Pancreatic cancer

Page editor		Section editor
	Candice Schwartz, MD University of Illinois at Chicago Chicago, IL		Neeta K. Venepalli, MD, MBA University of Illinois at Chicago Chicago, IL

49 regimens on this page 82 variants on this page

Guidelines

ASCO

• 2018: Sohal et al. Metastatic pancreatic cancer: ASCO Clinical Practice Guideline update PubMed
• 2017: Khorana et al. Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update PubMed

Older

• 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

• 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

Adjuvant therapy

Capecitabine & Gemcitabine

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GemCap: Gemcitabine & Capecitabine

Regimen

Study	Evidence	Comparator	Efficacy
Neoptolemos et al. 2017 (ESPAC-4)	Phase III (E)	Gemcitabine	Seems to have superior OS

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 protocol PubMed

Fluorouracil & Folinic acid

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Regimen

Study	Evidence	Comparator	Efficacy
Neoptolemos et al. 2001 (ESPAC-1)	Phase III (E)	1. 5-FU/5-FU & RT 2. 5-FU & RT, then 5-FU & Leucovorin	Seems to have superior OS (*)
		3. Observation	Superior OS (*)
Neoptolemos et al. 2010 (ESPAC-3 version 2)	Phase III (C)	Gemcitabine	Seems not superior
Schmidt et al. 2012 (CapRI)	Phase III (C)	5-FU, Cisplatin, IFN alfa-2b, RT	Seems not superior

Note: reported 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 verified protocol 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 verified protocol PubMed
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 verified protocol PubMed

Fluorouracil/Fluorouracil & RT

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

Regimen

Study	Evidence	Comparator	Efficacy
Neoptolemos et al. 2001 (ESPAC-1)	Phase III (E)	1. 5-FU & Leucovorin 2. Observation	Seems to have inferior OS (*)
		3. 5-FU & RT, then 5-FU & Leucovorin	Not reported
Regine et al. 2008 (RTOG 9704)	Phase III (C)	Gemcitabine/5-FU & RT	Seems not superior (*)

Note: reported efficacy for ESPAC-1 is based on the 2004 update. Reported 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 verified protocol 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 verified protocol PubMed
   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

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mFOLFIRINOX: modified FOLinic acid, Fluorouracil, IRINotecan, OXaliplatin

Regimen

Study	Evidence	Comparator	Efficacy	Toxicity
Conroy et al. 2018 (NCIC CTG PA.6)	Phase III (E)	Gemcitabine	Superior OS	More toxic

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, 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; Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018 Dec 20;379(25):2395-2406. link to original article contains verified protocol PubMed

Gemcitabine monotherapy

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Variant #1, 2 out of 3 weeks

Study	Evidence
Landry et al. 2010	Phase II

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

Variant #2, 3 out of 4 weeks

Study	Evidence	Comparator	Efficacy
Oettle et al. 2007 (CONKO-001)	Phase III (E)	Observation	Seems to have superior OS (*)
Ueno et al. 2009 (JSAP-02)	Phase III (E)	Observation	Superior DFS
Neoptolemos et al. 2010 (ESPAC-3 version 2)	Phase III (E)	Fluorouracil & Leucovorin	Seems not superior
Uesaka et al. 2016 (JASPAC 01)	Phase III (C)	S-1	Inferior OS
Neoptolemos et al. 2017 (ESPAC-4)	Phase III (C)	Capecitabine & Gemcitabine	Seems to have inferior OS
Sinn et al. 2017 (CONKO-005)	Phase III (C)	Erlotinib & Gemcitabine	Seems not superior
Conroy et al. 2018 (NCIC CTG PA.6)	Phase III (C)	mFOLFIRINOX	Inferior OS

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

Note: efficacy for CONKO-001 is based on the 2013 update.

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 verified protocol PubMed
   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. 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 protocol PubMed
3. 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 verified protocol 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 verified protocol PubMed
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 verified protocol PubMed
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 protocol PubMed
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 protocol PubMed
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; Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018 Dec 20;379(25):2395-2406. link to original article contains verified protocol PubMed

Gemcitabine/Fluorouracil & RT

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

Regimen

Study	Evidence	Comparator	Efficacy
Regine et al. 2008 (RTOG 9704)	Phase III (E)	5-FU/5-FU & RT	Seems not superior (*)

Note: reported 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 verified protocol PubMed
   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

Observation

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Regimen

Study	Evidence	Comparator	Efficacy
Klinkenbijl et al. 1999 (EORTC 40891)	Phase III (C)	5-FU & RT	Seems not superior
Neoptolemos et al. 2001 (ESPAC-1)	Phase III (C)	1. 5-FU & Leucovorin	Inferior OS
		2. 5-FU/5-FU & RT 3. 5-FU & RT, then 5-FU & Leucovorin	Seems to have superior OS
Oettle et al. 2007 (CONKO-001)	Phase III (C)	Gemcitabine	Seems to have inferior OS

No active antineoplastic treatment. Efficacy for ESPAC-1 is based on the 2004 update and efficacy for CONKO-001 is based on 2013 update.

