Colon cancer

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 Neeta K. Venepalli, MD, MBA
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Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. If you still can't find it, please let us know so we can add it!
Note: the page has adjuvant and perioperative regimens specific to colon cancer as well as systemic regimens for the more general category of colorectal cancer.

10 regimens on this page
20 variants on this page


Guidelines

ESMO

Japanese Society for Cancer of the Colon and Rectum

NCCN

Adjuvant therapy

Capecitabine monotherapy

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Regimen

Study Evidence Comparator Efficacy
Twelves et al. 2005 (X-ACT) Phase III (E) 5-FU & Leucovorin Seems to have superior OS (*)
Kerr et al. 2016 (QUASAR 2) Phase III (C) Capecitabine & Bevacizumab Seems not superior

Note: efficacy for X-ACT is based on the 2011 update.

Preceding treatment

  • Surgery

Chemotherapy

21-day cycle for 8 cycles

References

  1. X-ACT: Twelves C, Wong A, Nowacki MP, Abt M, Burris HA 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005 Jun 30;352(26):2696-704. link to original article contains verified protocol PubMed
    1. Update: Twelves C, Scheithauer W, McKendrick J, Seitz JF, Van Hazel G, Wong A, Díaz-Rubio E, Gilberg F, Cassidy J. Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy. Ann Oncol. 2012 May;23(5):1190-7. Epub 2011 Sep 6. link to original article PubMed
  2. QUASAR 2: Kerr RS, Love S, Segelov E, Johnstone E, Falcon B, Hewett P, Weaver A, Church D, Scudder C, Pearson S, Julier P, Pezzella F, Tomlinson I, Domingo E, Kerr DJ. Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial. Lancet Oncol. 2016 Nov;17(11):1543-1557. link to original article contains protocol PubMed

CapeOx

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CapeOX: Capecitabine & OXaliplatin
CAPOX: CAPecitabine & OXaliplatin
XELOX: XELoda (Capecitabine) & OXaliplatin

Example orders

Variant #1, 3 months

Study Evidence Comparator Efficacy
Iveson et al. 2018 (SCOT) Phase III (E) CAPOX x 6 mo Seems to have non-inferior DFS

Preceding treatment

  • Surgery

Chemotherapy

21-day cycle for 4 cycles

Variant #2, 6 months

Study Evidence Comparator Efficacy
Schmoll et al. 2007 (XELOXA) Phase III (E) 5-FU & Leucovorin Seems to have superior OS (*)
Iveson et al. 2018 (SCOT) Phase III (C) CAPOX x 3 mo Seems to have non-inferior DFS

Note: Efficacy for XELOXA is based on the 2015 update.

Preceding treatment

  • Surgery

Chemotherapy

  • Capecitabine (Xeloda) 1000 mg/m2 PO BID on days 1 to 14
    • Some references specify starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
  • Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1

21-day cycle for 8 cycles

References

  1. XELOXA: Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A, Maroun J, Price T, Lim R, Van Cutsem E, Park YS, McKendrick J, Topham C, Soler-Gonzalez G, de Braud F, Hill M, Sirzén F, Haller DG. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007 Jan 1;25(1):102-9. link to original article contains verified protocol PubMed
    1. Update: Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011 Apr 10;29(11):1465-71. Epub 2011 Mar 7. link to original article PubMed
    2. Update: Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: Final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015 Nov 10;33(32):3733-40. Epub 2015 Aug 31. link to original article PubMed
  2. IDEA: Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018 Mar 29;378(13):1177-1188. link to original article does not contain protocol PubMed
  3. SCOT: Iveson TJ, Kerr RS, Saunders MP, Cassidy J, Hollander NH, Tabernero J, Haydon A, Glimelius B, Harkin A, Allan K, McQueen J, Scudder C, Boyd KA, Briggs A, Waterston A, Medley L, Wilson C, Ellis R, Essapen S, Dhadda AS, Harrison M, Falk S, Raouf S, Rees C, Olesen RK, Propper D, Bridgewater J, Azzabi A, Farrugia D, Webb A, Cunningham D, Hickish T, Weaver A, Gollins S, Wasan HS, Paul J. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2018 Apr;19(4):562-578. link to original article contains verified protocol PubMed

Fluorouracil & Folinic acid

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FULV: 5-FU & LeucoVorin (Folinic acid)

Example orders

Variant #1, 20/425 (Mayo Clinic regimen/LDLV)

Study Evidence Comparator Efficacy
Twelves et al. 2005 (X-ACT) Phase III (C) Capecitabine Seems to have inferior OS (*)
Schmoll et al. 2007 (XELOXA) Phase III (C) XELOX Seems to have inferior OS

Note: efficacy for X-ACT is based on the 2011 update.

Preceding treatment

  • Surgery

Chemotherapy

28-day cycle for 6 cycles

Variant #2, 20/425, with cycle elongation (Mayo Clinic regimen/LDLV)

Study Evidence Comparator Efficacy
O'Connell et al. 1997 Phase III (E) Observation Seems to have superior OS
Haller et al. 2005 (Intergroup 0089) Phase III (E) High-dose 5-FU & Folinic acid Seems not superior
LDLV & Levamisole Seems not superior
5-FU & Levamisole Seems not superior

Preceding treatment

  • Surgery

Chemotherapy

28-day cycle for 3 cycles, then 35-day cycle for 3 cycles

Variant #3, 25/370, q4wk

Study Evidence Comparator Efficacy
Gray et al. 2000 (QUASAR) Phase III (C) 5-FU & HDLV Seems not superior
5-FU, LDLV, Levamisole
5-FU, HDLV, Levamisole 		Might have superior OS

Note: L-leucovorin is used in this regimen.

Preceding treatment

  • Surgery

Chemotherapy

28-day cycle for 6 cycles

Variant #4, 25/370, weekly

Study Evidence Comparator Efficacy
Gray et al. 2000 (QUASAR) Phase III (C) 5-FU & HDLV Seems not superior
5-FU, LDLV, Levamisole
5-FU, HDLV, Levamisole 		Might have superior OS

Note: L-leucovorin is used in this regimen.

Preceding treatment

  • Surgery

Chemotherapy

7-day cycle for 30 cycles

Variant #5, 200/400 (LV5FU2)

Study Evidence Comparator Efficacy
André et al. 2004 (MOSAIC) Phase III (C) FOLFOX4 Seems to have inferior OS (*)

Reported efficacy is based on 2009 updated results.

Preceding treatment

  • Surgery

Chemotherapy

  • Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, given first
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus, then 600 mg/m2/day IV continuous infusion over 22 hours once per day on days 1 & 2 (both bolus and continuous infusion are given on days 1 & 2)

14-day cycle for 12 cycles

Variant #6, 500/500 (Roswell Park regimen/HDLV)

Study Evidence Comparator Efficacy
Wolmark et al. 1993 (NSABP C-03) Phase III (E) MOF Superior OS
Haller et al. 2005 (Intergroup 0089) Phase III (E) Low-dose 5-FU & Folinic acid Seems not superior
LDLV & Levamisole Seems not superior
5-FU & Levamisole Seems not superior
Lembersky et al. 2006 (NSABP C-06) Phase III (C) Tegafur, Uracil, Folinic acid Seems not superior
Schmoll et al. 2007 (XELOXA) Phase III (C) CapeOx Seems to have inferior OS
Kuebler et al. 2007 (NSABP C-07) Phase III (C) FLOX Inferior DFS

Preceding treatment

  • Surgery

Chemotherapy

  • Folinic acid (Leucovorin) 500 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, given first
  • Fluorouracil (5-FU) 500 mg/m2 IV push once per day on days 1, 8, 15, 22, 29, 36; 1 hour after start of leucovorin

8-week cycle for 3 to 6 cycles

References

  1. NSABP C-03: Wolmark N, Rockette H, Fisher B, Wickerham DL, Redmond C, Fisher ER, Jones J, Mamounas EP, Ore L, Petrelli NJ, Spurr CL, Dimitrov N, Romond EH, Sutherland CM, Kardinal CG, DeFusco PA, Jochimsen P. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol. 1993 Oct;11(10):1879-87. link to original article contains verified protocol PubMed
  2. O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, Wieand HS. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997 Jan;15(1):246-50. link to original article contains verified protocol PubMed
  3. QUASAR: Gray RG, Kerr DJ, McConkey CC, Williams NS, Hills RK; QUASAR Collaborative Group. Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. Lancet. 2000 May 6;355(9215):1588-96. link to SD article contains verified protocol PubMed
  4. MOSAIC: André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004 Jun 3;350(23):2343-51. link to original article contains verified protocol PubMed
    1. Update: André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009 Jul 1;27(19):3109-16. Epub 2009 May 18. link to original article PubMed
    2. Update: André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, Scriva A, Hickish T, Tabernero J, Van Laethem JL, Banzi M, Maartense E, Shmueli E, Carlsson GU, Scheithauer W, Papamichael D, Möehler M, Landolfi S, Demetter P, Colote S, Tournigand C, Louvet C, Duval A, Fléjou JF, de Gramont A. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol. 2015 Dec 10;33(35):4176-87. Epub 2015 Nov 2. link to original article PubMed
  5. X-ACT: Twelves C, Wong A, Nowacki MP, Abt M, Burris HA 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005 Jun 30;352(26):2696-704. link to original article contains verified protocol PubMed
    1. Update: Twelves C, Scheithauer W, McKendrick J, Seitz JF, Van Hazel G, Wong A, Díaz-Rubio E, Gilberg F, Cassidy J. Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy. Ann Oncol. 2012 May;23(5):1190-7. Epub 2011 Sep 6. link to original article PubMed
  6. Intergroup 0089: Haller DG, Catalano PJ, Macdonald JS, O'Rourke MA, Frontiera MS, Jackson DV, Mayer RJ. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 2005 Dec 1;23(34):8671-8. link to original article contains verified protocol PubMed
  7. Lembersky BC, Wieand HS, Petrelli NJ, O'Connell MJ, Colangelo LH, Smith RE, Seay TE, Giguere JK, Marshall ME, Jacobs AD, Colman LK, Soran A, Yothers G, Wolmark N. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 2006 May 1;24(13):2059-64. link to original article contains verified protocol PubMed
  8. Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A, Maroun J, Price T, Lim R, Van Cutsem E, Park YS, McKendrick J, Topham C, Soler-Gonzalez G, de Braud F, Hill M, Sirzén F, Haller DG. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007 Jan 1;25(1):102-9. link to original article contains verified protocol PubMed
    1. Update: Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011 Apr 10;29(11):1465-71. Epub 2011 Mar 7. link to original article contains verified protocol PubMed
    2. Update: Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: Final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015 Nov 10;33(32):3733-40. Epub 2015 Aug 31. link to original article PubMed
  9. NSABP C-07: Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, Zapas JL, Goodwin JW, Fehrenbacher L, Ramanathan RK, Conley BA, Flynn PJ, Soori G, Colman LK, Levine EA, Lanier KS, Wolmark N. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007 Jun 1;25(16):2198-204. Epub 2007 Apr 30. link to original article contains protocol PubMed
    1. Update: Yothers G, O'Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, Wolmark N. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011 Oct 1;29(28):3768-74. Epub 2011 Aug 22. link to original article link to PMC article PubMed

FLOX

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FLOX: Fluorouracil, Leucovorin, OXaliplatin

Example orders

Regimen

Study Evidence Comparator Efficacy
Kuebler et al. 2007 (NSABP C-07) Phase III (E) 5-FU & Leucovorin Superior DFS

Preceding treatment

  • Surgery

Chemotherapy

8-week cycle for 3 cycles

References

  1. NSABP C-07: Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, Zapas JL, Goodwin JW, Fehrenbacher L, Ramanathan RK, Conley BA, Flynn PJ, Soori G, Colman LK, Levine EA, Lanier KS, Wolmark N. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007 Jun 1;25(16):2198-204. Epub 2007 Apr 30. link to original article contains verified protocol PubMed
    1. Update: Yothers G, O'Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, Wolmark N. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011 Oct 1;29(28):3768-74. Epub 2011 Aug 22. link to original article link to PMC article PubMed

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Evidence Comparator Efficacy
André et al. 2004 (MOSAIC) Phase III (E) 5-FU & Folinic acid Seems to have superior OS (*)
de Gramont et al. 2012 (AVANT) Phase III (C) FOLFOX4 & Bevacizumab Seems not superior
XELOX & Bevacizumab Seems not superior
Taieb et al. 2014 (PETACC-8) Phase III (C) FOLFOX4 & Cetuximab Seems not superior
Grothey et al. 2018 (IDEA) Phase III (C) FOLFOX4 x 6 Inconclusive whether non-inferior

Note: Reported efficacy for MOSAIC is based on the 2009 update. IDEA is a pooled analysis of six phase III RCTs.

Preceding treatment

  • Surgery

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus, then 600 mg/m2/day IV continuous infusion over 22 hours once per day on days 1 & 2 (total dose per cycle: 2000 mg/m2)
  • Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, before 5-FU
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, concurrent with leucovorin

14-day cycle for 12 cycles

References

  1. MOSAIC: André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004 Jun 3;350(23):2343-51. link to original article contains verified protocol PubMed
    1. Update: André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009 Jul 1;27(19):3109-16. Epub 2009 May 18. link to original article PubMed
    2. Update: André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, Scriva A, Hickish T, Tabernero J, Van Laethem JL, Banzi M, Maartense E, Shmueli E, Carlsson GU, Scheithauer W, Papamichael D, Möehler M, Landolfi S, Demetter P, Colote S, Tournigand C, Louvet C, Duval A, Fléjou JF, de Gramont A. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol. 2015 Dec 10;33(35):4176-87. Epub 2015 Nov 2. link to original article PubMed
  2. AVANT: de Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, Cunningham D, Cartwright TH, Hecht JR, Rivera F, Im SA, Bodoky G, Salazar R, Maindrault-Goebel F, Shacham-Shmueli E, Bajetta E, Makrutzki M, Shang A, André T, Hoff PM. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012 Dec;13(12):1225-33. Epub 2012 Nov 16. link to original article contains protocol PubMed
  3. PETACC-8: Taieb J, Tabernero J, Mini E, Subtil F, Folprecht G, Van Laethem JL, Thaler J, Bridgewater J, Petersen LN, Blons H, Collette L, Van Cutsem E, Rougier P, Salazar R, Bedenne L, Emile JF, Laurent-Puig P, Lepage C; PETACC-8 Study Investigators. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Jul;15(8):862-73. Epub 2014 Jun 11. link to original article PubMed
  4. IDEA: Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018 Mar 29;378(13):1177-1188. link to original article does not contain protocol PubMed

mFOLFOX6

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mFOLFOX6: modified FOLinic acid, Fluorouracil, OXaliplatin

Example orders

Variant #1, 3 months

Study Evidence Comparator Efficacy
Iveson et al. 2018 (SCOT) Phase III (E) mFOLFOX6 x 12 Seems to have non-inferior DFS

Preceding treatment

  • Surgery

Chemotherapy

14-day cycle for 6 cycles

Variant #2, 6 months

Study Evidence Comparator Efficacy
Allegra et al. 2009 (NSABP C-08) Phase III (C) mFOLFOX6 & Bevacizumab Seems not superior
Alberts et al. 2012 (N0147) Phase III (C) mFOLFOX6 & Cetuximab Might have superior DFS
Pectasides et al. 2015 Phase III (C) CAPOX Seems not superior
Grothey et al. 2018 (IDEA) Phase III (C) mFOLFOX6 x 6 Inconclusive whether non-inferior
Iveson et al. 2018 (SCOT) Phase III (C) mFOLFOX6 x 6 Seems to have non-inferior DFS

Preceding treatment

  • Surgery, within 10 weeks

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours, given last (total dose per cycle: 2800 mg/m2)
  • Folinic acid (Leucovorin) at one of the following doses, given with oxaliplatin:
    • Most trials: 400 mg/m2 IV over 2 hours once on day 1
    • Pectasides et al. 2015: 200 mg/m2 IV over 2 hours once on day 1
    • SCOT: 350 mg/m2 IV over 2 hours once on day 1 or Levoleucovorin (Fusilev) 175 mg/m2 IV over 2 hours once on day 1
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given with folinic acid

14-day cycle for 12 cycles

References

  1. NSABP C-08: Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Colangelo LH, Lopa SH, Petrelli NJ, Goldberg RM, Atkins JN, Seay TE, Fehrenbacher L, O'Reilly S, Chu L, Azar CA, Wolmark N. Initial safety report of NSABP C-08: A randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol. 2009 Jul 10;27(20):3385-90. Epub 2009 May 4. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Colangelo LH, Atkins JN, Seay TE, Fehrenbacher L, Goldberg RM, O'Reilly S, Chu L, Azar CA, Lopa S, Wolmark N. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011 Jan 1;29(1):11-6. link to original article link to PMC article PubMed
    2. Update: Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Lopa SH, Wolmark N. Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J Clin Oncol. 2013 Jan 20;31(3):359-64. link to original article link to PMC article PubMed
  2. N0147: Alberts SR, Sargent DJ, Nair S, Mahoney MR, Mooney M, Thibodeau SN, Smyrk TC, Sinicrope FA, Chan E, Gill S, Kahlenberg MS, Shields AF, Quesenberry JT, Webb TA, Farr GH Jr, Pockaj BA, Grothey A, Goldberg RM. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA. 2012 Apr 4;307(13):1383-93. link to original article contains verified protocol link to PMC article PubMed
  3. Pectasides D, Karavasilis V, Papaxoinis G, Gourgioti G, Makatsoris T, Raptou G, Vrettou E, Sgouros J, Samantas E, Basdanis G, Papakostas P, Bafaloukos D, Kotoula V, Kalofonos HP, Scopa CD, Pentheroudakis G, Fountzilas G. Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or stage III colorectal cancer. BMC Cancer. 2015 May 10;15:384. link to original article contains verified protocol link to PMC article PubMed
  4. IDEA: Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018 Mar 29;378(13):1177-1188. link to original article does not contain protocol PubMed
  5. SCOT: Iveson TJ, Kerr RS, Saunders MP, Cassidy J, Hollander NH, Tabernero J, Haydon A, Glimelius B, Harkin A, Allan K, McQueen J, Scudder C, Boyd KA, Briggs A, Waterston A, Medley L, Wilson C, Ellis R, Essapen S, Dhadda AS, Harrison M, Falk S, Raouf S, Rees C, Olesen RK, Propper D, Bridgewater J, Azzabi A, Farrugia D, Webb A, Cunningham D, Hickish T, Weaver A, Gollins S, Wasan HS, Paul J. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2018 Apr;19(4):562-578. link to original article contains verified protocol PubMed

Observation

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Regimen

Study Evidence Comparator Efficacy
Fielding et al. 1992 (AXIS-CRC) Phase III (C) Portal venous chemotherapy Seems not superior
Riethmüller et al. 1994 Phase III (C) Edrecolomab Seems to have inferior OS
O'Connell et al. 1997 Phase III (C) 5-FU & Leucovorin Seems to have inferior OS
Rougier et al. 1998 Phase III (C) Portal venous chemotherapy Seems not superior
Gray et al. 2007 (QUASAR) Phase III (C) 5-FU & Leucovorin Inferior OS
Niedzwiecki et al. 2011 (CALGB 9581) Phase III (C) Edrecolomab Seems not superior
Hasegawa et al. 2016 Phase III (C) Tegafur, Uracil, Leucovorin Inferior RFS

No systemic treatment after surgery. Patients in QUASAR & CALGB 9581 had stage II disease. The AXIS trial is named "AXIS-CRC" here so as not to confuse it with the AXIS trial in renal cell carcinoma.

Preceding treatment

  • Surgery

References

  1. AXIS-CRC: Fielding LP, Hittinger R, Grace RH, Fry JS. Randomised controlled trial of adjuvant chemotherapy by portal-vein perfusion after curative resection for colorectal adenocarcinoma. Lancet. 1992 Aug 29;340(8818):502-6. link to original article PubMed
  2. Riethmüller G, Schneider-Gädicke E, Schlimok G, Schmiegel W, Raab R, Höffken K, Gruber R, Pichlmaier H, Hirche H, Pichlmayr R, Buggisch P, Witte J; German Cancer Aid 17-1A Study Group. Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes' C colorectal carcinoma. Lancet. 1994 May 14;343(8907):1177-83. link to original article PubMed
  3. O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, Wieand HS. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997 Jan;15(1):246-50. link to original article contains verified protocol PubMed
  4. Rougier P, Sahmoud T, Nitti D, Curran D, Doci R, De Waele B, Nakajima T, Rauschecker H, Labianca R, Pector JC, Marsoni S, Apolone G, Lasser P, Couvreur ML, Wils J; European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group and the Gruppo Interdisciplinare Valutazione Interventi in Oncologia and the Japanese Foundation for Cancer Research. Adjuvant portal-vein infusion of fluorouracil and heparin in colorectal cancer: a randomised trial. Lancet. 1998 Jun 6;351(9117):1677-81. link to original article PubMed
  5. QUASAR: Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ; Quasar Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007 Dec 15;370(9604):2020-9. link to original article PubMed
  6. CALGB 9581: Niedzwiecki D, Bertagnolli MM, Warren RS, Compton CC, Kemeny NE, Benson AB 3rd, Eckhardt SG, Alberts S, Porjosh GN, Kerr DJ, Fields A, Rougier P, Pipas JM, