Pancreatic cancer

Section editor
	Eric I. Marks, MD Boston University Boston, MA

45 regimens on this page 74 variants on this page

Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: this page contains regimens for pancreatic adenocarcinoma which were not tested in biomarker-specific populations. The following links will take you to biomarker- and histology-specific subpages:

• Regimens for BRCA-mutated pancreatic cancer are here.
• Regimens for Pancreatic neuroendocrine tumor are here.

Guidelines

ASCO

• 2020: Sohal et al. Metastatic Pancreatic Cancer: ASCO Guideline Update
• 2017: Khorana et al. Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update PubMed

Older

• 2018: Sohal et al. Metastatic pancreatic cancer: ASCO Clinical Practice Guideline update PubMed
• 2016: Sohal et al. Metastatic pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline
• 2016: Balaban et al. Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline PubMed

ESMO

• 2019: Stjepanovic et al. Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
• 2019: eUpdate – Cancer of the Pancreas Treatment Recommendations
• 2017: eUpdate – Cancer of the Pancreas Treatment Recommendations
• 2015: Ducreux et al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015) PubMed

NCCN

• NCCN Guidelines - Pancreatic Adenocarcinoma

Older

• 2017: Tempero et al. Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology PubMed
• 2014: Tempero et al. Pancreatic Adenocarcinoma, Version 2.2014 PubMed

Adjuvant therapy

Capecitabine & Gemcitabine

GemCap: Gemcitabine & Capecitabine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Neoptolemos et al. 2017 (ESPAC-4) ESMO-MCBS (A)	2008-2014	Phase 3 (E-RT-esc)	Gemcitabine	Seems to have superior OS Median OS: 28 vs 25.5 mo (HR 0.82, 95% CI 0.68-0.98)

Treatment starts within 12 weeks of surgery.

Preceding treatment

• Surgery

Chemotherapy

• Capecitabine (Xeloda) 1660 mg/m²/day PO on days 1 to 21 (frequency of dosing not specified)
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

28-day cycle for 6 cycles

References

1. 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. link to original article contains dosing details in abstract PubMed ISRCTN96397434

FULV

FULV: 5-FU & LeucoVorin (Folinic acid)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Neoptolemos et al. 2001 (ESPAC-1)	1994-2000	Phase 3 (E-esc)	1. 5-FU/5-FU & RT 2. 5-FU & RT, then FULV	Seems to have superior OS1
			3. Observation	Superior OS1 Median OS: 20.1 vs 15.5 mo (HR 0.71, 95% CI 0.55-0.92)
Neoptolemos et al. 2010 (ESPAC-3 version 2)	2003-2007	Phase 3 (C)	Gemcitabine	Did not meet primary endpoint of OS
Schmidt et al. 2012 (CapRI)	2004-2007	Phase 3 (C)	5-FU, Cisplatin, IFN alfa-2b, RT	Did not meet primary endpoint of OS Median OS: 28.5 vs 26.5 mo (HR 0.96, 95% CI 0.65-1.52)

¹Reported efficacy for ESPAC-1 is based on the 2004 update.

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU) 425 mg/m² IV bolus once per day on days 1 to 5, given second
• Folinic acid (Leucovorin) 20 mg/m² IV bolus once per day on days 1 to 5, given first

28-day cycle for 6 cycles

References

1. 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. link to original article PubMed
   1. 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. link to original article contains dosing details in manuscript PubMed
2. 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00058201
3. 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. link to original article contains dosing details in manuscript PubMed ISRCTN62866759

Fluorouracil/Fluorouracil & RT

Fluorouracil/Fluorouracil & RT: Fluorouracil alternating with Fluorouracil & Radiation Therapy

Protocol

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Neoptolemos et al. 2001 (ESPAC-1)	1994-2000	Phase 3 (E=esc)	1. FULV 2. Observation	Seems to have inferior OS1
			3. 5-FU & RT, then FULV	Not reported
Regine et al. 2008 (RTOG 9704)	1998-2002	Phase 3 (C)	Gemcitabine/5-FU & RT	Did not meet primary endpoint of OS2

¹Reported efficacy for ESPAC-1 is based on the 2004 update.
²Reported efficacy for RTOG 9704 is based on the 2011 update.

Preceding treatment

• Surgery

Chemotherapy, part 1

• Fluorouracil (5-FU) 250 mg/m²/day IV continuous infusion over 21 days, started on day 1 (total dose: 5000 mg/m²)

21-day course, followed in 1 to 2 weeks by:

Chemotherapy, part 2

• Fluorouracil (5-FU) 250 mg/m²/day IV continuous infusion throughout radiation therapy

Radiotherapy

• Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.

6-week course, followed in 3 to 5 weeks by:

Chemotherapy, part 3

• Fluorouracil (5-FU) 250 mg/m²/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 7000 mg/m²)

6-week cycle for 2 cycles

References

1. 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. link to original article PubMed
   1. 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. link to original article contains dosing details in manuscript PubMed
2. 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00003216
   1. 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. link to original article link to PMC article PubMed

mFOLFIRINOX

mFOLFIRINOX: modified FOLinic acid, Fluorouracil, IRINotecan, OXaliplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Conroy et al. 2018 (NCIC-CTG PA.6) ESMO-MCBS (5)	2012-2016	Phase 3 (E-esc)	Gemcitabine	Superior DFS1 (primary endpoint) Median DFS: 21.4 vs 12.8 mo (HR 0.66, 95% CI 0.54-0.82) Superior OS1 (secondary endpoint) Median OS: 53.5 vs 35.5 mo (HR 0.68, 95% CI 0.54-0.85)	More toxic

¹Reported efficacy is based on the 2022 update.

Preceding treatment

• Surgery

Chemotherapy

• Folinic acid (Leucovorin) 400 mg/m² IV over 2 hours once on day 1, given second
• Fluorouracil (5-FU) 2400 mg/m² IV continuous infusion over 46 hours, started on day 1, given fourth
• Irinotecan (Camptosar) 150 mg/m² IV over 90 minutes once on day 1, given third
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1, given first

14-day cycle for 12 cycles

References

1. 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; NCIC-CTG; Unicancer-GI–PRODIGE Group. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018 Dec 20;379(25):2395-2406. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT01526135
   1. Update: Conroy T, Castan F, Lopez A, Turpin A, Ben Abdelghani M, Wei AC, Mitry E, Biagi JJ, Evesque L, Artru P, Lecomte T, Assenat E, Bauguion L, Ychou M, Bouché O, Monard L, Lambert A, Hammel P; Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group. Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer: A Randomized Clinical Trial. JAMA Oncol. 2022 Nov 1;8(11):1571-1578. Epub 2022 Sep 1. link to original article link to PMC article PubMed
2. Alliance A021806: https://clinicaltrials.gov/ct2/show/NCT04340141

Gemcitabine monotherapy

Regimen variant #1, 2 out of 3 weeks

Study	Dates of enrollment	Evidence
Landry et al. 2010 (ECOG E1200)	2003-2005	Phase 2

Preceding treatment

• Gemcitabine & RT, then surgery

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV over 100 minutes once per day on days 1 & 8

21-day cycle for 5 cycles

Regimen variant #2, 3 out of 4 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Oettle et al. 2007 (CONKO-001)	1998-2004	Phase 3 (E-esc)	Observation	Seems to have superior OS1 (secondary endpoint) OS60: 20.7% vs 10.4% (HR 0.76, 95% CI 0.61-0.95)
Ueno et al. 2009 (JSAP-02)	2002-2005	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of OS Median OS: 22.3 vs 18.4 mo (HR 0.77, 95% CI 0.51-1.14)
Neoptolemos et al. 2010 (ESPAC-3 version 2)	2003-2007	Phase 3 (E-switch-ic)	FULV	Did not meet primary endpoint of OS
Uesaka et al. 2016 (JASPAC 01)	2007-2010	Phase 3 (C)	S-1	Inferior OS
Sinn et al. 2017 (CONKO-005)	2008-2013	Phase 3 (C)	Erlotinib & Gemcitabine	Did not meet primary endpoint of DFS Median DFS: 11.4 vs 11.4 mo (HR 1.06, 95% CI 0.87-1.32)
Neoptolemos et al. 2017 (ESPAC-4)	2008-2014	Phase 3 (C)	Capecitabine & Gemcitabine	Seems to have inferior OS
Conroy et al. 2018 (NCIC-CTG PA.6)	2012-2016	Phase 3 (C)	mFOLFIRINOX	Inferior OS
Tempero et al. 2023 (APACT)	2014-04 to 2016-04	Phase 3 (C)	Gemcitabine & nab-Paclitaxel	Did not meet primary endpoint of DFS Median DFS: 18.8 vs 19.4 mo (HR 1.14, 95% CI 0.94-1.37)

¹Reported efficacy for CONKO-001 is based on the 2013 update.
Note: Treatment starts day 10 to 42 after surgery or after wound is healed.

Preceding treatment

• Surgery

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycle for up to 6 cycles

References

1. 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. link to original article contains dosing details in manuscript PubMed ISRCTN34802808
   1. 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. link to original article PubMed
2. 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; Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer. 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. link to original article link to original article contains dosing details in abstract PubMed
3. ECOG E1200: 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. link to original article contains dosing details in manuscript link to PMC article PubMed
4. 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00058201
5. 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. link to original article contains dosing details in manuscript PubMed UMIN000000655
6. 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. link to original article contains dosing details in abstract PubMed ISRCTN96397434
7. 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. link to original article contains dosing details in abstract PubMed DRKS00000247
8. 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; NCIC-CTG; Unicancer-GI–PRODIGE Group. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018 Dec 20;379(25):2395-2406. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT01526135
   1. Update: Conroy T, Castan F, Lopez A, Turpin A, Ben Abdelghani M, Wei AC, Mitry E, Biagi JJ, Evesque L, Artru P, Lecomte T, Assenat E, Bauguion L, Ychou M, Bouché O, Monard L, Lambert A, Hammel P; Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group. Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer: A Randomized Clinical Trial. JAMA Oncol. 2022 Nov 1;8(11):1571-1578. Epub 2022 Sep 1. link to original article link to PMC article PubMed
9. APACT: Tempero MA, Pelzer U, O'Reilly EM, Winter J, Oh DY, Li CP, Tortora G, Chang HM, Lopez CD, Bekaii-Saab T, Ko AH, Santoro A, Park JO, Noel MS, Frassineti GL, Shan YS, Dean A, Riess H, Van Cutsem E, Berlin J, Philip P, Moore M, Goldstein D, Tabernero J, Li M, Ferrara S, Le Bruchec Y, Zhang G, Lu B, Biankin AV, Reni M. Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial. J Clin Oncol. 2023 Apr 10;41(11):2007-2019. Epub 2022 Dec 15. link to original article link to PMC article contains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT01964430
10. NLG0405: https://clinicaltrials.gov/ct2/show/NCT01072981

Gemcitabine/Fluorouracil & RT

Gemcitabine/Fluorouracil & RT: Gemcitabine alternating with Fluorouracil & Radiation Therapy

Protocol

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Regine et al. 2008 (RTOG 9704)	1998-2002	Phase 3 (E-switch-ic)	5-FU/5-FU & RT	Did not meet primary endpoint of OS1

¹Reported efficacy is based on the 2011 update.

Preceding treatment

• Surgery

Chemotherapy, part 1

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

21-day course, followed in 1 to 2 weeks by:

Chemotherapy, part 2

• Fluorouracil (5-FU) 250 mg/m²/day IV continuous infusion throughout radiation therapy

Radiotherapy

• Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.

6-week course, followed in 3 to 5 weeks by:

Chemotherapy, part 3

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycle for 3 cycles

References

1. 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00003216
   1. 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. link to original article link to PMC article PubMed

S-1 monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Uesaka et al. 2016 (JASPAC 01)	2007-2010	Phase 3 (E-switch-ic)	Gemcitabine	Superior OS OS60: 44.1% vs 24.4% (HR 0.57, 95% CI 0.44-0.72)

Treatment starts 10 to 42 days after surgery or after wound is healed.

Preceding treatment

• Surgery

Chemotherapy

• Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
  • BSA less than 1.25 m²: 40 mg PO twice per day on days 1 to 28
  • BSA at least 1.25 m² and less than 1.5 m²: 50 mg PO twice per day on days 1 to 28
  • BSA 1.5 m² or more: 60 mg PO twice per day on days 1 to 28

42-day cycle for up to 4 cycles

References

1. 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. link to original article contains dosing details in manuscript PubMed UMIN000000655

Induction therapy for locally advanced disease, potentially resectable

Docetaxel, Gemcitabine, RT

DG & RT: Docetaxel, Gemcitabine, Radiation Therapy

Protocol

Study	Dates of enrollment	Evidence
Pipas et al. 2005	2002-2004	Phase 2

Chemotherapy, part 1

• Docetaxel (Taxotere) 65 mg/m² IV over 60 minutes once on day 1
• Gemcitabine (Gemzar) 4000 mg/m² IV over 30 minutes once on day 1

14-day cycle for 3 cycles, followed immediately (day 43) by:

Chemotherapy, part 2

• Gemcitabine (Gemzar) 50 mg/m² IV over 30 minutes once per day on either days 1, 4, 8, 11 or days 2, 5, 9, 12, completed 30 minutes to 2 hours prior to RT

Supportive therapy

• GI prophylaxis with a proton pump inhibitor

14-day cycle for 3 cycles

Radiotherapy

• Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions, 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.

6-week course

References

1. 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. link to original article contains dosing details in manuscript PubMed

Gemcitabine & RT

Gemcitabine & RT: Gemcitabine & Radiation Therapy

Regimen variant #1, 400 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Jang et al. 2018	2012-2014	Phase 2/3 (E-esc)	No neoadjuvant therapy	Seems to have superior OS

Chemotherapy

• Gemcitabine (Gemzar) 400 mg/m² IV over 50 minutes once per day on days 1, 8, 15, 22, 29, 36

Radiotherapy

• Concurrent radiation therapy, 45 Gy in 25 fractions, then 9 Gy in 5 fractions

6-week course

Subsequent treatment

• Surgery

Regimen variant #2, 500 mg/m²

Study	Dates of enrollment	Evidence
Landry et al. 2010 (ECOG E1200)	2003-2005	Phase 2

Chemotherapy

• Gemcitabine (Gemzar) 500 mg/m² IV over 50 minutes once per day on days 1, 8, 15, 22, 29, 36

Radiotherapy

• 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

6-week course

Subsequent treatment

• Restaging after radiation complete. 4 to 6 week break, then surgery, then 4 to 8 week break, then adjuvant gemcitabine

Regimen variant #3, 1000 mg/m²

Study	Dates of enrollment	Evidence
Takahashi et al. 2013	NR in abstract	Phase 2

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

28-day cycle for 3 cycles

Radiotherapy

• Concurrent radiation therapy, 2 Gy per fraction x 25 fractions, total dose of 50 Gy

5-week course

Subsequent treatment

• Restaging is performed 8 weeks after radiation complete (2 weeks after chemotherapy complete). Resection immediately thereafter, if feasible

Regimen variant #4, 1000 mg/m², short course RT

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Versteijne et al. 2020 (PREOPANC)	2013-2017	Phase 3 (E-esc)	Gemcitabine	Seems to have superior OS (primary endpoint)1 Median OS: 15.7 vs 14.3 mo (HR 0.73, 95% CI 0.56-0.96)

¹Reported efficacy is based on the 2022 update.

Chemotherapy, part 1

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle, followed by:

Chemotherapy, part 2, concurrent RT

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

Radiotherapy

• Concurrent radiation therapy, 2.4 Gy in 3 weeks to the pancreatic tumor and suspicious lymph nodes

4-week course, followed in 4 weeks by: Surgical resection, followed by:

Chemotherapy, part 3

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycle for 4 cycles

References

1. ECOG E1200: 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. link to original article contains dosing details in manuscript link to PMC article PubMed
2. 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.link to original article contains dosing details in manuscript PubMed UMIN000001804
3. Jang JY, Han Y, Lee H, Kim SW, Kwon W, Lee KH, Oh DY, Chie EK, Lee JM, Heo JS, Park JO, Lim DH, Kim SH, Park SJ, Lee WJ, Koh YH, Park JS, Yoon DS, Lee IJ, Choi SH. Oncological Benefits of Neoadjuvant Chemoradiation With Gemcitabine Versus Upfront Surgery in Patients With Borderline Resectable Pancreatic Cancer: A Prospective, Randomized, Open-label, Multicenter Phase 2/3 Trial. Ann Surg. 2018 Aug;268(2):215-222. link to original article contains dosing details in manuscript PubMed
4. PREOPANC: Versteijne E, Suker M, Groothuis K, Akkermans-Vogelaar JM, Besselink MG, Bonsing BA, Buijsen J, Busch OR, Creemers GM, van Dam RM, Eskens FALM, Festen S, de Groot JWB, Groot Koerkamp B, de Hingh IH, Homs MYV, van Hooft JE, Kerver ED, Luelmo SAC, Neelis KJ, Nuyttens J, Paardekooper GMRM, Patijn GA, van der Sangen MJC, de Vos-Geelen J, Wilmink JW, Zwinderman AH, Punt CJ, van Eijck CH, van Tienhoven G; Dutch Pancreatic Cancer Group. Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial. J Clin Oncol. 2020 Jun 1;38(16):1763-1773. Epub 2020 Feb 27. link to original article link to PMC article PubMed EudraCT 2012-003181-40
   1. Update: Versteijne E, van Dam JL, Suker M, Janssen QP, Groothuis K, Akkermans-Vogelaar JM, Besselink MG, Bonsing BA, Buijsen J, Busch OR, Creemers GM, van Dam RM, Eskens FALM, Festen S, de Groot JWB, Groot Koerkamp B, de Hingh IH, Homs MYV, van Hooft JE, Kerver ED, Luelmo SAC, Neelis KJ, Nuyttens J, Paardekooper GMRM, Patijn GA, van der Sangen MJC, de Vos-Geelen J, Wilmink JW, Zwinderman AH, Punt CJ, van Tienhoven G, van Eijck CHJ; Dutch Pancreatic Cancer Group. Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial. J Clin Oncol. 2022 Apr 10;40(11):1220-1230. Epub 2022 Jan 27. link to original article PubMed
5. PREOPANC-2: EudraCT 2017-002036-17

Gemcitabine, Cetuximab, RT

Gemcitabine, Cetuximab, RT: Gemcitabine, Cetuximab, Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence
Pipas et al. 2012	2005-2008	Phase 2

Chemotherapy

• Gemcitabine (Gemzar) 50 mg/m² IV over 30 minutes once per day on days 1 & 4 or days 2 & 5, completed 30 minutes to 2 hours prior to RT

Targeted therapy

• Cetuximab (Erbitux) as follows:
  • 6 to 8 days prior radiation: 400 mg/m² IV over 2 hours once
  • During radiation: 250 mg/m² IV over 60 minutes once on day 1

7-day cycle for 6 cycles

Radiotherapy

• 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.

Supportive therapy

• GI prophylaxis with a proton pump inhibitor during chemoradiotherapy

6-week course 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.

References

1. 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. link to original article contains dosing details in manuscript link to PMC article PubMed

FOLFIRINOX/modified FOLFIRINOX +/- Chemoradiation

mFOLFIRINOX: modified FOLinic acid, Fluorouracil, IRINotecan, OXaliplatin

Protocol

Study	Dates of enrollment	Evidence
Murphy et al. 2018 (MGH 11-328)	2012-2016	Phase 2

Note: FOLFIRINOX should be limited to those with ECOG 0-1. Amendment after first 6 patients were enrolled increased neoadjuvant cycles from 4 to 8 if no progression was detected on restaging CT

Chemotherapy

• Folinic acid (Leucovorin) 400 mg/m² IV over 2 hours once on day 1, given second
• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours, given fourth (total dose per cycle: 2800 mg/m²)
• Irinotecan (Camptosar) 180 mg/m² 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
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1, given first

Supportive therapy

• Pegfilgrastim (Neulasta) 6 mg SC once on day 4

14-day cycle for 4 to 8 cycles, followed by restaging with CT scan. If tumor was resectable (no vascular involvement), they received short-course proton chemoradiotherapy:

Chemotherapy

• Capecitabine (Xeloda) 825 mg/m² PO twice per day, Monday – Friday for 2 weeks

Radiotherapy

• Proton radiotherapy of 25 GyE in 5 treatments OR Intensity modulated radiotherapy (IMRT) of 30 Gy in 10 fractions

One course

References

1. MGH 11-328: Murphy JE, Wo JY, Ryan DP, Jiang W, Yeap BY, Drapek LC, Blaszkowsky LS, Kwak EL, Allen JN, Clark JW, Faris JE, Zhu AX, Goyal L, Lillemoe KD, DeLaney TF, Fernández-Del Castillo C, Ferrone CR, Hong TS. Total Neoadjuvant Therapy With FOLFIRINOX Followed by Individualized Chemoradiotherapy for Borderline Resectable Pancreatic Adenocarcinoma: A Phase 2 Clinical Trial. JAMA Oncol. 2018 Jul 1;4(7):963-969. link to original article contains dosing details in manuscript link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT01591733

mFOLFIRINOX

mFOLFIRINOX: modified FOLinic acid, Fluorouracil, IRINotecan, OXaliplatin

Regimen

Study	Dates of enrollment	Evidence
Awaiting publication (Alliance A021501)	2016-2020	Randomized Phase 2

Note: comparison was to historic control. Dosing details are from ASCO abstract 377 (2021).

Chemotherapy

• Folinic acid (Leucovorin) 400 mg/m² IV over 2 hours once on day 1
• Fluorouracil (5-FU) 2400 mg/m² IV continuous infusion over 46 hours, started on day 1
• Irinotecan (Camptosar) 180 mg/m² IV over 90 minutes once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1

14-day cycle for 8 cycles

Subsequent treatment

• Pancreatectomy, then mFOLFOX6 x 4

References

1. PILLAR: Hewitt DB, Nissen N, Hatoum H, Musher B, Seng J, Coveler AL, Al-Rajabi R, Yeo CJ, Leiby B, Banks J, Balducci L, Vaccaro G, LoConte N, George TJ, Brenner W, Elquza E, Vahanian N, Rossi G, Kennedy E, Link C, Lavu H. A Phase 3 Randomized Clinical Trial of Chemotherapy With or Without Algenpantucel-L (HyperAcute-Pancreas) Immunotherapy in Subjects With Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer. Ann Surg. 2022 Jan 1;275(1):45-53. link to original article PubMed https://clinicaltrials.gov/ct2/show/NCT01836432
2. Alliance A021501: https://clinicaltrials.gov/ct2/show/NCT02839343

mFOLFIRINOX, Gemcitabine, RT

mFOLFIRINOX, Gemcitabine, RT: modified FOLinic acid, Fluorouracil, IRINotecan, OXaliplatin, Gemcitabine, Radiation Therapy

Protocol variant #1

Study	Evidence
Blazer et al. 2015	Retrospective

Chemotherapy, mFOLFIRINOX portion

• Fluorouracil (5-FU) 2400 mg/m² IV continuous infusion over 46 hours, started on day 1
• Irinotecan (Camptosar) 165 mg/m² IV over 90 minutes once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 to 4 hours once on day 1

Supportive therapy, mFOLFIRINOX portion

• Pegfilgrastim (Neulasta) 6 mg SC once on day 4

14-day cycle for 4 to 8 cycles Followed by complete restaging. If tumor localized but still not resectable, chemoradiotherapy was administered:

Chemotherapy, consolidation portion

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

Radiotherapy, consolidation portion

• External beam radiotherapy was 36 Gy in 15 daily fractions

3-week course

Protocol variant #2

Study	Evidence
Hosein et al. 2012	Retrospective

Note: Protocol followed "per ACCORD-11 trial."

Chemotherapy, mFOLFIRINOX portion

• Folinic acid (Leucovorin) 400 mg/m² IV once on day 1
• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
• Irinotecan (Camptosar) 180 mg/m² IV once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1

Supportive therapy, mFOLFIRINOX portion

• Filgrastim (Neupogen) was given at the discretion of the treating physician

14-day cycle until maximum response or intolerance

Subsequent treatment

• Hosein et al. 2012, resectable patients by imaging criteria were offered: Surgery, then adjuvant chemoradiotherapy
• Hosein et al. 2012, unresectable patients were offered: Chemoradiotherapy, then surgery (if they became resectable):

Chemotherapy

• Gemcitabine (Gemzar) 600 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36

Radiotherapy

• External beam radiotherapy at 50.4 Gy in 28 fractions.

6-week course

References

1. 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. link to original article link to PMC article PubMed
2. 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. link to original article link to PMC article PubMed

Induction therapy for locally advanced disease, unresectable

Capecitabine monotherapy

Regimen

Study	Dates of enrollment	Evidence
Cartwright et al. 2002	1998-1999	Phase 2

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

21-day cycle for up to 18 cycles (1 year)

References

1. 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. link to original article contains dosing details in manuscript PubMed

Erlotinib & Gemcitabine

Regimen variant #1, Gem 3 out of 4 weeks x 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hammel et al. 2016 (GERCOR LAP07)	2008-2011	Phase 3 (E-esc)	See link	See link

Targeted therapy

• Erlotinib (Tarceva) 100 mg PO once per day

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycle for 4 cycles

Subsequent treatment

• GERCOR LAP07, patients without progression: Erlotinib & Gemcitabine x 2 (6 total) versus Capecitabine, Erlotinib, RT

Regimen variant #2, Gem 3 out of 4 weeks x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hammel et al. 2016 (GERCOR LAP07)	2008-2011	Phase 3 (E-esc)	See link	See link

Note: it is not clear from the protocol whether erlotinib is continued beyond the end of chemotherapy.

Targeted therapy

• Erlotinib (Tarceva) as follows:
  • Cycles 1 to 4: 100 mg PO once per day
  • Cycles 5 & 6: 150 mg PO once per day

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycle for 6 cycles

Regimen variant #3, gemcitabine lead-in, erlotinib 100 mg/day

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Moore et al. 2007 (NCIC-CTG PA.3) ESMO-MCBS (1)	2001-2003	Phase 3 (E-RT-esc)	Gemcitabine	Seems to have superior OS Median OS: 6.2 vs 5.9 mo (HR 0.82, 95% CI 0.69-0.99)

Targeted therapy

• Erlotinib (Tarceva) 100 mg PO once per day

Chemotherapy

• Gemcitabine (Gemzar) as follows:
  • Cycle 1: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43
  • Cycle 2 onwards: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

8-week cycle for 1 cycle, then 28-day cycles

Regimen variant #4, gemcitabine lead-in, erlotinib 150 mg/day

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Moore et al. 2007 (NCIC-CTG PA.3)	2001-2003	Phase 3 (E-RT-esc)	Gemcitabine	Not reported

Note: due to low accrual, the efficacy of this arm could not be determined.

Targeted therapy

• Erlotinib (Tarceva) 150 mg PO once per day

Chemotherapy

• Gemcitabine (Gemzar) as follows:
  • Cycle 1: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43
  • Cycle 2 onwards: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

8-week cycle for 1 cycle, then 28-day cycles

References

1. 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00026338
2. 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; GERCOR. 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00634725

Fluorouracil & RT

Fluorouracil & RT: Fluorouracil & Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Moertel et al. 1981	NR	Phase 3 (E-esc)	RT	Superior OS
Herman et al. 2013 (GV-001.004)	2005-2010	Phase 3 (C)	Fluorouracil & RT with TNFerade	Did not meet primary endpoint of OS Median OS: 10 vs 10 mo (HR 0.90, 95% CI 0.66-1.22)

Note: treatment is assumed to start on a Monday.

Chemotherapy

• Fluorouracil (5-FU) 200 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 1000 mg/m²)

7-day cycle for 5 cycles

Radiotherapy

• Concurrent radiation therapy: 1.8 Gy fractions x 25 fractions, for a total dose of 45 Gy, followed by 1.8 Gy x 3 fractions boost to the tumor bed (total dose of 50.4 Gy)

5.5-week course

Subsequent treatment

• GV-001.004: Gemcitabine or Erlotinib & Gemcitabine maintenance, starting four weeks after chemoradiotherapy

References

1. 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; Gastrointestinal Tumor Study Group. 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. link to original article PubMed
2. GV-001.004: 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. link to original article contains dosing details in manuscript link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00051467

Gemcitabine monotherapy

Regimen variant #1, 3 out of 4 weeks x 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hammel et al. 2016 (GERCOR LAP07)	2008-2011	Phase 3 (C)	See link	See link

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycle for 4 cycles

Subsequent treatment

• GERCOR LAP07, patients without progression: Gemcitabine x 2 (6 total) versus Capecitabine & RT

Regimen variant #2, 3 out of 4 weeks x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hammel et al. 2016 (GERCOR LAP07)	2008-2011	Phase 3 (C)	See link	See link

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycle for 6 cycles

Regimen variant #3, 8-week lead-in ("Burris regimen")

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cantore et al. 2004	1997-2001	Phase 3 (C)	Intraarterial FLEC	Seems to have inferior OS
Chauffert et al. 2008 (FFCD/SFRO 2000-01)	2000-2005	Phase 3 (E-de-esc)	CF & RT, then Gemcitabine	Might have superior OS
Louvet et al. 2005	2001-2003	Phase 3 (C)	GemOx	Seems to have inferior PFS
Loehrer et al. 2011 (ECOG E4201)	2003-2005	Phase 3 (C)	Gemcitabine & RT	Seems to have inferior OS

Chemotherapy

• Gemcitabine (Gemzar) as follows:
  • Cycle 1: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43
  • Cycle 2 onwards: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

8-week cycle for 1 cycle, then 28-day cycles

Subsequent treatment

• Louvet et al. 2005: 5-FU & RT consolidation was recommended but not mandated

References

1. 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. link to original article contains dosing details in abstract PubMed
2. 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. link to original article contains dosing details in manuscript PubMed
3. 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. link to original article contains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT00416507
4. 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. link to original article contains dosing details in manuscript link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00057876
5. 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; GERCOR. 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00634725
6. AB12005: https://clinicaltrials.gov/ct2/show/NCT03766295

Gemcitabine & RT

Gemcitabine & RT: Gemcitabine & Radiation Therapy

Protocol variant #1, 600 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cardenes et al. 2011	2001-2003	Phase 2
Loehrer et al. 2011 (ECOG E4201)	2003-2005	Phase 3 (E-esc)	Gemcitabine	Seems to have superior OS

Chemotherapy, induction

• Gemcitabine (Gemzar) 600 mg/m² IV over 30 to 60 minutes once per day on days 1, 8, 15, 22, 29

Radiotherapy

• Concurrent radiation therapy, 1.8 Gy per fraction x 28 fractions, total dose of 50.4 Gy

5.5-week course, followed in 4 weeks by:

Chemotherapy, consolidation

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycle for up to 5 cycles

Protocol variant #2, 400 mg/m²

Study	Dates of enrollment	Evidence
Epelbaum et al. 2002	1997-1999	Phase 2

Chemotherapy, part 1

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43

Radiation planning during this phase, followed by:

Chemotherapy, part 2

• Gemcitabine (Gemzar) 400 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycle for 2 cycles

Radiotherapy

• Concurrent radiation therapy 1.8 Gy x 28 fractions, total dose of 50.4 Gy

5.5-week course, followed by:

Chemotherapy, maintenance

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycles

References

1. 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. link to original article contains dosing details in manuscript PubMed
2. Cardenes HR, Moore AM, Johnson CS, Yu M, Helft P, Chiorean EG, Vinson J, Howard TJ, Stephens AW, Tai DF, Loehrer PJ Sr; Hoosier Oncology Group. 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.link to original article PubMed
3. 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. link to original article contains dosing details in manuscript link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00057876

GemOx

GemOx: Gemcitabine, Oxaliplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Louvet et al. 2005	2001-2003	Phase 3 (E-esc)	Gemcitabine	Seems to have superior PFS Median PFS: 5.8 vs 3.7 mo (HR 0.78, 95% CI 0.59-0.99)

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV over 100 minutes once on day 1
• Oxaliplatin (Eloxatin) 100 mg/m² IV over 2 hours once on day 2

14-day cycle for at least 6 cycles

Subsequent treatment

• 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.

References

1. 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. link to original article contains dosing details in manuscript PubMed

Radiation therapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cohen et al. 2005 (ECOG E8282)	1983-1989	Phase 3 (C)	5-FU, MMC, RT	Did not meet efficacy endpoints

Radiotherapy

• External beam radiotherapy

References

1. ECOG E8282: Cohen SJ, Dobelbower R Jr, Lipsitz S, Catalano PJ, Sischy B, Smith TJ, Haller DG; ECOG. 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. link to original article PubMed

Metastatic disease, first-line

Capecitabine monotherapy

Regimen

Study	Dates of enrollment	Evidence
Cartwright et al. 2002	1998-1999	Phase 2

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

21-day cycle for up to 18 cycles (1 year)

References

1. 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. link to original article contains dosing details in manuscript PubMed

Capecitabine & Gemcitabine

GemCap: Gemcitabine & Capecitabine
GEM-CAP: GEMcitabine & CAPecitabine

Regimen variant #1, q4wk x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Middleton et al. 2014 (TeloVac)	2007-2011	Phase 3 (C)	1. GemCap & GV1001	Did not meet primary endpoint of OS Median OS: 7.9 vs 8.4 mo (HR 0.95, 98.25% CI 0.85-1.29)
			2. GemCap x 2, then GV1001	Might have superior OS Median OS: 7.9 vs 6.9 mo (HR 0.9845, 98.25% CI 0.67-1.03)

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Capecitabine (Xeloda) 830 mg/m² PO twice per day on days 1 to 21
• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycle for 6 cycles

Regimen variant #2, q4wk indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lee et al. 2017	2007-2011	Phase 3 (E-esc)	Gemcitabine	Might have superior OS Median OS: 10.3 vs 7.5 mo (HR 0.82, 95% CI 0.67-1.01)

Chemotherapy

• Capecitabine (Xeloda) 830 mg/m² PO twice per day on days 1 to 21
• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycles

Regimen variant #3, induction followed by maintenance

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cunningham et al. 2009 (CRUK GEM-CAP)	2002-2005	Phase 3 (E-esc)	Gemcitabine	Might have superior OS Median OS: 7.1 vs 6.2 mo (HR 0.86, 95% CI 0.72-1.02)

Chemotherapy

• Capecitabine (Xeloda) as follows:
  • Cycle 1: 830 mg/m² PO twice per day on days 1 to 21, 29 to 49
  • Cycle 2 onwards: 830 mg/m² PO twice per day on days 1 to 21
• Gemcitabine (Gemzar) as follows:
  • Cycle 1: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43
  • Cycle 2 onwards: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

8-week cycle for 1 cycle, then 28-day cycles

Regimen variant #4, q3wk x 8

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)	2001-2004	Phase 3 (E-esc)	Gemcitabine	Did not meet primary endpoint of OS

Chemotherapy

• Capecitabine (Xeloda) 650 mg/m² PO twice per day on days 1 to 14
• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1 & 8

21-day cycle for up to 8 cycles

References

1. 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00030732
   1. 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. link to original article contains dosing details in manuscript PubMed
2. CRUK GEM-CAP: 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00032175
3. TeloVac: Middleton G, Silcocks P, Cox T, Valle J, Wadsley J, Propper D, Coxon F, Ross P, Madhusudan S, Roques T, Cunningham D, Falk S, Wadd N, Harrison M, Corrie P, Iveson T, Robinson A, McAdam K, Eatock M, Evans J, Archer C, Hickish T, Garcia-Alonso A, Nicolson M, Steward W, Anthoney A, Greenhalf W, Shaw V, Costello E, Naisbitt D, Rawcliffe C, Nanson G, Neoptolemos J. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. Lancet Oncol. 2014 Jul;15(8):829-40. Epub 2014 Jun 19. link to original article contains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT00425360
4. 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. link to original article contains dosing details in manuscript link to PMC article PubMed
5. KG 4/2015: https://clinicaltrials.gov/ct2/show/NCT02854072

Cisplatin & Gemcitabine (GC)

Regimen variant #1, 25/1000, weekly dosing

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Colucci et al. 2002	NR	Phase 3 (E-esc)	Gemcitabine	Seems to have superior TTP
Colucci et al. 2010 (GIP-1)	2002-2007	Phase 3 (E-esc)	Gemcitabine	Did not meet primary endpoint of OS

Note: Cisplatin is not given on day 22 of the first cycle; 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).

Chemotherapy

• Cisplatin (Platinol) as follows, given first; 60 minutes prior to gemcitabine:
  • Cycle 1: 25 mg/m² IV once per day on days 1, 8, 15, 29, 36, 43
  • Cycle 2 onwards: 25 mg/m² IV once per day on days 1, 8, 15
• Gemcitabine (Gemzar) as follows, given second:
  • Cycle 1: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43
  • Cycle 2 onwards: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

8-week cycle for 1 cycle, then 28-day cycles

Regimen variant #2, 35/1000, 2 out of 3 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cascinu et al. 2008 (SPaCe-01)	2005-2006	Randomized Phase 2 (C)	GC & Cetuximab	Did not meet primary endpoint of ORR

Chemotherapy

• Cisplatin (Platinol) 35 mg/m² IV over 30 minutes once per day on days 1 & 8 (with 1500 mL NS)
• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1 & 8

21-day cycles

Regimen variant #3, 50/1000, bi-weekly dosing

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Heinemann et al. 2006	1997-2002	Phase 3 (E-esc)	Gemcitabine	Might have superior PFS

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV over 60 minutes once per day on days 1 & 15
• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1 & 15

28-day cycles

References

1. 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. link to original article contains dosing details in abstract PubMed
2. 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. link to original article contains dosing details in manuscript PubMed
3. SPaCe-01: 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. 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. link to original article contains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT00536614
4. 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; GOIM; GISCAD; 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00813696

Erlotinib & Gemcitabine

Regimen variant #1, no gemcitabine lead-in

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kordes et al. 2015 (AMCmedonc10/003)	2010-2014	Randomized Phase 2 (C)	Erlotinib, Gemcitabine, Metformin	Did not meet primary endpoint of OS6

Targeted therapy

• Erlotinib (Tarceva) 100 mg PO once per day

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #2, gemcitabine lead-in, erlotinib 100 mg/day

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Moore et al. 2007 (NCIC-CTG PA.3) ESMO-MCBS (1)	2001-2003	Phase 3 (E-RT-esc)	Gemcitabine	Seems to have superior OS Median OS: 6.2 vs 5.9 mo (HR 0.82, 95% CI 0.69-0.99)
Van Cutsem et al. 2009 (BO17706)	2005-2006	Phase 3 (C)	Erlotinib, Gemcitabine, Bevacizumab	Did not meet primary endpoint of OS Median OS: 6 vs 7.1 mo (HR 1.12, 95% CI 0.93-1.35)

Targeted therapy

• Erlotinib (Tarceva) 100 mg PO once per day

Chemotherapy

• Gemcitabine (Gemzar) as follows:
  • Cycle 1: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43
  • Cycle 2 onwards: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

8-week cycle for 1 cycle, then 28-day cycles

Regimen variant #3, gemcitabine lead-in, erlotinib 150 mg/day

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Moore et al. 2007 (NCIC-CTG PA.3)	2001-2003	Phase 3 (E-RT-esc)	Gemcitabine	Not reported
Heinemann et al. 2012 (AIO-PK0104)	2006-2008	Phase 3 (C)	Capecitabine & Erlotinib	Inconclusive whether non-inferior TTF2

Note: due to low accrual in NCIC-CTG PA.3, the efficacy of this arm could not be determined.

Targeted therapy

• Erlotinib (Tarceva) 150 mg PO once per day

Chemotherapy

• Gemcitabine (Gemzar) as follows:
  • Cycle 1: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43
  • Cycle 2 onwards: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

8-week cycle for 1 cycle, then 28-day cycles

References

1. 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00026338
2. BO17706: 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT01214720
3. 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. link to original article contains dosing details in manuscript link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00440167
4. AMCmedonc10/003: 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. link to original articlecontains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT01210911

Fluorouracil monotherapy

Regimen variant #1, 300 mg/m²/day PVI

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Maisey et al. 2002	1994-2000	Phase 3 (C)	5-FU & Mitomycin	Seems to have inferior ORR

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Fluorouracil (5-FU) 300 mg/m²/day IV continuous infusion

Up to 24-week course

Regimen variant #2, 500 mg/m² intermittent 28-day cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ducreux et al. 2002 (EORTC 05962)	1992-1998	Phase 3 (C)	CF	Did not meet primary endpoint of OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 to 5

28-day cycles

Regimen variant #3, 500 mg/m² intermittent with spacing

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cullinan et al. 1985	NR	Phase 3 (E-de-esc)	1. FA 2. FAM	Did not meet primary endpoint of OS
Cullinan et al. 1990	NR	Phase 3 (C)	1. Mallinson regimen 2. FAP	Did not meet primary endpoint of OS

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.

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 to 5

28-day cycle for 2 cycles, then 35-day cycles

Regimen variant #4, 500 mg/m² intermittent 35-day cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Burch et al. 2000	NR	Phase 3 (C)	Octreotide	Did not meet primary endpoint of OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 to 5

35-day cycles

Regimen variant #5, 600 mg/m² weekly

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Burris et al. 1997	1992-1994	Phase 3 (C)	Gemcitabine	Inferior OS

Note: this variant is here for historical reference purposes, only. To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Fluorouracil (5-FU) 600 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycles

References

1. 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. link to original article PubMed
2. 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. link to original article PubMed
3. 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. link to original article contains dosing details in manuscript PubMed
4. Burch PA, Block M, Schroeder G, Kugler JW, Sargent DJ, Braich TA, Mailliard JA, Michalak JC, Hatfield AK, Wright K, Kuross SA; NCCTG. Phase III evaluation of octreotide versus chemotherapy with 5-fluorouracil or 5-fluorouracil plus leucovorin in advanced exocrine pancreatic cancer: a North Central Cancer Treatment Group study. Clin Cancer Res. 2000 Sep;6(9):3486-92. link to original article contains dosing details in manuscript PubMed
5. 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. link to original article contains dosing details in abstract PubMed
6. EORTC 05962: Ducreux M, Rougier P, Pignon JP, Douillard JY, Seitz JF, Bugat R, Bosset JF, Merouche Y, Raoul JL, Ychou M, Adenis A, Berthault-Cvitkovic F, Luboinski M; Groupe Digestif of the Fédération Nationale des Centres de Lutte Contre le Cancer Digestif. A randomised trial comparing 5-FU with 5-FU plus cisplatin in advanced pancreatic carcinoma. Ann Oncol. 2002 Aug;13(8):1185-91. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00003029

FOLFIRINOX

FOLFIRINOX: FOLinic acid, Fluorouracil, IRINotecan, OXaliplatin
FFX: Folinic acid, Fluorouracil, Irinotecan, Oxaliplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Conroy et al. 2011 (PRODIGE 4/ACCORD 11) ESMO-MCBS (5)	2005-2009	Phase 3 (E-esc)	Gemcitabine	Superior OS Median OS: 11.1 vs 6.8 mo (HR 0.57, 95% CI 0.45-0.73)	Superior QoL by EORTC QLQ-C30

Chemotherapy

• Folinic acid (Leucovorin) 400 mg/m² IV over 2 hours once on day 1, given second
• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours, given fourth (total dose per cycle: 2800 mg/m²)
• Irinotecan (Camptosar) 180 mg/m² 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
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1, given first

14-day cycles

References

1. 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00112658
   1. HRQoL 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. link to original article PubMed
2. PANC003: https://clinicaltrials.gov/ct2/show/NCT03504423

Gemcitabine monotherapy

Regimen variant #1, 900 mg/m², 3 out of 4 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Stathopoulos et al. 2006	2001-2005	Phase 3 (C)	IG	Did not meet primary endpoint of OS Median OS: 6.5 vs 6.4 mo

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Gemcitabine (Gemzar) 900 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #2, 1000 mg/m², 8-week lead-in ("Burris regimen")

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Burris et al. 1997	1992-1994	Phase 3 (E-RT-switch-ic)	5-FU	Superior OS
Colucci et al. 2002	NR	Phase 3 (C)	GC	Seems to have inferior TTP
Moore et al. 2003 (NCIC-CTG PA.1)	1997-1999	Phase 3 (C)	Tanomastat	Superior OS
Van Cutsem et al. 2004 (CR003976)	1999-2001	Phase 3 (C)	Gemcitabine & Tipifarnib	Did not meet primary endpoint of OS
Rocha Lima et al. 2004	2000-2001	Phase 3 (C)	IG	Did not meet primary endpoint of OS Median OS: 6.6 vs 6.3 mo
Reni et al. 2005	2000-2003	Phase 3 (C)	PEFG	Seems to have inferior PFS
Louvet et al. 2005	2001-2003	Phase 3 (C)	GemOx	Seems to have inferior PFS
Abou-Alfa et al. 2006 (MSKCC 02-011)	2001-2003	Phase 3 (C)	Gemcitabine & Exatecan	Did not meet primary endpoint of OS Median OS: 6.2 vs 6.7 mo
Moore et al. 2007 (NCIC-CTG PA.3)	2001-2003	Phase 3 (C)	Erlotinib & Gemcitabine	Seems to have inferior OS
Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)	2001-2004	Phase 3 (C)	GemCap	Did not meet primary endpoint of OS
Poplin et al. 2009 (ECOG E6201)	2003-2005	Phase 3 (C)	1. Gemcitabine; fixed dose rate	Might have inferior OS
			2. GEMOX	Did not meet primary endpoint of OS
Cunningham et al. 2009 (CRUK GEM-CAP)	2002-2005	Phase 3 (C)	GEM-CAP	Might have inferior OS
Colucci et al. 2010 (GIP-1)	2002-2007	Phase 3 (C)	GC	Did not meet primary endpoint of OS
Dahan et al. 2010 (FFCD 0301)	2003-2006	Phase 3 (C)	LV5FU2-CDDP	Did not meet primary endpoint of OS Median OS: 8 vs 6.6 mo
Philip et al. 2010 (SWOG S0205)	2004-2006	Phase 3 (C)	Gemcitabine & Cetuximab	Did not meet primary endpoint of OS Median OS: 5.9 vs 6.3 mo (HR 0.94, 95% CI 0.81-1.10)
Conroy et al. 2011 (PRODIGE 4/ACCORD 11)	2005-2009	Phase 3 (C)	FOLFIRINOX	Inferior OS
Gonçalves et al. 2012 (BAYPAN)	2006-2009	Phase 3 (C)	Gemcitabine & Sorafenib	Did not meet primary endpoint of PFS Median PFS: 5.7 vs 3.8 mo (HR 0.96, 95% CI 0.65-1.43)
Rougier et al. 2013 (VANILLA)	2007-2009 (F)	Phase 3 (C)	Gemcitabine & Ziv-aflibercept	Did not meet primary endpoint of OS Median OS: 7.8 vs 6.5 mo (HR 0.86, 95% CI 0.68-1.09)
Von Hoff et al. 2013 (MPACT)	2009-2012	Phase 3 (C)	Gemcitabine & nab-Paclitaxel	Inferior OS
Deplanque et al. 2015 (AB07012)	NR	Phase 3 (C)	Gemcitabine & Masitinib	Did not meet primary endpoint of OS
Middleton et al. 2017 (ViP)	2011-2013 (C)	Randomized Phase 2 (C)	Gemcitabine & Vandetanib	Did not meet primary endpoint of OS Median OS: 8.95 vs 8.8 mo (HR 0.83, 80.8% CI 0.65-1.05)

Note: Colucci et al. 2002 stopped treatment after 3 cycles (16 weeks).

Chemotherapy

• Gemcitabine (Gemzar) as follows:
  • Cycle 1: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43
  • Cycle 2 onwards: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15
    • In Burris et al. 1997, patients with grade 2 or lower toxicities could have had doses increased to 1250 mg/m²

8-week cycle for 1 cycle, then 28-day cycles

Regimen variant #3, 1000 mg/m², 3 out of 4 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Heinemann et al. 2006	1997-2002	Phase 3 (C)	Cisplatin & Gemcitabine	Might have inferior PFS
Berlin et al. 2002 (ECOG E2297)	1998-1999	Phase 3 (C)	5-FU & Gemcitabine	Might have inferior OS
Oettle et al. 2005 (JMES)	2001-2003	Phase 3 (C)	Gemcitabine & Pemetrexed	Did not meet primary endpoint of OS Median OS: 6.3 vs 6.2 mo (HR 1.02, 95% CI 0.85-1.22)
Kindler et al. 2010 (CALGB 80303)	2004-2006	Phase 3 (C)	Gemcitabine & Bevacizumab	Did not meet primary endpoint of OS Median OS: 5.9 vs 5.8 mo (HR 0.96, 95% CI 0.81-1.14)
Spano et al. 2008 (A4061016)	2006	Randomized Phase 2 (C)	Gemcitabine & Axitinib	Did not meet primary endpoint of OS
Kindler et al. 2011 (A4061028)	2007-2008	Phase 3 (C)	Gemcitabine & Axitinib	Did not meet primary endpoint of OS Median OS: 8.3 vs 8.5 mo (HR 0.99, 95% CI 0.76-1.27)
Ueno et al. 2013 (GEST)	2007-2009	Phase 3 (C)	1. S-1	Non-inferior OS
			2. Gemcitabine & S-1	Did not meet primary endpoint of OS
Lee et al. 2017	2007-2011	Phase 3 (C)	GemCap	Might have inferior OS
Catenacci et al. 2015 (UCCRC-8418)	2010-2012	Randomized Phase 1b/2 (C)	Gemcitabine & Vismodegib	Did not meet primary endpoint of PFS
Fuchs et al. 2015 (GAMMA)	2011-2012	Randomized Phase 1b/2 (C)	Gemcitabine & Ganitumab	Did not meet primary endpoint of OS
O'Neil et al. 2015 (ONTRAC)	2011-2013	Phase 2/3 (C)	Gemcitabine & Rigosertib	Did not meet primary endpoint of OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycles

Regimen variant #4, 1000 mg/m², weekly

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hong et al. 2013 (SMC 2008-07-065)	2008-2012	Randomized Phase 2 (C)	Gemcitabine & Simvastatin	Did not meet primary endpoint of TTP

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

21-day cycles

Regimen variant #5, 1500 mg/m², fixed-dose rate (FDR)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Poplin et al. 2009 (ECOG E6201)	2003-2005	Phase 3 (E-switch-ic)	1. Gemcitabine; standard	Might have superior OS Median OS: 6.2 vs 4.9 mo (HR 0.83, 95% CI 0.69-1.00)
			2. GEMOX	Did not meet primary endpoint of OS

Chemotherapy

• Gemcitabine (Gemzar) 1500 mg/m² IV at fixed dose rate over 150 minutes once per day on days 1, 8, 15

28-day cycles

References

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17. CRUK GEM-CAP: 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00032175
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30. 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. link to original article link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00789633
31. ONTRAC: 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. link to original article link to PMC article contains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT01360853
32. UCCRC-8418: 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. link to original article contains dosing details in supplement link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT01064622
33. 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. link to original article contains dosing details in manuscript link to PMC article PubMed
34. 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. link to original article contains dosing details in abstract PubMed ISRCTN96397434

GemOx

GemOx: Gemcitabine & Oxaliplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Louvet et al. 2005	2001-2003	Phase 3 (E-esc)	Gemcitabine	Seems to have superior PFS
Poplin et al. 2009 (ECOG E6201)	2003-2005	Phase 3 (E-esc)	1. Gemcitabine; standard	Did not meet primary endpoint of OS
			2. Gemcitabine; fixed dose rate	Did not meet primary endpoint of OS

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV over 100 minutes once on day 1
• Oxaliplatin (Eloxatin) 100 mg/m² IV over 2 hours once on day 2

14-day cycles

References

1. 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. link to original article contains dosing details in manuscript PubMed
2. 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. link to original article contains dosing details in manuscript link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00058149

Gemcitabine & nab-Paclitaxel

NG: Nab-Paclitaxel & Gemcitabine
AG: Abraxane (nab-Paclitaxel) & Gemcitabine

Regimen variant #1, with 8-week lead-in

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Von Hoff et al. 2013 (MPACT) ESMO-MCBS (3)	2009-2012	Phase 3 (E-RT-esc)	Gemcitabine	Superior OS1 Median OS: 8.7 vs 6.6 mo (HR 0.72, 95% CI 0.62-0.83)

¹Reported efficacy is based on the 2015 update.

Chemotherapy

• Gemcitabine (Gemzar) as follows, given second:
  • Cycle 1: 1000 mg/m² IV once per day on days 1, 8, 15, 29, 36, 43
  • Cycle 2 onwards: 1000 mg/m² IV once per day on days 1, 8, 15
• Paclitaxel, nanoparticle albumin-bound (Abraxane) as follows, given first:
  • Cycle 1: 125 mg/m² IV over 30 to 40 minutes once per day on days 1, 8, 15, 29, 36, 43
  • Cycle 2 onwards: 125 mg/m² IV over 30 to 40 minutes once per day on days 1, 8, 15

8-week cycle for 1 cycle, then 28-day cycles

Regimen variant #2, no lead-in

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Von Hoff et al. 2011 (CA040)	2006-NR	Phase 1/2
Tempero et al. 2021 (RESOLVE)	2015-NR	Phase 3 (C)	Ibrutinib, Gemcitabine, nab-Paclitaxel	Did not meet primary endpoint of OS
Van Cutsem et al. 2020 (HALO 109-301)	2016-2018	Phase 3 (C)	AG & PEGPH20	Did not meet primary endpoint of OS

Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen. The dosing here is from HALO 109-301. To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Biomarker eligibility criteria

• HALO 109-301: Hyaluronan-high

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15
• Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m² IV once per day on days 1, 8, 15

28-day cycles

References

1. CA040: 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. link to original article contains dosing details in manuscript link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00398086
2. 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. link to original article contains dosing details in manuscript link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00844649
   1. 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). link to original article PubMed
   2. Subgroup analysis: Young R, Mainwaring P, Clingan P, Parnis FX, Asghari G, Beale P, Aly A, Botteman M, Romano A, Ferrara S, Margunato-Debay S, Harris M. nab-Paclitaxel plus gemcitabine in metastatic pancreatic adenocarcinoma: Australian subset analyses of the phase III MPACT trial. Asia Pac J Clin Oncol. 2018 Oct;14(5):e325-e331. Epub 2018 Jun 22. link to original article PubMed
3. HALO 109-301: Van Cutsem E, Tempero MA, Sigal D, Oh DY, Fazio N, Macarulla T, Hitre E, Hammel P, Hendifar AE, Bates SE, Li CP, Hingorani SR, de la Fouchardiere C, Kasi A, Heinemann V, Maraveyas A, Bahary N, Layos L, Sahai V, Zheng L, Lacy J, Park JO, Portales F, Oberstein P, Wu W, Chondros D, Bullock AJ; HALO 109-301 Investigators. Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma. J Clin Oncol. 2020 Sep 20;38(27):3185-3194. Epub 2020 Jul 24. link to original article contains dosing details in manuscript link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT02715804
4. RESOLVE: Tempero M, Oh DY, Tabernero J, Reni M, Van Cutsem E, Hendifar A, Waldschmidt DT, Starling N, Bachet JB, Chang HM, Maurel J, Garcia-Carbonero R, Lonardi S, Coussens LM, Fong L, Tsao LC, Cole G Jr, James D, Macarulla T. Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study. Ann Oncol. 2021 May;32(5):600-608. Epub 2021 Feb 1. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT02436668
5. CanStem111P: https://clinicaltrials.gov/ct2/show/NCT02993731
6. GRASPANC 2018-01: https://clinicaltrials.gov/ct2/show/NCT03665441

GTX

GTX: Gemcitabine, Taxotere (Docetaxel), Xeloda (Capecitabine)

Regimen

Study	Evidence
Fine et al. 2007	Retrospective

Note: De Jesus-Acosta et al. 2012 lists the capecitabine dose as "750 mg/m²/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/m² PO twice per day. The 2009 ASCO abstract by Fine also lists this 750 mg/m² PO twice per day (1500 mg/m²/day) dose.

Chemotherapy

• Gemcitabine (Gemzar) 750 mg/m² IV over 75 minutes once per day on days 4 & 11
• Docetaxel (Taxotere) 30 mg/m² IV once per day on days 4 & 11
• Capecitabine (Xeloda) 750 mg/m² PO twice per day on days 1 to 14

21-day cycles

References

1. 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. link to original article contains dosing details in abstract PubMed
2. 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. link to abstract content property of HemOnc.org
3. 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. link to original article contains dosing details in manuscript--with error as noted above link to PMC article PubMed

S-1 monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ueno et al. 2013 (GEST)	2007-2009	Phase 3 (E-switch-ic)	1. Gemcitabine	Non-inferior OS
			2. Gemcitabine & S-1	Not reported

Chemotherapy

• Tegafur, gimeracil, oteracil (S-1) by the following weight-based criteria:
  • BSA less than 1.25 m²: 40 mg PO twice per day on days 1 to 28
  • BSA at least 1.25 m² and less than 1.5 m²: 50 mg PO twice per day on days 1 to 28
  • BSA 1.5 m² or more: 60 mg PO twice per day on days 1 to 28

42-day cycles

References

1. 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00498225
   1. Update: Okusaka T, Miyakawa H, Fujii H, Nakamori S, Satoh T, Hamamoto Y, Ito T, Maguchi H, Matsumoto S, Ueno H, Ioka T, Boku N, Egawa S, Hatori T, Furuse J, Mizumoto K, Ohkawa S, Yamaguchi T, Yamao K, Funakoshi A, Chen JS, Cheng AL, Sato A, Ohashi Y, Tanaka M; GEST group. Updated results from GEST study: a randomized, three-arm phase III study for advanced pancreatic cancer. J Cancer Res Clin Oncol. 2017 Jun;143(6):1053-1059. Epub 2017 Feb 16. link to original article link to PMC article PubMed

Metastatic disease, gemcitabine-refractory

Capecitabine & Erlotinib

Regimen

Study	Dates of enrollment	Evidence
Kulke et al. 2007	NR	Phase 2

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² (rounded to the nearest 150 mg tablet) PO twice per day on days 1 to 14

Targeted therapy

• Erlotinib (Tarceva) 150 mg PO on days 1 to 21

21-day cycles

References

1. 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. link to original article contains dosing details in manuscript PubMed

CapeOx

CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda (Capecitabine), OXaliplatin

Regimen

Study	Dates of enrollment	Evidence
Xiong et al. 2008	2004-2005	Phase 2

Chemotherapy

• Capecitabine (Xeloda) by the following age- and performance-based criteria:
  • Age less than 65 years old and ECOG performance status less than 2: 1000 mg/m² PO twice per day on days 1 to 14
  • Age greater than 65 years old and/or ECOG performance status greater than or equal to 2: 750 mg/m² PO twice per day on days 1 to 14
• Oxaliplatin (Eloxatin) by the following age- and performance-based criteria:
  • Age less than 65 years old and ECOG performance status less than 2: 130 mg/m² IV over 2 hours once on day 1
  • Age greater than 65 years old and/or ECOG performance status greater than or equal to 2: 110 mg/m² IV over 2 hours once on day 1

21-day cycles

References

1. 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. link to original article contains dosing details in manuscript PubMed

FULV

FULV: 5-FU & LeucoVorin (Folinic acid)
FF: Fluorouracil & Folinic acid

Regimen variant #1, 2000/200

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Oettle et al. 2014 (CONKO-003 part 2)	2004-2007	Phase 3 (C)	OFF	Inferior OS
Wang-Gillam et al. 2015 (NAPOLI-1)	2012-01-11 to 2013-09-11	Phase 3 (C)	1. FULV & nanoliposomal Irinotecan	Seems to have inferior OS1
			2. Irinotecan, nanoliposomal	Not reported

¹Reported efficacy is based on the 2019 update.

Chemotherapy

• Fluorouracil (5-FU) 2000 mg/m² IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, given second (total dose per cycle: 8000 mg/m²)
• Folinic acid (Leucovorin) 200 mg/m² IV once per day on days 1, 8, 15, 22, given first

42-day cycles

Regimen variant #2, 2800/400

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gill et al. 2016 (PANCREOX)	2010-2012	Phase 3 (C)	mFOLFOX6	Did not meet primary endpoint of PFS

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours, given second (total dose per cycle: 2800 mg/m²)
• Folinic acid (Leucovorin) 400 mg/m² IV over 2 hours once on day 1, given first

14-day cycles

References

1. CONKO-003 part 2: 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00786058
2. 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT01494506
   1. HRQoL analysis: Hubner RA, Cubillo A, Blanc JF, Melisi D, Von Hoff DD, Wang-Gillam A, Chen LT, Becker C, Mamlouk K, Belanger B, Yang Y, de Jong FA, Siveke JT. Quality of life in metastatic pancreatic cancer patients receiving liposomal irinotecan plus 5-fluorouracil and leucovorin. Eur J Cancer. 2019 Jan;106:24-33. Epub 2018 Nov 17. link to original article PubMed
   2. Update: 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. link to original article PubMed
   3. Subgroup analysis: Bang YJ, Li CP, Lee KH, Chiu CF, Park JO, Shan YS, Kim JS, Chen JS, Shim HJ, Rau KM, Choi HJ, Oh DY, Belanger B, Chen LT. Liposomal irinotecan in metastatic pancreatic adenocarcinoma in Asian patients: Subgroup analysis of the NAPOLI-1 study. Cancer Sci. 2020 Feb;111(2):513-527. Epub 2019 Dec 20. link to original article link to PMC article PubMed
3. 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT01121848

FULV & nanoliposomal Irinotecan

FULV & nanoliposomal Irinotecan: 5-FU, LeucoVorin (Folinic acid), nanoliposomal Irinotecan

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wang-Gillam et al. 2015 (NAPOLI-1) ESMO-MCBS (3)	2012-01-11 to 2013-09-11	Phase 3 (E-RT-esc)	1. FULV	Seems to have superior OS1 (primary endpoint) Median OS: 4.9 vs 4.2 mo (HR 0.75, 95% CI 0.57-0.99)
			2. Irinotecan, nanoliposomal	Not reported

¹Reported efficacy is based on the 2019 update.

Chemotherapy

• Fluorouracil (5-FU) 2400 mg/m² IV continuous infusion over 46 hours, started on day 1, given third
• Folinic acid (Leucovorin) 400 mg/m² IV over 30 minutes once on day 1, given second
• Irinotecan liposome (Onivyde) 70 mg/m² (irinotecan free base) IV over 90 minutes once on day 1, given first
  • Per Wang-Gillam et al. 2015 (NAPOLI-1), 70 mg/m² irinotecan free base is equivalent to 80 mg/m² 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/m² dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/m² of irinotecan free base."

14-day cycles

References

1. 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT01494506
   1. HRQoL analysis: Hubner RA, Cubillo A, Blanc JF, Melisi D, Von Hoff DD, Wang-Gillam A, Chen LT, Becker C, Mamlouk K, Belanger B, Yang Y, de Jong FA, Siveke JT. Quality of life in metastatic pancreatic cancer patients receiving liposomal irinotecan plus 5-fluorouracil and leucovorin. Eur J Cancer. 2019 Jan;106:24-33. Epub 2018 Nov 17. link to original article PubMed
   2. Update: 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. link to original article PubMed
   3. Subgroup analysis: Bang YJ, Li CP, Lee KH, Chiu CF, Park JO, Shan YS, Kim JS, Chen JS, Shim HJ, Rau KM, Choi HJ, Oh DY, Belanger B, Chen LT. Liposomal irinotecan in metastatic pancreatic adenocarcinoma in Asian patients: Subgroup analysis of the NAPOLI-1 study. Cancer Sci. 2020 Feb;111(2):513-527. Epub 2019 Dec 20. link to original article link to PMC article PubMed

FOLFIRI

FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Regimen variant #1

Study	Dates of enrollment	Evidence
Zaniboni et al. 2012 (SLAP)	2010-2011	Phase 2

Chemotherapy

• Folinic acid (Leucovorin) 200 mg/m² IV once per day on days 1 & 2
• Fluorouracil (5-FU) 400 mg/m² IV bolus once per day on days 1 & 2, then 600 mg/m² IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m²)
• Irinotecan (Camptosar) 180 mg/m² IV once on day 1

14-day cycles

Regimen variant #2, modified FOLFIRI.3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yoo et al. 2009 (AMC P 01)	2007-2008	Randomized Phase 2 (E-switch-ic)	mFOLFOX	Did not meet primary endpoint of OS6

Chemotherapy

• Folinic acid (Leucovorin) 400 mg/m² IV over 2 hours once on day 1
• Fluorouracil (5-FU) 2000 mg/m² IV continuous infusion over 46 hours, started on day 1
• Irinotecan (Camptosar) 70 mg/m² IV once per day on days 1 & 3, with day 3 dose given at end of 5-FU infusion

14-day cycles

References

1. AMC P 01: 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. link to original article contains dosing details in manuscript link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00786006
2. SLAP: 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. link to original article contains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT01543412

mFOLFIRINOX

mFOLFIRINOX: modified FOLinic acid, Fluorouracil, IRINotecan, OXaliplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Go et al. 2021 (MPACA-3)	2017-2019	Phase 3 (E-esc)	S-1	Superior OS Median OS: 9.2 vs 4.9 mo (aHR 0.40, 95% CI 0.20-0.70)

Chemotherapy

• Folinic acid (Leucovorin) 400 mg/m² IV once on day 1
• Fluorouracil (5-FU) 1000 mg/m² IV continuous infusion over 24 hours, started on day 1
• Irinotecan (Camptosar) 135 mg/m² IV once on day 1
• Oxaliplatin (Eloxatin) 65 mg/m² IV once on day 1

14-day cycles

References

1. MPACA-3: Go SI, Lee SC, Bae WK, Zang DY, Lee HW, Jang JS, Ji JH, Kim JH, Park S, Sym SJ, Yang Y, Jeon SY, Hwang IG, Oh SY, Kang JH. Modified FOLFIRINOX versus S-1 as second-line chemotherapy in gemcitabine-failed metastatic pancreatic cancer patients: A randomised controlled trial (MPACA-3). Eur J Cancer. 2021 Nov;157:21-30. Epub 2021 Aug 28. link to original article PubMed KCT0003534

FOLFOX

FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yoo et al. 2009 (AMC P 01)	2007-2008	Randomized Phase 2 (E-switch-ic)	mFOLFIRI.3	Did not meet primary endpoint of OS6

Chemotherapy

• Folinic acid (Leucovorin) 400 mg/m² IV once on day 1
• Fluorouracil (5-FU) 2000 mg/m² IV once per day on days 1 & 2
• Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1

14-day cycles

References

1. AMC P 01: 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. link to original article contains dosing details in abstract link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00786006

mFOLFOX6

mFOLFOX6: modified FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hecht et al. 2021 (SEQUOIA)	2017-2019	Phase 3 (C)	mFOLFOX6 & Pegilodecakin	Did not meet primary endpoint of OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, given third, then 2400 mg/m² IV continuous infusion over 46 to 48 hours (total dose per cycle: 2800 mg/m²)
• Folinic acid (Leucovorin) 400 mg/m² IV over 120 minutes once on day 1, given first
• Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1

14-day cycle for up to 12 cycles

References

1. SEQUOIA: Hecht JR, Lonardi S, Bendell J, Sim HW, Macarulla T, Lopez CD, Van Cutsem E, Muñoz Martin AJ, Park JO, Greil R, Wang H, Hozak RR, Gueorguieva I, Lin Y, Rao S, Ryoo BY. Randomized Phase III Study of FOLFOX Alone or With Pegilodecakin as Second-Line Therapy in Patients With Metastatic Pancreatic Cancer That Progressed After Gemcitabine (SEQUOIA). J Clin Oncol. 2021 Apr 1;39(10):1108-1118. Epub 2021 Feb 8. link to original article contains dosing details in manuscript link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT02923921

Irinotecan liposomal monotherapy

Regimen

Study	Dates of enrollment	Evidence
Ko et al. 2013 (PEP0208)	2009-2010	Phase 2

Chemotherapy

• Irinotecan liposome (Onivyde) 120 mg/m² IV once on day 1

21-day cycles

References

1. 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. link to original article link to PMC article contains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT00813163

OLF

OLF: Oxaliplatin, Leucovorin (Folinic acid), Fluorouracil
OFF: Oxaliplatin, Fluorouracil, Folinic acid

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Pelzer et al. 2011 (CONKO-003)	2002-2003	Phase 3 (E-esc)	Best supportive care	Superior OS
Oettle et al. 2014 (CONKO-003 part 2)	2004-2007	Phase 3 (E-esc)	FULV	Superior OS Median OS: 5.9 vs 3.3 mo (HR 0.66, 95% CI 0.48-0.91)

Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m²," or 850 mg/m². Note also that the trial was modified and reinitiated and is labeled as "part 2" to explain this.

Chemotherapy

• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 to 4 hours once per day on days 8 & 22, given first
• Folinic acid (Leucovorin) 200 mg/m² IV bolus once per day on days 1, 8, 15, 22, given second
• Fluorouracil (5-FU) 2000 mg/m² IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, given third (total dose per cycle: 8000 mg/m²)

42-day cycles

References

1. CONKO-003: 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. link to original article contains dosing details in manuscript--with error as noted above PubMed https://clinicaltrials.gov/ct2/show/NCT00786058
2. CONKO-003 part 2: 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. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00786058

nab-Paclitaxel monotherapy

Regimen

Study	Dates of enrollment	Evidence
Hosein et al. 2013	NR in abstract	Phase 2

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycles

References

1. 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. link to original article contains dosing details in abstract PubMed

S-1 monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ioka et al. 2018 (GRAPE)	2013-2015	Phase 3 (C)	TAS-118	Did not meet primary endpoint of OS
Go et al. 2021 (MPACA-3)	2017-2019	Phase 3 (C)	mFOLFIRINOX	Inferior OS

Chemotherapy

• Tegafur, gimeracil, oteracil (S-1) by the following weight-based criteria:
  • BSA less than 1.25 m²: 40 mg PO twice per day on days 1 to 28
  • BSA at least 1.25 m² and less than 1.5 m²: 50 mg PO twice per day on days 1 to 28
  • BSA 1.5 m² or more: 60 mg PO twice per day on days 1 to 28

42-day cycles

References

1. GRAPE: Ioka T, Ueno M, Ueno H, Park JO, Chang HM, Sasahira N, Kanai M, Chung IJ, Ikeda M, Nakamori S, Mizuno N, Omuro Y, Yamaguchi T, Hara H, Sugimori K, Furuse J, Maguchi H, Furukawa M, Fukuzawa K, Kim JS, Yukisawa S, Takeuchi M, Okusaka T, Boku N, Hyodo I. TAS-118 (S-1 plus leucovorin) versus S-1 in patients with gemcitabine-refractory advanced pancreatic cancer: a randomised, open-label, phase 3 study (GRAPE trial). Eur J Cancer. 2019 Jan;106:78-88. Epub 2018 Nov 22. link to original article PubMed
2. MPACA-3: Go SI, Lee SC, Bae WK, Zang DY, Lee HW, Jang JS, Ji JH, Kim JH, Park S, Sym SJ, Yang Y, Jeon SY, Hwang IG, Oh SY, Kang JH. Modified FOLFIRINOX versus S-1 as second-line chemotherapy in gemcitabine-failed metastatic pancreatic cancer patients: A randomised controlled trial (MPACA-3). Eur J Cancer. 2021 Nov;157:21-30. Epub 2021 Aug 28. link to original article PubMed KCT0003534

Metastatic disease, 5-FU-refractory

Gemcitabine monotherapy

Regimen

Study	Dates of enrollment	Evidence
Rothenberg et al. 1996a	1992-1994	Phase 2 (RT)

Chemotherapy

• Gemcitabine (Gemzar) as follows:
  • Cycle 1: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, 43
  • Cycle 2 onwards: 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

8-week cycle for 1 cycle, then 28-day cycles

References

1. Rothenberg ML, Moore MJ, Cripps MC, Andersen JS, Portenoy RK, Burris HA 3rd, Green MR, Tarassoff PG, Brown TD, Casper ES, Storniolo AM, Von Hoff DD. A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol. 1996 Apr;7(4):347-53. link to original article PubMed
2. PRODIGE 65: https://clinicaltrials.gov/ct2/show/NCT03943667

Metastatic disease, second-line

Capecitabine monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hurwitz et al. 2018 (JANUS 1)	2014-2016	Phase 3 (C)	Capecitabine & Ruxolitinib	Did not meet primary endpoint of OS
Hurwitz et al. 2018 (JANUS 2)	2014-2016	Phase 3 (C)	Capecitabine & Ruxolitinib	Did not meet primary endpoint of OS

Note: the same publication reports on both of these studies.

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

21-day cycles

References

1. 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. link to original article link to PMC article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT02117479
2. JANUS 2: 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. link to original article link to PMC article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT02119663

Sotorasib monotherapy

Regimen

Study	Dates of enrollment	Evidence
Strickler et al. 2022 (CodeBreaK100)	2019-2021	Phase 1/2

Biomarker eligibility criteria

• KRAS p.G12C mutation

Targeted therapy

• Sotorasib (Lumakras) 960 mg PO once per day

Continued indefinitely

References

1. CodeBreaK100: Strickler JH, Satake H, George TJ, Yaeger R, Hollebecque A, Garrido-Laguna I, Schuler M, Burns TF, Coveler AL, Falchook GS, Vincent M, Sunakawa Y, Dahan L, Bajor D, Rha SY, Lemech C, Juric D, Rehn M, Ngarmchamnanrith G, Jafarinasabian P, Tran Q, Hong DS. Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer. N Engl J Med. 2023 Jan 5;388(1):33-43. Epub 2022 Dec 21. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT03600883