Preceding treatment

• Surgery

References

1. EORTC 40891: Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH, Arnaud JP, Gonzalez DG, de Wit LT, Hennipman A, Wils J. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999 Dec;230(6):776-82. link to original article link to PMC article PubMed
   1. Update: Smeenk HG, van Eijck CH, Hop WC, Erdmann J, Tran KC, Debois M, van Cutsem E, van Dekken H, Klinkenbijl JH, Jeekel J. Long-term survival and metastatic pattern of pancreatic and periampullary cancer after adjuvant chemoradiation or observation: long-term results of EORTC trial 40891. Ann Surg. 2007 Nov;246(5):734-40. link to original article PubMed
2. 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 verified protocol PubMed
3. 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 verified protocol PubMed
   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

S-1 monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Uesaka et al. 2016 (JASPAC 01)	Phase III (E)	Gemcitabine	Superior OS

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

Preceding treatment

• Surgery

Chemotherapy

• Tegafur, gimeracil, oteracil (S-1) as follows:
  • 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 verified protocol PubMed

Induction therapy for locally advanced disease, potentially resectable

Docetaxel, Gemcitabine, RT

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DG & RT: Docetaxel, Gemcitabine, Radiation Therapy

Regimen

Study	Evidence
Pipas et al. 2005	Phase II

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 medications

• 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 verified protocol PubMed

Gemcitabine & RT

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Gemcitabine & RT: Gemcitabine & Radiation Therapy

Variant #1, 400 mg/m²

Study	Evidence	Comparator	Comparative Efficacy
Jang et al. 2018	Phase II/III (E)	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

Variant #2, 500 mg/m²

Study	Evidence
Landry et al. 2010	Phase II

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

Variant #3, 1000 mg/m²

Study	Evidence
Takahashi et al. 2013	Phase II

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

References

1. 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 verified protocol 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 verified protocol PubMed
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 verified protocol PubMed

Gemcitabine, Cetuximab, RT

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

Regimen

Study	Evidence
Pipas et al. 2012	Phase II

Chemotherapy

• 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
• 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

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 medications

• 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 verified protocol link to PMC article PubMed

FOLFIRINOX/modified FOLFIRINOX +/- Chemoradiation

Study	Evidence
Murphy et al. 2018 (MGH 11-328)	Phase II

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 medications

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

14-day cycle for 4 to 8 cycles (see note)

Subsequent treatment

• Followed by restaging with CT scan. If tumor was resectable (no vascular involvement), they received short-course proton chemoradiotherapy:

Proton Chemoradiotherapy

• Capecitabine 825 mg/m² PO twice per day, Monday – Friday for 2 weeks
• Proton radiotherapy of 25 GyE in 5 treatments OR Intensity modulated radiotherapy (IMRT) of 30 Gy in 10 fractions

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 verified protocol PubMed

mFOLFIRINOX, Gemcitabine, RT

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

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 medications

• 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

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

Radiotherapy

• External beam radiotherapy was 36 Gy in 15 daily fractions

3-week course

Variant #2

Study	Evidence
Hosein et al. 2012	Retrospective

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 medications

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

14-day cycle until maximum response or intolerance

Subsequent treatment

• Resectable patients by imaging criteria were offered: Surgery, then adjuvant chemoradiotherapy
• 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

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Regimen

Study	Evidence
Cartwright et al. 2002	Phase II

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 verified protocol PubMed

Erlotinib & Gemcitabine

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Variant #1, Gem 3 out of 4 weeks x 4

Study	Evidence	Comparator	Efficacy
Hammel et al. 2016 (GERCOR LAP07)	Phase III (E)	See link	See link

Chemotherapy

• Erlotinib (Tarceva) 100 mg PO once per day
• 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

• Patients without progression: Erlotinib & Gemcitabine x 2 more cycles (6 total) versus Capecitabine, Erlotinib, RT

Variant #2, Gem 3 out of 4 weeks x 6

Study	Evidence	Comparator	Efficacy
Hammel et al. 2016 (GERCOR LAP07)	Phase III (E)	See link	See link

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

Chemotherapy

• Erlotinib (Tarceva) as follows:
  • Cycles 1 to 4: 100 mg PO once per day
  • Cycles 5 & 6: 150 mg PO once per day
• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycle for 6 cycles

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

FDA-recommended dose

Study	Evidence	Comparator	Efficacy
Moore et al. 2007 (NCIC CTG PA.3)	Phase III (E)	Gemcitabine	Seems to have superior OS

Chemotherapy

• Erlotinib (Tarceva) 100 mg PO once per day
• 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

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

Study	Evidence	Comparator	Efficacy
Moore et al. 2007 (NCIC CTG PA.3)	Phase III (E)	Gemcitabine	Not reported

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

Chemotherapy

• Erlotinib (Tarceva) 150 mg PO once per day
• 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 verified protocol PubMed
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; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. link to original article contains verified protocol PubMed

FLEC

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FLEC: Fluorouracil, Leucovorin (Folinic acid), Epirubicin, Carboplatin

Regimen

Study	Evidence	Comparator	Efficacy
Cantore et al. 2004	Phase III (E)	Gemcitabine	Seems to have superior OS

Chemotherapy

• Fluorouracil (5-FU)
• Leucovorin (Folinic acid)
• Epirubicin (Ellence)
• Carboplatin (Paraplatin)

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 PubMed

Fluorouracil & RT

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Fluorouracil & RT: Fluorouracil & Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
Moertel et al. 1981	Phase III (E)	RT	Superior OS
Herman et al. 2013	Phase III (C)	Fluorouracil & RT with TNFerade	Seems not superior

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: 1.80 Gy fractions x 25 fractions, for a total dose of 45 Gy, followed by 1.80 Gy x 3 fractions boost to the tumor bed (total dose of 50.4 Gy)

5.5-week course

Subsequent treatment

• Herman et al. 2013: 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. 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. 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 verified protocol link to PMC article PubMed

Gemcitabine monotherapy

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Variant #1, 3 out of 4 weeks x 4

Study	Evidence	Comparator	Efficacy
Hammel et al. 2016 (GERCOR LAP07)	Phase III (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

• Patients without progression: Gemcitabine x 2 more cycles (6 total) versus Capecitabine & RT

Variant #2, 3 out of 4 weeks x 6

Study	Evidence	Comparator	Efficacy
Hammel et al. 2016 (GERCOR LAP07)	Phase III (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

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

Study	Evidence	Comparator	Efficacy
Cantore et al. 2004	Phase III (C)	Intraarterial FLEC	Seems to have inferior OS
Louvet et al. 2005	Phase III (C)	GemOx	Seems to have inferior PFS
Chauffert et al. 2008 (FFCD/SFRO 2000-01)	Phase III (E)	CF & RT, then Gemcitabine	Might have superior OS
Loehrer et al. 2011 (ECOG E4201)	Phase III (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 protocol 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 verified protocol 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 protocol PubMed
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 verified protocol link to PMC article PubMed
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; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. link to original article contains verified protocol PubMed

Gemcitabine & RT

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Gemcitabine & RT: Gemcitabine & Radiation Therapy

Variant #1, 600 mg/m²

Study	Evidence	Comparator	Efficacy
Cardenes et al. 2011	Phase II
Loehrer et al. 2011 (ECOG E4201)	Phase III (E)	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

Variant #2, 400 mg/m²

Study	Evidence
Epelbaum et al. 2002	Phase II

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 1.80 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 verified protocol 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. 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. link to original article contains verified protocol link to PMC article PubMed

GemOx

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GemOx: Gemcitabine, Oxaliplatin

Regimen

Study	Evidence	Comparator	Efficacy
Louvet et al. 2005	Phase III (E)	Gemcitabine	Seems to have superior PFS

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 verified protocol PubMed

Radiation therapy

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Regimen

Study	Evidence	Comparator	Efficacy
Cohen et al. 2005 (ECOG E8282)	Phase III (C)	5-FU, MMC, RT	Seems not superior

Radiotherapy

• External beam radiotherapy

References

1. ECOG E8282: Cohen SJ, Dobelbower R Jr, Lipsitz S, Catalano PJ, Sischy B, Smith TJ, Haller DG; Eastern Cooperative Oncology Group. A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282. Int J Radiat Oncol Biol Phys. 2005 Aug 1;62(5):1345-50. link to original article PubMed

Metastatic disease, first-line

Capecitabine monotherapy

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Regimen

Study	Evidence
Cartwright et al. 2002	Phase II

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 verified protocol PubMed

Capecitabine & Gemcitabine

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

Variant #1, q4wk x 6

Study	Evidence	Comparator	Efficacy
Middleton et al. 2014 (TeloVac)	Phase III (C)	GemCap & GV1001	Might have superior OS

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

Variant #2, q4wk indefinite

Study	Evidence	Comparator	Efficacy
Lee et al. 2017	Phase III (E)	Gemcitabine	Might have superior OS

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

Variant #3, induction followed by maintenance

Study	Evidence	Comparator	Efficacy
Cunningham et al. 2009	Phase III (E)	Gemcitabine	Superior PFS

Chemotherapy, initial

• 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

Variant #4, q3wk x 8

Study	Evidence	Comparator	Efficacy
Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)	Phase III (E)	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 verified protocol PubMed
   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 verified protocol PubMed
2. 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 verified protocol PubMed
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 protocol PubMed
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. contains verified protocol link to PMC article PubMed

Cisplatin & Gemcitabine

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Variant #1, 25/1000, weekly dosing

Study	Evidence	Comparator	Efficacy
Colucci et al. 2002	Phase III (E)	Gemcitabine	Seems to have superior TTP
Colucci et al. 2010 (GIP-1)	Phase III (E)	Gemcitabine	Did not meet primary endpoint of OS

Note that 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

Variant #2, 35/1000, 2 out of 3 weeks

Study	Evidence	Comparator	Efficacy
Cascinu et al. 2008 (SPaCe-01)	Randomized Phase II (C)	Cisplatin, Gemcitabine, 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

Variant #3, 50/1000, bi-weekly dosing

Study	Evidence	Comparator	Efficacy
Heinemann et al. 2006	Phase III (E)	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 protocol 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 verified regimen 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 (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008 Jan;9(1):39-44. link to original article contains protocol PubMed
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; Gruppo Oncologico Italia Meridionale (GOIM); Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD); Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. link to original article contains verified protocol PubMed

Erlotinib & Gemcitabine

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Variant #1, no gemcitabine lead-in

Study	Evidence	Comparator	Efficacy
Kordes et al. 2015 (AMCmedonc10/003)	Randomized Phase II (C)	Erlotinib, Gemcitabine, Metformin	Did not meet primary endpoint of OS6

Chemotherapy

• Erlotinib (Tarceva) 100 mg PO once per day
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

28-day cycles

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

FDA-recommended dose

Study	Evidence	Comparator	Efficacy
Moore et al. 2007 (NCIC CTG PA.3)	Phase III (E-RT)	Gemcitabine	Seems to have superior OS
Van Cutsem et al. 2009	Phase III (C)	Erlotinib, Gemcitabine, Bevacizumab	Did not meet primary endpoint of OS

Chemotherapy

• Erlotinib (Tarceva) 100 mg PO once per day
• 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

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

Study	Evidence	Comparator	Efficacy
Moore et al. 2007 (NCIC CTG PA.3)	Phase III (E)	Gemcitabine	Not reported
Heinemann et al. 2012 (AIO-PK0104)	Phase III (C)	Capecitabine & Erlotinib	Superior TTF1

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

Chemotherapy

• Erlotinib (Tarceva) 150 mg PO once per day
• 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 verified protocol PubMed
2. 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 verified protocol PubMed
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 verified protocol' PubMed
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 protocol PubMed

Fluorouracil monotherapy

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Variant #1, 300 mg/m²/day PVI

Study	Evidence	Comparator	Efficacy
Maisey et al. 2002	Phase III (C)	5-FU & Mitomycin	Seems to have inferior ORR

Chemotherapy

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

Up to 24-week course

Variant #2, 500 mg/m² intermittent

Study	Evidence	Comparator	Efficacy
Cullinan et al. 1985	Phase III (E)	1. FA 2. FAM	Did not meet primary endpoint of OS
Cullinan et al. 1990	Phase III (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

Variant #2, 600 mg/m² weekly

Study	Evidence	Comparator	Efficacy
Burris et al. 1997	Phase III (C)	Gemcitabine	Inferior OS

Inferior to gemcitabine. Here for historical reference purposes, only.

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 verified protocol PubMed
4. 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 protocol PubMed

FOLFIRINOX

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FOLFIRINOX: FOLinic acid, Fluorouracil, IRINotecan, OXaliplatin

Regimen

Study	Evidence	Comparator	Efficacy	Toxicity
Conroy et al. 2011 (PRODIGE 4/ACCORD 11)	Phase III (E)	Gemcitabine	Superior OS	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 verified protocol PubMed
   1. QoL analysis: Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. link to original article PubMed

Gemcitabine monotherapy

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

Study	Evidence	Comparator	Efficacy
Stathopoulos et al. 2006	Phase III (C)	Gemcitabine & Irinotecan	Did not meet primary endpoint of OS50%

