long link to original article] '''contains protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527777 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
# '''ViP:''' Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr;18(4):486-499. Epub 2017 Mar 2. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28259610 PubMed]<br />
<br />
==GemOx {{#subobject:520af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:9d3266|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine, FDR]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
<br />
==Gemcitabine & nab-Paclitaxel {{#subobject:fbd698|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:63ba04|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] as follows, '''given first''':<br />
**Cycle 1: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15<br />
<br />
'''8-week cycle followed by 28-day cycles until disease progression or intolerance'''<br />
<br />
===Variant #2 {{#subobject:ecc1c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ Von Hoff et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 or 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/34/4548.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969517 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
<br />
==GTX {{#subobject:f0d62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
GTX: '''<u>G</u>'''emcitabine, '''<u>T</u>'''axotere (Docetaxel), '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:fc0e50|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.springerlink.com/content/75m422843l3461m0/ Fine et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: De Jesus-Acosta et al. 2012 lists the capecitabine dose as "750 mg/m<sup>2</sup>/day orally divided into two doses," but this is believed to be a typographical error since the original reference that it cites, Fine et al. 2007, uses capecitabine at 750 mg/m<sup>2</sup> PO BID. The 2009 ASCO abstract by Fine also lists this 750 mg/m<sup>2</sup> PO BID (1500 mg/m<sup>2</sup>/day) dose.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 75 minutes once per day on days 4 & 11<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 11<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75. Epub 2007 Apr 18. [http://www.springerlink.com/content/75m422843l3461m0/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17440727 PubMed]<br />
# '''Abstract:''' R. L. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. 2009 ASCO Annual Meeting abstract 4623. [http://ascopubs.org/doi/full/10.1200/jco.2009.27.15s.4623 link to abstract] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012 Feb;69(2):415-24. Epub 2011 Jul 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723 link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21800112 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:759f1a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:94d490|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<br />
=Metastatic disease, refractory=<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#OFF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Best supportive care. Placed here because one or more randomized clinical trials included a best supportive care arm in this disease context.''<br />
<br />
===References===<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<br />
==Capecitabine & Erlotinib {{#subobject:4655b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d5c799|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4787.full Kulke et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> (rounded to the nearest 150 mg tablet) PO BID on days 1 to 14<br />
*[[Erlotinib (Tarceva)]] 150 mg PO on days 1 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak EL, Muzikansky A, Lawrence C, Fuchs CS. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007 Oct 20;25(30):4787-92. [http://jco.ascopubs.org/content/25/30/4787.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947726 PubMed]<br />
<br />
==CapeOx {{#subobject:d09d5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:57ad5f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full Xiong et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 1000 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 110 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008 Oct 15;113(8):2046-52. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18756532 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, nanoliposomal Irinotecan {{#subobject:72308d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a81310|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''started on day 1 after folinic acid'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given prior to fluorouracil'''<br />
*[[Irinotecan liposome (Onivyde)]] 70 mg/m<sup>2</sup> (irinotecan free base) IV over 90 minutes once on day 1, '''given first'''<br />
**Per Wang-Gillam et al. 2015 (NAPOLI-01), 70 mg/m<sup>2</sup> irinotecan free base is equivalent to 80 mg/m<sup>2</sup> nanoliposomal irinotecan. According to the trial's ClinicalTrials.gov page: "The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m<sup>2</sup> dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/ m2 of irinotecan free base."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
<br />
==FOLFIRI {{#subobject:6fd426|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br />
===Variant #1 {{#subobject:6a9cae|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 Zaniboni et al. 2012 (GISCAD)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, and 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, modified FOLFIRI.3 {{#subobject:4758e8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFOX|mFOLFOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Irinotecan (Camptosar)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 3<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [http://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
# Zaniboni A, Aitini E, Barni S, Ferrari D, Cascinu S, Catalano V, Valmadre G, Ferrara D, Veltri E, Codignola C, Labianca R. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jun;69(6):1641-5. Epub 2012 May 11. [http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22576338 PubMed]<br />
<br />
==FOLFOX {{#subobject:377e80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:33ef68|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFIRI|mFOLFIRI.3]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [http://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
<br />
==OFF {{#subobject:8b32c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OFF: '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil, '''<u>F</u>'''olinic acid <br />
===Regimen {{#subobject:ae57d5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
<br />
''Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m<sup>2</sup>," or 850 mg/m<sup>2</sup>.''<br />
====Chemotherapy====<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once per day on days 8 & 22, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous 24-hour infusion on days 1, 8, 15, 22, '''started after folinic acid bolus'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, '''given prior to fluorouracil'''<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
# Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
<br />
==Olaparib monotherapy {{#subobject:0c2eb3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:21eb78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/3/244.long Kaufman et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients had germline BRCA1/2 mutations and had previously received gemcitabine.''<br />
====Chemotherapy====<br />
*[[Olaparib (Lynparza)]] 400 mg PO BID<br />
<br />
'''Continued until progression'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
# Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/33/3/244.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed]<br />
<br />
==Paclitaxel, nanoparticle albumin-bound monotherapy {{#subobject:ab9fc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8d38d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract Hosein et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Hosein PJ, de Lima Lopes G Jr, Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013 Apr;36(2):151-6. Epub 2012 Feb 2. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22307213 PubMed]<br />
<br />
[[Category:Pancreatic cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdheryhttps://hemonc.org/w/index.php?title=Pancreatic_cancer&diff=25824Pancreatic cancer2018-03-22T21:30:48Z<p>Rozinachowdhery: /* Gemcitabine monotherapy */</p>
<hr />
<div><!--'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]]. If this is your first time visiting, we suggest you read the [[tutorial]].'''--><br />
<!--Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are [[How_to_contribute|invited to contribute to the site]].-->{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>Chicago, IL</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2017:''' [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.4948 Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/28398845 PubMed]<br />
*'''2016:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019760/ Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2016:''' [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.5561 Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/27247216 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2015:''' [http://annonc.oxfordjournals.org/content/26/suppl_5/v56.full.pdf+html Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015)] [https://www.ncbi.nlm.nih.gov/pubmed/26314780 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf NCCN Guidelines - Pancreatic Adenocarcinoma]<br />
<br />
=Adjuvant therapy=<br />
==Capecitabine & Gemcitabine {{#subobject:17f9f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Regimen {{#subobject:e6a3e3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Treatment starts within 12 weeks of surgery.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week on weeks 1 to 3<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Fluorouracil & Leucovorin {{#subobject:29266e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:242770|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_monotherapy_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
<br />
==Fluorouracil, then Fluorouracil & RT {{#subobject:331d4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:89426a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Leucovorin|5-FU & Leucovorin]]<br> [[#Observation|Observation]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine.2C_then_Fluorouracil_.26_RT.2C_then_Gemcitabine|Gemcitabine, then Fluorouracil & RT, then Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Chemotherapy portion====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 21<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy portion====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 28<br />
<br />
'''6-week cycle for 2 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:34e70d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a756a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Leucovorin|Fluorouracil & Leucovorin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine|Capecitabine & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
<br />
''Note: efficacy for CONKO-001 is based on the 2013 update.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
# Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Gemcitabine, then Fluorouracil & RT, then Gemcitabine {{#subobject:f8c8d9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:3fef3f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_monotherapy_.26_RT|Fluorouracil & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy portion, part 1====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy portion====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy portion, part 2====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Leucovorin|5-FU & Leucovorin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[[#Fluorouracil_monotherapy_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
<br />
''No active antineoplastic treatment. Efficacy for ESPAC-1 is based on the 2004 update.''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cdcc15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, potentially resectable=<br />
<br />
==Docetaxel, Gemcitabine, RT {{#subobject:49a407|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:78b0ba|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1245%2FASO.2005.04.503 Pipas et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 65 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Gemcitabine (Gemzar)]] 4000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29<br />
<br />
'''6-week course, followed immediately (day 43) by:'''<br />
<br />
====Chemoradiation====<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy to primary target volume. Then 5.4 Gy boost to secondary target volume of 1- to 1.5-cm margin on all sides, including proven nodal involvement. Total 50.4 Gy in 28 fractions.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
# Pipas JM, Barth RJ Jr, Zaki B, Tsapakos MJ, Suriawinata AA, Bettmann MA, Cates JM, Ripple GH, Sutton JE, Gordon SR, McDonnell CE, Perez RP, Redfield N, Meyer LP, Marshall JF, Cole BF, Colacchio TA. Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2005 Dec;12(12):995-1004. Epub 2005 Nov 1. [http://link.springer.com/article/10.1245%2FASO.2005.04.503 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16252135 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:55e32d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen 1 {{#subobject:6ce551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract Takahashi et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*Concurrent radiation therapy, 2 Gy per fraction, 5 days per week, 25 fractions, total dose of 50 Gy over 5 weeks.<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
''Restaging is performed 8 weeks after radiation complete (2 weeks after chemotherapy complete). Resection immediately thereafter, if feasible.''<br />
<br />
===Regimen 2 {{#subobject:dc32dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 500 mg/m<sup>2</sup> IV over 50 minutes once per week for 6 weeks<br />
*Concurrent radiation therapy, 180 cGy x 22 with 3 cm margin to GTV then 180 cGy x 6 with 2 cm margin to GTV, total 50.4 Gy over 6 weeks<br />
<br />
''Restaging after radiation complete. 4 to 6 week break, followed by surgery, followed by 4 to 8 week break. Then adjuvant chemotherapy:''<br />
<br />
====Adjuvant chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 5 cycles'''<br />
<br />
===References===<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [http://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, Ioka T, Uehara H, Yano M, Ishikawa O. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013 Dec;258(6):1040-50.[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23799421 PubMed]<br />
<br />
==Gemcitabine, Cetuximab, RT {{#subobject:aea7b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c38534|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ Pipas et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**6 to 8 days prior radiation: 400 mg/m<sup>2</sup> IV over 2 hours once<br />
**During radiation: 250 mg/m<sup>2</sup> over 60 minutes once per week for 6 doses<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, delivered using IMRT. Gross tumor volume (GTV) was all known disease including imaging proven nodal disease. The primary planning target volume (PTV1) included the GTV with 2- to 3-cm margins in all directions as well as potential nodal involvement. Secondary planning target volume (PTV2) included the GTV with 1- to 1.5-cm margins on all sides including proven nodal involvement. Tertiary planning treatment volume (PTV3) included the area of the GTV adjacent to the vascular structures specifically the mesenteric and portal vessels with a 0.5-cm margin. The prescription dose delivered to PTV3 was 54 Gy in 28 fractions. Synchronously, PTV1 and PTV2 received 45 and 50.4 Gy, respectively. All fields were treated daily at five fractions per week.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
''One month following therapy, patients were restaged with CT scan of chest/abdomen/pelvis. Patients deemed to be candidates for surgical resection were offered laparotomy ∼6to 10 weeks after completion of neoadjuvant therapy.''<br />
<br />
===References===<br />
# Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, Tsongalis GJ, Colacchio TA, Gordon SR, Sutton JE, Srivastava A, Smith KD, Gardner TB, Korc M, Davis TH, Preis M, Tarczewski SM, Mackenzie TA, Barth RJ Jr. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. 2012 Nov;23(11):2820-7. Epub 2012 May 9. [http://annonc.oxfordjournals.org/content/23/11/2820.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571859 PubMed]<br />
<br />
==mFOLFIRINOX, Gemcitabine, RT {{#subobject:b71003|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
mFOLFIRINOX: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
<br>RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:d87ec0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ Blazer et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Modified FOLFIRINOX portion====<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion for 46 h on days 1 to 3<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 4<br />
<br />
'''14-day cycle for 4 to 8 cycles'''<br />
<br />
''Followed by complete restaging. If tumor localized but still not resectable, chemoradiotherapy was administered:''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup>/week concurrent with radiation<br />
*Radiation was 36 Gy in 15 daily fractions<br />
<br />
===Variant #2 {{#subobject:7bb0e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ Hosein et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====FOLFIRINOX portion====<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
*[[Folinic acid (Leucovorin)]] 400mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400mg/m<sup>2</sup> IV bolus on day 1<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion for 46 hours on days 1 to 3<br />
<br />
'''Cycles repeated every 2 weeks. Protocol followed "per ACCORD-11 trial"'''<br />
<br />
''Treatment stopped at maximum response or tolerability. Resectable patients by imaging criteria were offered surgery, followed by postoperative chemoradiotherapy. Unresectable patients were offered chemoradiotherapy, followed by surgery (if they became resectable):''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup>/week<br />
*Radiation at 50.4 Gy in 28 fractions.<br />
<br />
===References===<br />
# '''Retrospective:''' Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, Narayanan G, Ribeiro A, Portelance L, Merchan JR, Levi JU, Rocha-Lima CM. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012 May 29;12:199. [http://www.biomedcentral.com/1471-2407/12/199 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22642850 PubMed]<br />
# '''Retrospective:''' Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, Wuthrick E, Williams TM, Reardon J, Christopher Ellison E, Bloomston M, Bekaii-Saab T. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015 Apr;22(4):1153-9. [http://link.springer.com/article/10.1245%2Fs10434-014-4225-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25358667 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, unresectable=<br />
<br />
==Capecitabine monotherapy {{#subobject:dbd841|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dc4779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:6d97a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===Variant #1, Gem 3 out of 4 weeks x 4 {{#subobject:87edde|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Erlotinib & Gemcitabine x 2 more cycles (6 total) versus Capecitabine, Erlotinib, RT<br />
<br />
===Variant #2, Gem 3 out of 4 weeks x 6 {{#subobject:5a5e14|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
''Note: it is not clear from the protocol whether erlotinib is continued beyond the end of chemotherapy.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] as follows:<br />
**Cycles 1 to 4: 100 mg PO once per day<br />
**Cycles 5 & 6: 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in {{#subobject:b4258e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: although this is technically a superior arm, the effect size is considered to be not clinically meaningful.''<br />
====Initial chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 or 150 mg (100 mg dose recommended) PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 or 150 mg (100 mg dose recommended) PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Fluorouracil & RT {{#subobject:26f1c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:29784e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ Herman et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Fluorouracil & RT with TNFerade<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion once per day on radiation days (total dose per week: 1000 mg/m<sup>2</sup>)<br />
*Concurrent radiation therapy, 50.4 Gy total: 1.80 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy, followed by 1.80 Gy x 3 fractions boost to the tumor bed.<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
*Gemcitabine or Erlotinib & Gemcitabine maintenance<br />
<br />
===References===<br />
# Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, Donehower RC, Pawlik TM, Ziegler MA, Cai H, Savage DT, Canto MI, Klapman J, Reid T, Shah RJ, Hoffe SE, Rosemurgy A, Wolfgang CL, Laheru DA. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013 Mar 1;31(7):886-94. Epub 2013 Jan 22. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.7516 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23341531 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:4f0be9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 3 out of 4 weeks x 4 {{#subobject:c511a7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Gemcitabine x 2 more cycles (6 total) versus Capecitabine & RT<br />
<br />
===Variant #2, 3 out of 4 weeks x 6 {{#subobject:cf89f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in {{#subobject:82f8b2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#GemOx|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_.26_RT_2|Gemcitabine & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent 4-week cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''Continued for at least 3 months'''<br />
<br />
''Per '''Louvet et al. 2005''', subsequent chemoradiotherapy was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:a6e6fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 (600 mg/m<sup>2</sup>) {{#subobject:a6de29|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract Cardenes et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV over 30 to 60 minutes once per week during radiation<br />
*Concurrent radiation therapy, 1.8 Gy per fraction, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks.<br />
<br />
'''One course, followed in 4 weeks by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycle for 5 cycles or until disease progression'''<br />
<br />
===Variant #2 (400 mg/m<sup>2</sup>) {{#subobject:c1ac3c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract Epelbaum et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week for 7 weeks<br />
<br />
'''Radiation planning during this phase, followed by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 400 mg/m<sup>2</sup> IV over 30 minutes once per week (days 1, 8, 15)<br />
*Concurrent radiation therapy, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks<br />
<br />
'''28 day cycle for 2 cycles (completion of radiation), followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycles until disease progression'''<br />
<br />
===References===<br />
# Epelbaum R, Rosenblatt E, Nasrallah S, Faraggi D, Gaitini D, Mizrahi S, Kuten A. Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J Surg Oncol. 2002 Nov;81(3):138-43. [http://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12407726 PubMed]<br />
# Cardenes HR, Moore AM, Johnson CS, Yu M, Helft P, Chiorean EG, Vinson J, Howard TJ, Stephens AW, Tai DF, Loehrer PJ Sr. A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study. Am J Clin Oncol. 2011 Oct;34(5):460-5.[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20881474 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
<br />
==GemOx {{#subobject:19d87f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:5a25e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_2|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycle for at least 3 months'''<br />
<br />
''Subsequent chemoradiotherapy was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
<br />
=Metastatic disease, first-line=<br />
<br />
==Capecitabine monotherapy {{#subobject:4f5f03|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b31bbb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Capecitabine & Gemcitabine {{#subobject:2f0431|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Variant #1 {{#subobject:fcd708|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Note: this is essentially identical to the maintenance phase of Cunningham et al. 2009, below.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:e8f0bf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21, 29 to 49<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:a7e551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 650 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 24 weeks'''<br />
<br />
===References===<br />
# Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:c30d8f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, weekly dosing {{#subobject:20a0f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note that cisplatin is not given on day 22 of the first 8 weeks; otherwise, the schedule is identical to the schedule for gemcitabine.''<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] as follows, '''given 60 minutes prior to gemcitabine''':<br />
**First 8 weeks: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Subsequent cycles: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, bi-weekly dosing {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract Cascinu et al. 2008 (GISCAD)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Cisplatin, Gemcitabine, Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 Jan;9(1):39-44. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18077217 PubMed]<br />
# Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:bf797a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:43fe43|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext Kordes et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|Erlotinib, Gemcitabine, Metformin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:fc43f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 or 150 mg (100 mg dose recommended) PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 or 150 mg (100 mg dose recommended) PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47. Epub 2015 Jun 8. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext link to original article]'''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26067687 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:c6c509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:3ca01f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Inferior to gemcitabine. Here for historical reference purposes, only.''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
<br />
==FOLFIRINOX {{#subobject:aaa3c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e140cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior QoL by [http://groups.eortc.be/qol/eortc-qlq-c30 EORTC QLQ-C30]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 1200 mg/m<sup>2</sup>/day IV continuous 46-hour infusion on days 1 to 2; '''given last''' (total dose per cycle: 2400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1; '''given third together with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:3a0f4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 8-week lead-in {{#subobject:5d6dd0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx_2|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract Reni et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PEFG<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|GEM FDR<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GEM-CAP]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ Philip et al. 2010 (SWOG S0205)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_nab-Paclitaxel|Gemcitabine & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext Middleton et al. 2017 (ViP)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Vandetanib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
***In Burris et al. 1997, patients with grade 2 or lower toxicities could have had doses increased to 1250 mg/m<sup>2</sup><br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 4 week cycles {{#subobject:c6349|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract Kindler et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ Fuchs et al. 2015 (GAMMA)]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & [[Ganitumab (AMG 479)|Ganitumab]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ Catenacci et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & Vismodegib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 3 week cycles {{#subobject:8bae67|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 Hong et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|Gemcitabine & Simvastatin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, fixed-dose rate (FDR) {{#subobject:5114cc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 150 minutes (10 mg/m<sup>2</sup>/min) once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15925814 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
# '''SWOG S0205:''' Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 1;28(22):3605-10. Epub 2010 Jul 6. [http://jco.ascopubs.org/content/28/22/3605.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20606093 PubMed]<br />
# Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306953 PubMed]<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
# Hong JY, Nam EM, Lee J, Park JO, Lee SC, Song SY, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol. 2014 Jan;73(1):125-30. Epub 2013 Oct 27. [https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24162380 PubMed]<br />
# '''GAMMA:''' Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921-7. Epub 2015 Jan 21. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25609246 PubMed]<br />
# Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D, Wade J, Sleckman B, Lenz HJ, Stiff P, Kumar P, Xu P, Henderson L, Takebe N, Salgia R, Wang X, Stadler WM, de Sauvage FJ, Kindler HL. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015 Dec 20;33(36):4284-92. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/36/4284.long link to original article] '''contains protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527777 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
# '''ViP:''' Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr;18(4):486-499. Epub 2017 Mar 2. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28259610 PubMed]<br />
<br />
==GemOx {{#subobject:520af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:9d3266|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine, FDR]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
<br />
==Gemcitabine & nab-Paclitaxel {{#subobject:fbd698|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:63ba04|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] as follows, '''given first''':<br />
**Cycle 1: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15<br />
<br />
'''8-week cycle followed by 28-day cycles until disease progression or intolerance'''<br />
<br />
===Variant #2 {{#subobject:ecc1c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ Von Hoff et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 or 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/34/4548.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969517 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
<br />
==GTX {{#subobject:f0d62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
GTX: '''<u>G</u>'''emcitabine, '''<u>T</u>'''axotere (Docetaxel), '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:fc0e50|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.springerlink.com/content/75m422843l3461m0/ Fine et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: De Jesus-Acosta et al. 2012 lists the capecitabine dose as "750 mg/m<sup>2</sup>/day orally divided into two doses," but this is believed to be a typographical error since the original reference that it cites, Fine et al. 2007, uses capecitabine at 750 mg/m<sup>2</sup> PO BID. The 2009 ASCO abstract by Fine also lists this 750 mg/m<sup>2</sup> PO BID (1500 mg/m<sup>2</sup>/day) dose.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 75 minutes once per day on days 4 & 11<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 11<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75. Epub 2007 Apr 18. [http://www.springerlink.com/content/75m422843l3461m0/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17440727 PubMed]<br />
# '''Abstract:''' R. L. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. 2009 ASCO Annual Meeting abstract 4623. [http://ascopubs.org/doi/full/10.1200/jco.2009.27.15s.4623 link to abstract] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012 Feb;69(2):415-24. Epub 2011 Jul 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723 link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21800112 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:759f1a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:94d490|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<br />
=Metastatic disease, refractory=<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#OFF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Best supportive care. Placed here because one or more randomized clinical trials included a best supportive care arm in this disease context.''<br />
<br />
===References===<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<br />
==Capecitabine & Erlotinib {{#subobject:4655b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d5c799|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4787.full Kulke et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> (rounded to the nearest 150 mg tablet) PO BID on days 1 to 14<br />
*[[Erlotinib (Tarceva)]] 150 mg PO on days 1 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak EL, Muzikansky A, Lawrence C, Fuchs CS. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007 Oct 20;25(30):4787-92. [http://jco.ascopubs.org/content/25/30/4787.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947726 PubMed]<br />
<br />
==CapeOx {{#subobject:d09d5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:57ad5f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full Xiong et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 1000 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 110 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008 Oct 15;113(8):2046-52. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18756532 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, nanoliposomal Irinotecan {{#subobject:72308d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a81310|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''started on day 1 after folinic acid'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given prior to fluorouracil'''<br />
*[[Irinotecan liposome (Onivyde)]] 70 mg/m<sup>2</sup> (irinotecan free base) IV over 90 minutes once on day 1, '''given first'''<br />
**Per Wang-Gillam et al. 2015 (NAPOLI-01), 70 mg/m<sup>2</sup> irinotecan free base is equivalent to 80 mg/m<sup>2</sup> nanoliposomal irinotecan. According to the trial's ClinicalTrials.gov page: "The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m<sup>2</sup> dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/ m2 of irinotecan free base."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
<br />
==FOLFIRI {{#subobject:6fd426|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br />
===Variant #1 {{#subobject:6a9cae|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 Zaniboni et al. 2012 (GISCAD)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, and 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, modified FOLFIRI.3 {{#subobject:4758e8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFOX|mFOLFOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Irinotecan (Camptosar)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 3<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [http://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
# Zaniboni A, Aitini E, Barni S, Ferrari D, Cascinu S, Catalano V, Valmadre G, Ferrara D, Veltri E, Codignola C, Labianca R. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jun;69(6):1641-5. Epub 2012 May 11. [http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22576338 PubMed]<br />
<br />
==FOLFOX {{#subobject:377e80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:33ef68|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFIRI|mFOLFIRI.3]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [http://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
<br />
==OFF {{#subobject:8b32c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OFF: '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil, '''<u>F</u>'''olinic acid <br />
===Regimen {{#subobject:ae57d5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
<br />
''Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m<sup>2</sup>," or 850 mg/m<sup>2</sup>.''<br />
====Chemotherapy====<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once per day on days 8 & 22, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous 24-hour infusion on days 1, 8, 15, 22, '''started after folinic acid bolus'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, '''given prior to fluorouracil'''<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
# Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
<br />
==Olaparib monotherapy {{#subobject:0c2eb3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:21eb78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/3/244.long Kaufman et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients had germline BRCA1/2 mutations and had previously received gemcitabine.''<br />
====Chemotherapy====<br />
*[[Olaparib (Lynparza)]] 400 mg PO BID<br />
<br />
'''Continued until progression'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
# Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/33/3/244.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed]<br />
<br />
==Paclitaxel, nanoparticle albumin-bound monotherapy {{#subobject:ab9fc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8d38d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract Hosein et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Hosein PJ, de Lima Lopes G Jr, Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013 Apr;36(2):151-6. Epub 2012 Feb 2. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22307213 PubMed]<br />
<br />
[[Category:Pancreatic cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdheryhttps://hemonc.org/w/index.php?title=Pancreatic_cancer&diff=25823Pancreatic cancer2018-03-22T20:02:01Z<p>Rozinachowdhery: /* Regimen */</p>
<hr />
<div><!--'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]]. If this is your first time visiting, we suggest you read the [[tutorial]].'''--><br />
<br />
<!--Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are [[How_to_contribute|invited to contribute to the site]].-->{| class="wikitable" style="text-align:center; width:50%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0" |[[File:nkv.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>Chicago, IL</big><br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=Guidelines=<br />
==[https://www.asco.org/ ASCO]==<br />
*'''2017:''' [http://ascopubs.org/doi/full/10.1200/JCO.2017.72.4948 Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/28398845 PubMed]<br />
*'''2016:''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019760/ Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline]<br />
*'''2016:''' [http://ascopubs.org/doi/full/10.1200/JCO.2016.67.5561 Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/27247216 PubMed]<br />
<br />
==[http://www.esmo.org/ ESMO]==<br />
*'''2015:''' [http://annonc.oxfordjournals.org/content/26/suppl_5/v56.full.pdf+html Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015)] [https://www.ncbi.nlm.nih.gov/pubmed/26314780 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf NCCN Guidelines - Pancreatic Adenocarcinoma]<br />
<br />
=Adjuvant therapy=<br />
==Capecitabine & Gemcitabine {{#subobject:17f9f2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Regimen {{#subobject:e6a3e3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Treatment starts within 12 weeks of surgery.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day PO on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per week on weeks 1 to 3<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Fluorouracil & Leucovorin {{#subobject:29266e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:242770|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_monotherapy_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS (*)<br />
|-<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior OS (*)<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''<br />
*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
<br />
==Fluorouracil, then Fluorouracil & RT {{#subobject:331d4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:89426a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Leucovorin|5-FU & Leucovorin]]<br> [[#Observation|Observation]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS (*)<br />
|-<br />
|5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine.2C_then_Fluorouracil_.26_RT.2C_then_Gemcitabine|Gemcitabine, then Fluorouracil & RT, then Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note: efficacy for ESPAC-1 is based on the 2004 update.''<br />
====Chemotherapy portion====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 21<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy portion====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 28<br />
<br />
'''6-week cycle for 2 cycles'''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:34e70d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a756a2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior DFS<br />
|-<br />
|[http://jama.ama-assn.org/content/304/10/1073.long Neoptolemos et al. 2010 (ESPAC-3)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_.26_Leucovorin|Fluorouracil & Leucovorin]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy|S-1]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext Neoptolemos et al. 2017 (ESPAC-4)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine|Capecitabine & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 6 cycles'''<br />
<br />
===References===<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
# Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. [http://jama.ama-assn.org/content/304/10/1073.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823433 PubMed]<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
# Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. Epub 2017 Jan 25. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32409-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28129987 PubMed]<br />
<br />
==Gemcitabine, then Fluorouracil & RT, then Gemcitabine {{#subobject:f8c8d9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:3fef3f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Fluorouracil_monotherapy_.26_RT|Fluorouracil & RT]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy portion, part 1====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day course, followed in 1 to 2 weeks by:'''<br />
<br />
====Chemoradiotherapy portion====<br />
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.<br />
<br />
'''6-week course, followed in 3 to 5 weeks by:'''<br />
<br />
====Chemotherapy portion, part 2====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
===References===<br />
# Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18319412 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext Neoptolemos et al. 2001 (ESPAC-1)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#Fluorouracil_.26_Leucovorin|5-FU & Leucovorin]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[[#Fluorouracil_monotherapy_.26_RT|5-FU & RT]]<br> 5-FU & RT, then 5-FU & Leucovorin<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|[http://jama.ama-assn.org/content/297/3/267.long Oettle et al. 2007 (CONKO-001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
<br />
''No active antineoplastic treatment. Efficacy for ESPAC-1 is based on the 2004 update.''<br />
<br />
===References===<br />
# Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001 Nov 10;358(9293):1576-85. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06651-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11716884 PubMed]<br />
## '''Update:''' Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW; European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar 18;350(12):1200-10. [http://www.nejm.org/doi/full/10.1056/NEJMoa032295 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15028824 PubMed]<br />
# Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007 Jan 17;297(3):267-77. [http://jama.ama-assn.org/content/297/3/267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17227978 PubMed] <br />
## '''Update:''' Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. [http://jama.jamanetwork.com/article.aspx?articleid=1750131 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24104372 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:252c51|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:cdcc15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext Uesaka et al. 2016 (JASPAC 01)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Treatment starts day 10 to 42 after surgery or after wound is healed.''<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycle for up to 4 cycles'''<br />
<br />
===References===<br />
# Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. Epub 2016 Jun 2. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30583-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27265347 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, potentially resectable=<br />
<br />
==Docetaxel, Gemcitabine, RT {{#subobject:49a407|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:78b0ba|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1245%2FASO.2005.04.503 Pipas et al. 2005]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Docetaxel (Taxotere)]] 65 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 15, 29<br />
*[[Gemcitabine (Gemzar)]] 4000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29<br />
<br />
'''6-week course, followed immediately (day 43) by:'''<br />
<br />
====Chemoradiation====<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy to primary target volume. Then 5.4 Gy boost to secondary target volume of 1- to 1.5-cm margin on all sides, including proven nodal involvement. Total 50.4 Gy in 28 fractions.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
===References===<br />
# Pipas JM, Barth RJ Jr, Zaki B, Tsapakos MJ, Suriawinata AA, Bettmann MA, Cates JM, Ripple GH, Sutton JE, Gordon SR, McDonnell CE, Perez RP, Redfield N, Meyer LP, Marshall JF, Cole BF, Colacchio TA. Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2005 Dec;12(12):995-1004. Epub 2005 Nov 1. [http://link.springer.com/article/10.1245%2FASO.2005.04.503 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16252135 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:55e32d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen 1 {{#subobject:6ce551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract Takahashi et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*Concurrent radiation therapy, 2 Gy per fraction, 5 days per week, 25 fractions, total dose of 50 Gy over 5 weeks.<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
''Restaging is performed 8 weeks after radiation complete (2 weeks after chemotherapy complete). Resection immediately thereafter, if feasible.''<br />
<br />
===Regimen 2 {{#subobject:dc32dc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ Landry et al. 2010]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 500 mg/m<sup>2</sup> IV over 50 minutes once per week for 6 weeks<br />
*Concurrent radiation therapy, 180 cGy x 22 with 3 cm margin to GTV then 180 cGy x 6 with 2 cm margin to GTV, total 50.4 Gy over 6 weeks<br />
<br />
''Restaging after radiation complete. 4 to 6 week break, followed by surgery, followed by 4 to 8 week break. Then adjuvant chemotherapy:''<br />
<br />
====Adjuvant chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for 5 cycles'''<br />
<br />
===References===<br />
# Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010 Jun 1;101(7):587-92. [http://onlinelibrary.wiley.com/doi/10.1002/jso.21527/epdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403240/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20461765 PubMed]<br />
# Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, Ioka T, Uehara H, Yano M, Ishikawa O. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013 Dec;258(6):1040-50.[http://journals.lww.com/annalsofsurgery/pages/articleviewer.aspx?year=2013&issue=12000&article=00029&type=abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23799421 PubMed]<br />
<br />
==Gemcitabine, Cetuximab, RT {{#subobject:aea7b3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:c38534|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ Pipas et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Cetuximab (Erbitux)]] as follows:<br />
**6 to 8 days prior radiation: 400 mg/m<sup>2</sup> IV over 2 hours once<br />
**During radiation: 250 mg/m<sup>2</sup> over 60 minutes once per week for 6 doses<br />
*[[Gemcitabine (Gemzar)]] 50 mg/m<sup>2</sup> IV over 30 minutes twice per week for 12 doses<br />
**Given Monday/Thursday or Tuesday/Friday. Infusion completed ½ to 2 hours prior to RT.<br />
*Concurrent radiation therapy, delivered using IMRT. Gross tumor volume (GTV) was all known disease including imaging proven nodal disease. The primary planning target volume (PTV1) included the GTV with 2- to 3-cm margins in all directions as well as potential nodal involvement. Secondary planning target volume (PTV2) included the GTV with 1- to 1.5-cm margins on all sides including proven nodal involvement. Tertiary planning treatment volume (PTV3) included the area of the GTV adjacent to the vascular structures specifically the mesenteric and portal vessels with a 0.5-cm margin. The prescription dose delivered to PTV3 was 54 Gy in 28 fractions. Synchronously, PTV1 and PTV2 received 45 and 50.4 Gy, respectively. All fields were treated daily at five fractions per week.<br />
<br />
====Supportive medications====<br />
*GI prophylaxis with a proton pump inhibitor during chemoradiotherapy<br />
<br />
'''6-week course'''<br />
<br />
''One month following therapy, patients were restaged with CT scan of chest/abdomen/pelvis. Patients deemed to be candidates for surgical resection were offered laparotomy ∼6to 10 weeks after completion of neoadjuvant therapy.''<br />
<br />
===References===<br />
# Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, Tsongalis GJ, Colacchio TA, Gordon SR, Sutton JE, Srivastava A, Smith KD, Gardner TB, Korc M, Davis TH, Preis M, Tarczewski SM, Mackenzie TA, Barth RJ Jr. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. 2012 Nov;23(11):2820-7. Epub 2012 May 9. [http://annonc.oxfordjournals.org/content/23/11/2820.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577039/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571859 PubMed]<br />
<br />
==mFOLFIRINOX, Gemcitabine, RT {{#subobject:b71003|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
mFOLFIRINOX: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
<br>RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 {{#subobject:d87ec0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ Blazer et al. 2015]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====Modified FOLFIRINOX portion====<br />
*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 90 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once on day 1<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion for 46 h on days 1 to 3<br />
<br />
====Supportive medications====<br />
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 4<br />
<br />
'''14-day cycle for 4 to 8 cycles'''<br />
<br />
''Followed by complete restaging. If tumor localized but still not resectable, chemoradiotherapy was administered:''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup>/week concurrent with radiation<br />
*Radiation was 36 Gy in 15 daily fractions<br />
<br />
===Variant #2 {{#subobject:7bb0e7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ Hosein et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
====FOLFIRINOX portion====<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
*[[Folinic acid (Leucovorin)]] 400mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 400mg/m<sup>2</sup> IV bolus on day 1<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion for 46 hours on days 1 to 3<br />
<br />
'''Cycles repeated every 2 weeks. Protocol followed "per ACCORD-11 trial"'''<br />
<br />
''Treatment stopped at maximum response or tolerability. Resectable patients by imaging criteria were offered surgery, followed by postoperative chemoradiotherapy. Unresectable patients were offered chemoradiotherapy, followed by surgery (if they became resectable):''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup>/week<br />
*Radiation at 50.4 Gy in 28 fractions.<br />
<br />
===References===<br />
# '''Retrospective:''' Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, Narayanan G, Ribeiro A, Portelance L, Merchan JR, Levi JU, Rocha-Lima CM. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012 May 29;12:199. [http://www.biomedcentral.com/1471-2407/12/199 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404979/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22642850 PubMed]<br />
# '''Retrospective:''' Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, Wuthrick E, Williams TM, Reardon J, Christopher Ellison E, Bloomston M, Bekaii-Saab T. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015 Apr;22(4):1153-9. [http://link.springer.com/article/10.1245%2Fs10434-014-4225-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373613/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25358667 PubMed]<br />
<br />
=Induction therapy for locally advanced disease, unresectable=<br />
<br />
==Capecitabine monotherapy {{#subobject:dbd841|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:dc4779|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:6d97a7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===Variant #1, Gem 3 out of 4 weeks x 4 {{#subobject:87edde|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Erlotinib & Gemcitabine x 2 more cycles (6 total) versus Capecitabine, Erlotinib, RT<br />
<br />
===Variant #2, Gem 3 out of 4 weeks x 6 {{#subobject:5a5e14|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
''Note: it is not clear from the protocol whether erlotinib is continued beyond the end of chemotherapy.''<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] as follows:<br />
**Cycles 1 to 4: 100 mg PO once per day<br />
**Cycles 5 & 6: 150 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in {{#subobject:b4258e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: although this is technically a superior arm, the effect size is considered to be not clinically meaningful.''<br />
====Initial chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 or 150 mg (100 mg dose recommended) PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 or 150 mg (100 mg dose recommended) PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Fluorouracil & RT {{#subobject:26f1c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Regimen {{#subobject:29784e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ Herman et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Fluorouracil & RT with TNFerade<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion once per day on radiation days (total dose per week: 1000 mg/m<sup>2</sup>)<br />
*Concurrent radiation therapy, 50.4 Gy total: 1.80 Gy fractions x 25 fractions given 5 days per week, for a total dose of 45 Gy, followed by 1.80 Gy x 3 fractions boost to the tumor bed.<br />
<br />
'''One course'''<br />
====Subsequent treatment====<br />
*Gemcitabine or Erlotinib & Gemcitabine maintenance<br />
<br />
===References===<br />
# Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, Donehower RC, Pawlik TM, Ziegler MA, Cai H, Savage DT, Canto MI, Klapman J, Reid T, Shah RJ, Hoffe SE, Rosemurgy A, Wolfgang CL, Laheru DA. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013 Mar 1;31(7):886-94. Epub 2013 Jan 22. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.7516 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820756/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23341531 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:4f0be9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 3 out of 4 weeks x 4 {{#subobject:c511a7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression: Gemcitabine x 2 more cycles (6 total) versus Capecitabine & RT<br />
<br />
===Variant #2, 3 out of 4 weeks x 6 {{#subobject:cf89f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 Hammel et al. 2016 (GERCOR LAP07)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|[[Complex_multipart_regimens#GERCOR_LAP07|See link]]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Variant #3, 8-week lead-in {{#subobject:82f8b2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#GemOx|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_.26_RT_2|Gemcitabine & RT]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent 4-week cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''Continued for at least 3 months'''<br />
<br />
''Per '''Louvet et al. 2005''', subsequent chemoradiotherapy was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]<br />
<br />
==Gemcitabine & RT {{#subobject:a6e6fc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy<br />
===Variant #1 (600 mg/m<sup>2</sup>) {{#subobject:a6de29|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract Cardenes et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ Loehrer et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 600 mg/m<sup>2</sup> IV over 30 to 60 minutes once per week during radiation<br />
*Concurrent radiation therapy, 1.8 Gy per fraction, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks.<br />
<br />
'''One course, followed in 4 weeks by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycle for 5 cycles or until disease progression'''<br />
<br />
===Variant #2 (400 mg/m<sup>2</sup>) {{#subobject:c1ac3c|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract Epelbaum et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week for 7 weeks<br />
<br />
'''Radiation planning during this phase, followed by:'''<br />
<br />
====Chemoradiotherapy====<br />
*[[Gemcitabine (Gemzar)]] 400 mg/m<sup>2</sup> IV over 30 minutes once per week (days 1, 8, 15)<br />
*Concurrent radiation therapy, 5 days per week, 28 fractions, total dose of 50.4 Gy over 5.5 weeks<br />
<br />
'''28 day cycle for 2 cycles (completion of radiation), followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000mg/m<sup>2</sup> IV over 30 minutes once per week, 3 out of 4 weeks<br />
<br />
'''28-day cycles until disease progression'''<br />
<br />
===References===<br />
# Epelbaum R, Rosenblatt E, Nasrallah S, Faraggi D, Gaitini D, Mizrahi S, Kuten A. Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J Surg Oncol. 2002 Nov;81(3):138-43. [http://onlinelibrary.wiley.com/doi/10.1002/jso.10159/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12407726 PubMed]<br />
# Cardenes HR, Moore AM, Johnson CS, Yu M, Helft P, Chiorean EG, Vinson J, Howard TJ, Stephens AW, Tai DF, Loehrer PJ Sr. A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study. Am J Clin Oncol. 2011 Oct;34(5):460-5.[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2011&issue=10000&article=00004&type=abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20881474 PubMed]<br />
# Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. [http://jco.ascopubs.org/content/29/31/4105.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525836/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969502 PubMed]<br />
<br />
==GemOx {{#subobject:19d87f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:5a25e9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_2|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycle for at least 3 months'''<br />
<br />
''Subsequent chemoradiotherapy was recommended but not mandated.''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
<br />
=Metastatic disease, first-line=<br />
<br />
==Capecitabine monotherapy {{#subobject:4f5f03|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:b31bbb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/1/160.long Cartwright et al. 2002]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycle for up to 1 year'''<br />
<br />
===References===<br />
# Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol. 2002 Jan 1;20(1):160-4. [http://jco.ascopubs.org/content/20/1/160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11773165 PubMed]<br />
<br />
==Capecitabine & Gemcitabine {{#subobject:2f0431|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
GemCap/GEM-CAP: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine<br />
===Variant #1 {{#subobject:fcd708|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|}<br />
''Note: this is essentially identical to the maintenance phase of Cunningham et al. 2009, below.''<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1660 mg/m<sup>2</sup>/day on days 1 to 21 (frequency of dosing not specified)<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:e8f0bf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21, 29 to 49<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 830 mg/m<sup>2</sup> PO BID on days 1 to 21<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3 {{#subobject:a7e551|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 650 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8<br />
<br />
'''21-day cycle for up to 24 weeks'''<br />
<br />
===References===<br />
# Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
<br />
==Cisplatin & Gemcitabine {{#subobject:c30d8f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, weekly dosing {{#subobject:20a0f9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Note that cisplatin is not given on day 22 of the first 8 weeks; otherwise, the schedule is identical to the schedule for gemcitabine.''<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] as follows, '''given 60 minutes prior to gemcitabine''':<br />
**First 8 weeks: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Subsequent cycles: 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, bi-weekly dosing {{#subobject:38caf7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d9ef8b" |Might have superior PFS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract Cascinu et al. 2008 (GISCAD)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Cisplatin, Gemcitabine, Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 15<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 Jan;9(1):39-44. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70383-2/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18077217 PubMed]<br />
# Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
<br />
==Erlotinib & Gemcitabine {{#subobject:bf797a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1 {{#subobject:43fe43|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext Kordes et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|Erlotinib, Gemcitabine, Metformin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 mg PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2 {{#subobject:fc43f2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Initial chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 or 150 mg (100 mg dose recommended) PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
<br />
'''8-week course, followed by:'''<br />
<br />
====Maintenance chemotherapy====<br />
*[[Erlotinib (Tarceva)]] 100 or 150 mg (100 mg dose recommended) PO once per day<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47. Epub 2015 Jun 8. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00027-3/fulltext link to original article]'''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26067687 PubMed]<br />
<br />
==Fluorouracil monotherapy {{#subobject:c6c509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:3ca01f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Inferior to gemcitabine. Here for historical reference purposes, only.''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
<br />
==FOLFIRINOX {{#subobject:aaa3c4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:e140cb|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
![[Levels_of_Evidence#Toxicity|Toxicity]]<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
| style="background-color:#1a9850" |Superior QoL by [http://groups.eortc.be/qol/eortc-qlq-c30 EORTC QLQ-C30]<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 1200 mg/m<sup>2</sup>/day IV continuous 46-hour infusion on days 1 to 2; '''given last''' (total dose per cycle: 2400 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1; '''given third together with the last 90 minutes of leucovorin; that is, irinotecan starts 30 minutes after the start of leucovorin'''<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
<br />
==Gemcitabine monotherapy {{#subobject:3a0f4d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 8-week lead-in {{#subobject:5d6dd0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/15/6/2403.long Burris et al. 1997]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Fluorouracil_monotherapy|5-FU]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#GemOx_2|GemOx]]<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract Reni et al. 2005]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|PEFG<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/15/1960.long Moore et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/25/16/2212.long Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|GEM FDR<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://jco.ascopubs.org/content/27/33/5513.long Cunningham et al. 2009]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Capecitabine_.26_Gemcitabine_2|GEM-CAP]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 Colucci et al. 2010 (GIP-1)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ Philip et al. 2010 (SWOG S0205)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|Gemcitabine & Cetuximab<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 Conroy et al. 2011 (PRODIGE 4/ACCORD 11)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#FOLFIRINOX|FOLFIRINOX]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Gemcitabine_.26_nab-Paclitaxel|Gemcitabine & nab-Paclitaxel]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext Middleton et al. 2017 (ViP)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|Gemcitabine & Vandetanib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows:<br />
**First 8 weeks: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43<br />
**Subsequent cycles: 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
***In Burris et al. 1997, patients with grade 2 or lower toxicities could have had doses increased to 1250 mg/m<sup>2</sup><br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, 4 week cycles {{#subobject:c6349|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/24/24/3946.long Heinemann et al. 2006]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Cisplatin_.26_Gemcitabine|Cisplatin & Gemcitabine]]<br />
| style="background-color:#fee08b" |Might have inferior PFS<br />
|-<br />
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract Kindler et al. 2011]<br />
| style="background-color:#1a9851" |Phase III<br />
|Gemcitabine & Axitinib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|[[#S-1_monotherapy_2|S-1]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ Fuchs et al. 2015 (GAMMA)]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & [[Ganitumab (AMG 479)|Ganitumab]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ Catenacci et al. 2015]<br />
| style="background-color:#1a9851" |Randomized Phase Ib/II<br />
|Gemcitabine & Vismodegib<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ Lee et al. 2017]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Capecitabine_.26_Gemcitabine_2|GemCap]]<br />
| style="background-color:#fee08b" |Might have inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, 3 week cycles {{#subobject:8bae67|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 Hong et al. 2013]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|Gemcitabine & Simvastatin<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''21-day cycles'''<br />
<br />
===Variant #4, fixed-dose rate (FDR) {{#subobject:5114cc|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (ECOG E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Gemcitabine<br />
| style="background-color:#d9ef8b" |Might have superior OS<br />
|-<br />
|[[#GemOx_2|GEMOX]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 150 minutes (10 mg/m<sup>2</sup>/min) once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. [http://jco.ascopubs.org/content/15/6/2403.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9196156 PubMed]<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(05)70175-3/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15925814 PubMed]<br />
# Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006 Aug 20;24(24):3946-52. [http://jco.ascopubs.org/content/24/24/3946.long link to original article] '''contains verified regimen''' [https://www.ncbi.nlm.nih.gov/pubmed/16921047 PubMed]<br />
# Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [http://jco.ascopubs.org/content/25/15/1960.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17452677 PubMed]<br />
# '''SAKK 44/00-CECOG/PAN.1.3.001:''' Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W; Swiss Group for Clinical Cancer Research; Central European Cooperative Oncology Group. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007 Jun 1;25(16):2212-7. [http://jco.ascopubs.org/content/25/16/2212.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538165 PubMed]<br />
## '''CBR/QoL analysis:''' Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi BC, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Herrmann R; Central European Cooperative Oncology Group. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008 Aug 1;26(22):3695-701. [http://jco.ascopubs.org/content/26/22/3695.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669454 PubMed]<br />
# '''ECOG E6201:''' Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
# Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009 Nov 20;27(33):5513-8. Epub 2009 Oct 26. [http://jco.ascopubs.org/content/27/33/5513.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19858379 PubMed]<br />
# '''GIP-1:''' Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM).; Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD).; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. [http://ascopubs.org/doi/full/10.1200/JCO.2009.25.4433 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20194854 PubMed]<br />
# '''SWOG S0205:''' Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 1;28(22):3605-10. Epub 2010 Jul 6. [http://jco.ascopubs.org/content/28/22/3605.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917315/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20606093 PubMed]<br />
# Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70004-3/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21306953 PubMed]<br />
# '''PRODIGE 4/ACCORD 11:''' Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1011923 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21561347 PubMed]<br />
## '''QoL analysis:''' Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4869 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23213101 PubMed]<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# '''MPACT:''' Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
# Hong JY, Nam EM, Lee J, Park JO, Lee SC, Song SY, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol. 2014 Jan;73(1):125-30. Epub 2013 Oct 27. [https://link.springer.com/article/10.1007%2Fs00280-013-2328-1 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24162380 PubMed]<br />
# '''GAMMA:''' Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921-7. Epub 2015 Jan 21. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804122/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25609246 PubMed]<br />
# Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D, Wade J, Sleckman B, Lenz HJ, Stiff P, Kumar P, Xu P, Henderson L, Takebe N, Salgia R, Wang X, Stadler WM, de Sauvage FJ, Kindler HL. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015 Dec 20;33(36):4284-92. Epub 2015 Nov 2. [http://jco.ascopubs.org/content/33/36/4284.long link to original article] '''contains protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678179/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26527777 PubMed]<br />
# Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY; Korean Society of Gastrointestinal Cancer. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore). 2017 Jan;96(1):e5702. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228666/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28072706 PubMed]<br />
# '''ViP:''' Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr;18(4):486-499. Epub 2017 Mar 2. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30084-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28259610 PubMed]<br />
<br />
==GemOx {{#subobject:520af|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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|}<br />
GemOx: '''<u>Gem</u>'''citabine, '''<u>Ox</u>'''aliplatin<br />
===Regimen {{#subobject:9d3266|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/23/15/3509.long Louvet et al. 2005]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#91cf60" |Seems to have superior PFS<br />
|-<br />
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ Poplin et al. 2009 (E6201)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine, FDR]]<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once on day 1<br />
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 2<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A; GERCOR; GISCAD. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16. [http://jco.ascopubs.org/content/23/15/3509.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15908661 PubMed]<br />
# Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Aug 10;27(23):3778-85. Epub 2009 Jul 6. [http://jco.ascopubs.org/content/27/23/3778.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19581537 PubMed]<br />
<br />
==Gemcitabine & nab-Paclitaxel {{#subobject:fbd698|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===Variant #1 {{#subobject:63ba04|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ Von Hoff et al. 2013 (MPACT)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] as follows, '''given second''':<br />
**Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] as follows, '''given first''':<br />
**Cycle 1: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15, 29, 36, 43<br />
**Cycle 2 onwards: 125 mg/m<sup>2</sup> IV over 30 to 40 minutes once per day on days 1, 8, 15<br />
<br />
'''8-week cycle followed by 28-day cycles until disease progression or intolerance'''<br />
<br />
===Variant #2 {{#subobject:ecc1c9|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ Von Hoff et al. 2011]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 or 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. Epub 2011 Oct 3. [http://jco.ascopubs.org/content/29/34/4548.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21969517 PubMed]<br />
<!-- # '''Abstract:''' Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 ASCO Gastrointestinal Cancers Symposium abstract LBA148. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=106143 link to abstract] [http://clinicaltrials.gov/show/NCT00844649 ClinicalTrials.gov NCT00844649] --><br />
# Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Epub 2013 Oct 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1304369 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631139/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24131140 PubMed]<br />
<br />
==GTX {{#subobject:f0d62|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
GTX: '''<u>G</u>'''emcitabine, '''<u>T</u>'''axotere (Docetaxel), '''<u>X</u>'''eloda (Capecitabine)<br />