Chemotherapy

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

28-day cycles

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

Study	Evidence	Comparator	Efficacy
Burris et al. 1997	Phase III (E-RT)	5-FU	Superior OS
Colucci et al. 2002	Phase III (C)	Cisplatin & Gemcitabine	Seems to have inferior TTP
Moore et al. 2003 (NCIC CTG PA.1)	Phase III (C)	Tanomastat	Superior OS
Van Cutsem et al. 2004	Phase III (C)	Gemcitabine & Tipifarnib	Did not meet primary endpoint of OS
Rocha Lima et al. 2004	Phase III (C)	Gemcitabine & Irinotecan	Did not meet primary endpoint of OS
Louvet et al. 2005	Phase III (C)	GemOx	Seems to have inferior PFS
Reni et al. 2005	Phase III (C)	PEFG	Seems to have inferior PFS
Abou-Alfa et al. 2006a	Phase III (C)	Gemcitabine & Exatecan	Did not meet primary endpoint of OS
Moore et al. 2007 (NCIC CTG PA.3)	Phase III (C)	Erlotinib & Gemcitabine	Seems to have inferior OS
Herrmann et al. 2007 (SAKK 44/00-CECOG/PAN.1.3.001)	Phase III (C)	GemCap	Did not meet primary endpoint of OS
Poplin et al. 2009 (ECOG E6201)	Phase III (C)	1. GEM FDR	Might have inferior OS50%
		2. GEMOX	Did not meet primary endpoint of OS50%
Cunningham et al. 2009	Phase III (C)	GEM-CAP	Inferior PFS
Colucci et al. 2010 (GIP-1)	Phase III (C)	Cisplatin & Gemcitabine	Did not meet primary endpoint of OS
Philip et al. 2010 (SWOG S0205)	Phase III (C)	Gemcitabine & Cetuximab	Did not meet primary endpoint of OS
Dahan et al. 2010 (FFCD 0301)	Phase III (C)	LV5FU2-CDDP	Did not meet primary endpoint of OS50%
Conroy et al. 2011 (PRODIGE 4/ACCORD 11)	Phase III (C)	FOLFIRINOX	Inferior OS
Gonçalves et al. 2012 (BAYPAN)	Phase III (C)	Gemcitabine & Sorafenib	Did not meet primary endpoint of PFS
Rougier et al. 2013 (VANILLA)	Phase III (C)	Gemcitabine & Ziv-aflibercept	Did not meet primary endpoint of OS
Von Hoff et al. 2013 (MPACT)	Phase III (C)	Gemcitabine & nab-Paclitaxel	Inferior OS
Deplanque et al. 2015 (AB07012)	Phase III (C)	Gemcitabine & Masitinib	Did not meet primary endpoint of OS
Middleton et al. 2017 (ViP)	Randomized Phase II (C)	Gemcitabine & Vandetanib	Did not meet primary endpoint of OS

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

Variant #3, 1000 mg/m², 3 out of 4 weeks

Study	Evidence	Comparator	Efficacy
Berlin et al. 2002 (ECOG E2297)	Phase III (C)	5-FU & Gemcitabine	Might have inferior OS
Oettle et al. 2005	Phase III (C)	Gemcitabine & Pemetrexed	Did not meet primary endpoint of OS
Heinemann et al. 2006	Phase III (C)	Cisplatin & Gemcitabine	Might have inferior PFS
Spano et al. 2008 (A4061016)	Randomized Phase II (C)	Gemcitabine & Axitinib	Did not meet primary endpoint of OS
Kindler et al. 2010 (CALGB 80303)	Phase III (C)	Gemcitabine & Bevacizumab	Did not meet primary endpoint of OS
Kindler et al. 2011 (A4061028)	Phase III (C)	Gemcitabine & Axitinib	Did not meet primary endpoint of OS
Ueno et al. 2013 (GEST)	Phase III (C)	1. S-1	Non-inferior OS
		2. Gemcitabine & S-1	Did not meet primary endpoint of OS
Fuchs et al. 2015 (GAMMA)	Randomized Phase Ib/II (C)	Gemcitabine & Ganitumab	Did not meet primary endpoint of OS
O'Neil et al. 2015	Phase II/III (C)	Gemcitabine & Rigosertib	Did not meet primary endpoint of OS
Catenacci et al. 2015 (UCCRC-8418)	Randomized Phase Ib/II (C)	Gemcitabine & Vismodegib	Did not meet primary endpoint of PFS
Lee et al. 2017	Phase III (C)	GemCap	Might have inferior OS

Chemotherapy

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

28-day cycles

Variant #4, 1000 mg/m², weekly

Study	Evidence	Comparator	Efficacy
Hong et al. 2013 (SMC 2008-07-065)	Randomized Phase II (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

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

Study	Evidence	Comparator	Efficacy
Poplin et al. 2009 (ECOG E6201)	Phase III (E)	1. Gemcitabine	Might have superior OS
		2. GEMOX	Not reported

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

1. 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 verified protocol PubMed
2. 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 protocol PubMed
3. ECOG E2297: Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, Benson AB 3rd. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol. 2002 Aug 1;20(15):3270-5. link to original article contains protocol PubMed
4. NCIC CTG PA.1: Moore MJ, Hamm J, Dancey J, Eisenberg PD, Dagenais M, Fields A, Hagan K, Greenberg B, Colwell B, Zee B, Tu D, Ottaway J, Humphrey R, Seymour L; National Cancer Institute of Canada Clinical Trials Group. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Sep 1;21(17):3296-302. link to original article contains protocol PubMed
5. Van Cutsem E, van de Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A, Schoffski P, Post S, Verslype C, Neumann H, Safran H, Humblet Y, Perez Ruixo J, Ma Y, Von Hoff D. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol. 2004 Apr 15;22(8):1430-8. link to original article contains protocol PubMed
6. Rocha Lima CM, Green MR, Rotche R, Miller WH Jr, Jeffrey GM, Cisar LA, Morganti A, Orlando N, Gruia G, Miller LL. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol. 2004 Sep 15;22(18):3776-83. link to original article contains protocol PubMed
7. 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 verified protocol PubMed
8. Oettle H, Richards D, Ramanathan RK, van Laethem JL, Peeters M, Fuchs M, Zimmermann A, John W, Von Hoff D, Arning M, Kindler HL. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol. 2005 Oct;16(10):1639-45. Epub 2005 Aug 8. Erratum in: Ann Oncol. 2006 Mar;17(3):535. link to original article contains protocol PubMed
9. Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. link to original article contains protocol PubMed
10. Stathopoulos GP, Syrigos K, Aravantinos G, Polyzos A, Papakotoulas P, Fountzilas G, Potamianou A, Ziras N, Boukovinas J, Varthalitis J, Androulakis N, Kotsakis A, Samonis G, Georgoulias V. A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. Br J Cancer. 2006 Sep 4;95(5):587-92. Epub 2006 Aug 8. link to original article link to PMC article contains protocol PubMed
11. 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 verified regimen PubMed
12. Abou-Alfa GK, Letourneau R, Harker G, Modiano M, Hurwitz H, Tchekmedyian NS, Feit K, Ackerman J, De Jager RL, Eckhardt SG, O'Reilly EM. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J Clin Oncol. 2006 Sep 20;24(27):4441-7. link to original article contains protocol PubMed
13. 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 verified protocol PubMed
14. 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 verified protocol PubMed
    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 verified protocol PubMed
15. A4061016: Spano JP, Chodkiewicz C, Maurel J, Wong R, Wasan H, Barone C, Létourneau R, Bajetta E, Pithavala Y, Bycott P, Trask P, Liau K, Ricart AD, Kim S, Rixe O. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet. 2008 Jun 21;371(9630):2101-8. Epub 2008 May 29. link to original article contains verified protocol PubMed
16. 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 verified protocol link to PMC article PubMed
17. 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 verified protocol PubMed
18. GIP-1: Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolò M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F; Gruppo Oncologico Italia Meridionale (GOIM); Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD); Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010 Apr 1;28(10):1645-51. link to original article contains protocol PubMed
19. SWOG S0205: Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 1;28(22):3605-10. Epub 2010 Jul 6. link to original article contains verified protocol link to PMC article PubMed
20. CALGB 80303: Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, Innocenti F, Mulcahy MF, O'Reilly E, Wozniak TF, Picus J, Bhargava P, Mayer RJ, Schilsky RL, Goldberg RM. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010 Aug 1;28(22):3617-22. Epub 2010 Jul 6. link to original article link to PMC article contains protocol PubMed
21. FFCD 0301: Dahan L, Bonnetain F, Ychou M, Mitry E, Gasmi M, Raoul JL, Cattan S, Phelip JM, Hammel P, Chauffert B, Michel P, Legoux JL, Rougier P, Bedenne L, Seitz JF; Fédération Francophone de Cancérologie Digestive. Combination 5-fluorouracil, folinic acid and cisplatin (LV5FU2-CDDP) followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: final results of a randomised strategic phase III trial (FFCD 0301). Gut. 2010 Nov;59(11):1527-34. link to original article link to PMC article contains protocol PubMed
22. A4061028: Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Ioka T, Okusaka T, Ohkawa S, Boku N, Sawaki A, Fujii Y, Kamei Y, Takahashi S, Namazu K, Umeyama Y, Bycott P, Furuse J. Efficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer: subgroup analyses by region, including Japan, from the global randomized phase III trial. Jpn J Clin Oncol. 2015 May;45(5):439-48. Epub 2015 Feb 3. link to original article link to PMC article PubMed
23. 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 verified protocol PubMed
    1. QoL analysis: Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V, Bérille J, Conroy T. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013 Jan 1;31(1):23-9. Epub 2012 Dec 3. link to original article PubMed
24. BAYPAN: Gonçalves A, Gilabert M, François E, Dahan L, Perrier H, Lamy R, Re D, Largillier R, Gasmi M, Tchiknavorian X, Esterni B, Genre D, Moureau-Zabotto L, Giovannini M, Seitz JF, Delpero JR, Turrini O, Viens P, Raoul JL. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol. 2012 Nov;23(11):2799-805. Epub 2012 Jul 5. link to original article contains protocol PubMed
25. 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 verified protocol PubMed
26. VANILLA: Rougier P, Riess H, Manges R, Karasek P, Humblet Y, Barone C, Santoro A, Assadourian S, Hatteville L, Philip PA. Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. Eur J Cancer. 2013 Aug;49(12):2633-42. Epub 2013 Apr 30. link to original article contains protocol PubMed
27. 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 verified protocol link to PMC article PubMed
    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
28. SMC 2008-07-065: Hong JY, Nam EM, Lee J, Park JO, Lee SC, Song SY, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol. 2014 Jan;73(1):125-30. Epub 2013 Oct 27. link to original article contains verified protocol PubMed
29. GAMMA: Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015 May;26(5):921-7. Epub 2015 Jan 21. contains verified protocol link to PMC article PubMed
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
31. 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 protocol PubMed
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 protocol in supplement link to PMC article PubMed
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. contains verified protocol 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 protocol PubMed