===Regimen {{#subobject:fc0e50|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.springerlink.com/content/75m422843l3461m0/ Fine et al. 2007]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: De Jesus-Acosta et al. 2012 lists the capecitabine dose as "750 mg/m<sup>2</sup>/day orally divided into two doses," but this is believed to be a typographical error since the original reference that it cites, Fine et al. 2007, uses capecitabine at 750 mg/m<sup>2</sup> PO BID. The 2009 ASCO abstract by Fine also lists this 750 mg/m<sup>2</sup> PO BID (1500 mg/m<sup>2</sup>/day) dose.''<br />
====Chemotherapy====<br />
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 75 minutes once per day on days 4 & 11<br />
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 11<br />
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75. Epub 2007 Apr 18. [http://www.springerlink.com/content/75m422843l3461m0/ link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17440727 PubMed]<br />
# '''Abstract:''' R. L. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. 2009 ASCO Annual Meeting abstract 4623. [http://ascopubs.org/doi/full/10.1200/jco.2009.27.15s.4623 link to abstract] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012 Feb;69(2):415-24. Epub 2011 Jul 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723 link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265723/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21800112 PubMed]<br />
<br />
==S-1 monotherapy {{#subobject:759f1a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:94d490|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 Ueno et al. 2013 (GEST)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (E)<br />
|[[#Gemcitabine_monotherapy_3|Gemcitabine]]<br />
| style="background-color:#eeee01" |Non-inferior OS<br />
|-<br />
|Gemcitabine & S-1<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:<br />
**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 28<br />
**BSA at least 1.25 m<sup>2</sup> and less than 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 28<br />
**BSA 1.5 m<sup>2</sup> or more: 60 mg PO BID on days 1 to 28<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
# '''GEST:''' Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013 May 1;31(13):1640-8. Epub 2013 Apr 1. [http://ascopubs.org/doi/full/10.1200/JCO.2012.43.3680 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23547081 PubMed]<br />
<br />
=Metastatic disease, refractory=<br />
<br />
==Best supportive care==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#OFF|OFF]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
<br />
''Best supportive care. Placed here because one or more randomized clinical trials included a best supportive care arm in this disease context.''<br />
<br />
===References===<br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
<br />
==Capecitabine & Erlotinib {{#subobject:4655b7|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:d5c799|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/30/4787.full Kulke et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> (rounded to the nearest 150 mg tablet) PO BID on days 1 to 14<br />
*[[Erlotinib (Tarceva)]] 150 mg PO on days 1 to 21<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak EL, Muzikansky A, Lawrence C, Fuchs CS. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007 Oct 20;25(30):4787-92. [http://jco.ascopubs.org/content/25/30/4787.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17947726 PubMed]<br />
<br />
==CapeOx {{#subobject:d09d5a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin<br />
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin<br />
<br />
===Regimen {{#subobject:57ad5f|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full Xiong et al. 2008]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Capecitabine (Xeloda)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 1000 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 750 mg/m<sup>2</sup> PO BID on days 1 to 14<br />
*[[Oxaliplatin (Eloxatin)]] as follows:<br />
**Age less than 65 years old and [[Performance status|ECOG performance status]] less than 2: 130 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
**Age greater than 65 years old and/or [[Performance status|ECOG performance status]] greater than or equal to 2: 110 mg/m<sup>2</sup> IV over 2 hours once on day 1<br />
<br />
'''21-day cycles'''<br />
<br />
===References===<br />
# Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008 Oct 15;113(8):2046-52. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.23810/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18756532 PubMed]<br />
<br />
==Fluorouracil, Folinic acid, nanoliposomal Irinotecan {{#subobject:72308d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:a81310|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
| rowspan="2" |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract Wang-Gillam et al. 2015 (NAPOLI-01)]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|Irinotecan, nanoliposomal<br />
| style="background-color:#d3d3d3" |Not reported<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''started on day 1 after folinic acid'''<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given prior to fluorouracil'''<br />
*[[Irinotecan liposome (Onivyde)]] 70 mg/m<sup>2</sup> (irinotecan free base) IV over 90 minutes once on day 1, '''given first'''<br />
**Per Wang-Gillam et al. 2015 (NAPOLI-01), 70 mg/m<sup>2</sup> irinotecan free base is equivalent to 80 mg/m<sup>2</sup> nanoliposomal irinotecan. According to the trial's ClinicalTrials.gov page: "The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m<sup>2</sup> dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/ m2 of irinotecan free base."<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-57. Epub 2015 Nov 29. Erratum in: Lancet. 2016 Feb 6;387(10018):536. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00986-1/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26615328 PubMed]<br />
<br />
==FOLFIRI {{#subobject:6fd426|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan<br />
<br />
===Variant #1 {{#subobject:6a9cae|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 Zaniboni et al. 2012 (GISCAD)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, and 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)<br />
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===Variant #2, modified FOLFIRI.3 {{#subobject:4758e8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFOX|mFOLFOX]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Irinotecan (Camptosar)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 3<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [http://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
# Zaniboni A, Aitini E, Barni S, Ferrari D, Cascinu S, Catalano V, Valmadre G, Ferrara D, Veltri E, Codignola C, Labianca R. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jun;69(6):1641-5. Epub 2012 May 11. [http://link.springer.com/article/10.1007%2Fs00280-012-1875-1 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22576338 PubMed]<br />
<br />
==FOLFOX {{#subobject:377e80|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
FOLFOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin<br />
===Regimen {{#subobject:33ef68|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ Yoo et al. 2009]<br />
| style="background-color:#1a9851" |Randomized Phase II<br />
|[[#FOLFIRI|mFOLFIRI.3]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycles'''<br />
<br />
===References===<br />
# Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Han DJ, Kim SC, Lee JL. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009 Nov 17;101(10):1658-63. Epub 2009 Oct 13. [http://www.nature.com/bjc/journal/v101/n10/full/6605374a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778540/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19826418 PubMed]<br />
<br />
==OFF {{#subobject:8b32c0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
OFF: '''<u>O</u>'''xaliplatin, '''<u>F</u>'''luorouracil, '''<u>F</u>'''olinic acid <br />
===Regimen {{#subobject:ae57d5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
!Comparator<br />
![[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract Pelzer et al. 2011 (CONKO)]<br />
| style="background-color:#1a9851" |Phase III<br />
|[[#Best_supportive_care|Best supportive care]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/32/23/2423.long Oettle et al. 2014 (CONKO-003)]<br />
| style="background-color:#1a9851" |Phase III<br />
|Fluorouracil & Folinic acid<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
<br />
''Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m<sup>2</sup>," or 850 mg/m<sup>2</sup>.''<br />
====Chemotherapy====<br />
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 to 4 hours once per day on days 8 & 22, '''given first'''<br />
*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous 24-hour infusion on days 1, 8, 15, 22, '''started after folinic acid bolus'''<br />
*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, '''given prior to fluorouracil'''<br />
<br />
'''42-day cycles'''<br />
<br />
===References===<br />
<!-- # U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Riess, H. Oettle. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. 2008 ASCO Annual Meeting abstract 4508. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34567 link to abstract] --><br />
# Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011 Jul;47(11):1676-81. Epub 2011 May 10. [http://www.ejcancer.com/article/S0959-8049(11)00260-7/abstract link to original article] '''contains verified protocol'''--with error as noted above [https://www.ncbi.nlm.nih.gov/pubmed/21565490 PubMed]<br />
# Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. [http://jco.ascopubs.org/content/32/23/2423.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24982456 PubMed]<br />
<br />
==Olaparib monotherapy {{#subobject:0c2eb3|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:21eb78|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/3/244.long Kaufman et al. 2014]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Patients had germline BRCA1/2 mutations and had previously received gemcitabine.''<br />
====Chemotherapy====<br />
*[[Olaparib (Lynparza)]] 400 mg PO BID<br />
<br />
'''Continued until progression'''<br />
<br />
===References===<br />
<!-- Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. --><br />
# Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. [http://jco.ascopubs.org/content/33/3/244.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25366685 PubMed]<br />
<br />
==Paclitaxel, nanoparticle albumin-bound monotherapy {{#subobject:ab9fc2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:8d38d2|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!Study<br />
![[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract Hosein et al. 2013]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Hosein PJ, de Lima Lopes G Jr, Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013 Apr;36(2):151-6. Epub 2012 Feb 2. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=9000&issue=00000&article=99592&type=abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22307213 PubMed]<br />
<br />
[[Category:Pancreatic cancer regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Gastrointestinal cancers]]</div>Rozinachowdhery