GemOx

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GemOx: Gemcitabine & Oxaliplatin

Regimen

Study	Evidence	Comparator	Efficacy
Louvet et al. 2005	Phase III (E)	Gemcitabine	Seems to have superior PFS
Poplin et al. 2009 (ECOG E6201)	Phase III (E)	1. Gemcitabine	Did not meet primary endpoint of OS50%
		2. Gemcitabine, FDR	Not reported

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 verified protocol 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 verified protocol link to PMC article PubMed

Gemcitabine & nab-Paclitaxel

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NG: Nab-Paclitaxel & Gemcitabine

Variant #1, with 8-week lead-in

Study	Evidence	Comparator	Efficacy
Von Hoff et al. 2013 (MPACT)	Phase III (E-RT)	Gemcitabine	Superior OS

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

Variant #2, no lead-in

Study	Evidence
Von Hoff et al. 2011 (CA040)	Phase II

Note: The abstract and body of Von Hoff et al. 2011 contradicted each other about which drug is given first in this regimen.

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15
• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 or 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 verified protocol link to PMC article PubMed
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 verified protocol link to PMC article PubMed
   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

GTX

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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 protocol 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 verified protocol--with error as noted above link to PMC article PubMed

PEFG

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PEFG: Platinol (Cisplatin), Epirubicin, Fluorouracil, Gemcitabine

Regimen

Study	Evidence	Comparator	Efficacy
Reni et al. 2005	Phase III (E)	Gemcitabine	Seems to have superior PFS

Chemotherapy

• Cisplatin (Platinol) 40 mg/m² IV once on day 1
• Epirubicin (Ellence) 40 mg/m² IV once on day 1
• Fluorouracil (5-FU) 200 mg/m²/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 5600 mg/m²)
• Gemcitabine (Gemzar) 600 mg/m² IV over 60 minutes once per day on days 1 & 8

28-day cycles

References

1. Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun;6(6):369-76. link to original article contains protocol PubMed

S-1 monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Ueno et al. 2013 (GEST)	Phase III (E)	1. Gemcitabine	Non-inferior OS
		2. Gemcitabine & S-1	Not reported

Chemotherapy

• Tegafur, gimeracil, oteracil (S-1) as follows:
  • 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 verified protocol PubMed

Maintenance after first-line therapy

Olaparib monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Golan et al. 2019 (POLO)	Phase III (E)	Placebo	Superior PFS

Patients in this study had germline BRCA1 or BRCA2 mutations

Preceding treatment

• Platinum-based chemotherapy for at least 16 weeks

Chemotherapy

• Olaparib (Lynparza) 300 mg PO twice per day

Continued indefinitely

References

1. POLO: Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, Park JO, Hochhauser D, Arnold D, Oh DY, Reinacher-Schick A, Tortora G, Algül H, O'Reilly EM, McGuinness D, Cui KY, Schlienger K, Locker GY, Kindler HL. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019 Jul 25;381(4):317-327. Epub 2019 Jun 2. link to original article contains protocol link to PMC article PubMed

Placebo

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Regimen

Study	Evidence	Comparator	Efficacy
Golan et al. 2019 (POLO)	Phase III (C)	Olaparib	Inferior PFS

Preceding treatment

• Platinum-based chemotherapy for at least 16 weeks

References

1. POLO: Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, Park JO, Hochhauser D, Arnold D, Oh DY, Reinacher-Schick A, Tortora G, Algül H, O'Reilly EM, McGuinness D, Cui KY, Schlienger K, Locker GY, Kindler HL. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019 Jul 25;381(4):317-327. Epub 2019 Jun 2. link to original article link to PMC article PubMed

Metastatic disease, refractory

Best supportive care

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Regimen

Study	Evidence	Comparator	Efficacy
Ciuleanu et al. 2009	Phase III (C)	Glufosfamide	Did not meet primary endpoint of OS
Pelzer et al. 2011	Phase III (C)	OFF	Inferior OS

Best supportive care. Placed here because one or more randomized clinical trials included a best supportive care arm in this disease context.

References

1. Ciuleanu TE, Pavlovsky AV, Bodoky G, Garin AM, Langmuir VK, Kroll S, Tidmarsh GT. A randomised Phase III trial of glufosfamide compared with best supportive care in metastatic pancreatic adenocarcinoma previously treated with gemcitabine. Eur J Cancer. 2009 Jun;45(9):1589-96. Epub 2009 Jan 31. link to original article PubMed
2. 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 verified protocol--with error as noted above PubMed

Capecitabine monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Hurwitz et al. 2018 (JANUS 1)	Phase III (C)	Capecitabine & Ruxolitinib	Did not meet primary endpoint of OS
Hurwitz et al. 2018 (JANUS 2)	Phase III (C)	Capecitabine & Ruxolitinib	Did not meet primary endpoint of OS

Chemotherapy

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

21-day cycles

References

1. JANUS 1/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 contains protocol PubMed

Capecitabine & Erlotinib

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Regimen

Study	Evidence
Kulke et al. 2007	Phase II

Chemotherapy

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

CapeOx

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

Regimen

Study	Evidence
Xiong et al. 2008	Phase II

Chemotherapy

• Capecitabine (Xeloda) as follows:
  • 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) as follows:
  • 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 verified protocol PubMed

Fluorouracil & Folinic acid

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FF: Fluorouracil & Folinic acid

Variant #1, 2000/200

Study	Evidence	Comparator	Efficacy
Oettle et al. 2014 (CONKO-003)	Phase III (C)	OFF	Inferior OS
Wang-Gillam et al. 2015 (NAPOLI-01)	Phase III (E)	1. Fluorouracil, Folinic acid, nanoliposomal Irinotecan	Seems to have inferior OS
		2. Irinotecan, nanoliposomal	Not reported

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

Variant #2, 2800/400

Study	Evidence	Comparator	Efficacy
Gill et al. 2016 (PANCREOX)	Phase III (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: 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 verified protocol PubMed
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 verified protocol PubMed
   1. 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. 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 verified protocol PubMed

Fluorouracil, Folinic acid, nanoliposomal Irinotecan

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Regimen

Study	Evidence	Comparator	Efficacy
Wang-Gillam et al. 2015 (NAPOLI-01)	Phase III (E-RT)	1. Fluorouracil & Folinic acid	Superior OS
		2. Irinotecan, nanoliposomal	Not reported

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-01), 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 verified protocol PubMed
   1. 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

FOLFIRI

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Variant #1

Study	Evidence
Zaniboni et al. 2012	Phase II

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 on days 1 & 2 (total dose per cycle: 2000 mg/m²)
• Irinotecan (Camptosar) 180 mg/m² IV once on day 1

14-day cycles

Variant #2, modified FOLFIRI.3

Study	Evidence	Comparator	Efficacy
Yoo et al. 2009	Randomized Phase II (E)	mFOLFOX	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
• Irinotecan (Camptosar) 70 mg/m² IV once per day on days 1 & 3

14-day cycles

References

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

FOLFOX

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FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study	Evidence	Comparator	Efficacy
Yoo et al. 2009	Randomized Phase II (E)	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. 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 protocol link to PMC article PubMed

Gemcitabine monotherapy

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Regimen

Study	Evidence
Rothenberg et al. 1996a	Phase II (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

Irinotecan liposomal monotherapy

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Regimen

Study	Evidence
Ko et al. 2013 (PEP0208)	Phase II

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 protocol PubMed

OLF

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

Regimen

Study	Evidence	Comparator	Efficacy
Pelzer et al. 2011	Phase III (E)	Best supportive care	Superior OS
Oettle et al. 2014 (CONKO-003)	Phase III (E)	Fluorouracil & Folinic acid	Superior OS

Note: The treatment section of Pelzer et al. 2011 incorrectly lists the oxaliplatin dose as "0.85 g/m²," or 850 mg/m².

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. 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 verified protocol--with error as noted above PubMed
2. CONKO-003: Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014 Aug 10;32(23):2423-9. Epub 2014 Jun 30. link to original article contains verified protocol PubMed

Olaparib monotherapy

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Regimen

Study	Evidence
Kaufman et al. 2014 (Study 42)	Phase II

Patients had germline BRCA1/2 mutations.

Preceding treatment

• Gemcitabine, with progression

Chemotherapy

• Olaparib (Lynparza) 400 mg PO twice per day

Continued indefinitely

References

1. Study 42: Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. link to original article contains verified protocol PubMed

nab-Paclitaxel monotherapy

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Regimen

Study	Evidence
Hosein et al. 2013	Phase II

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 protocol PubMed

S-1 monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Ioka et al. 2018 (GRAPE)	Phase III (C)	TAS-118	Did not meet primary endpoint of OS

Chemotherapy

• Tegafur, gimeracil, oteracil (S-1) as follows:
  • 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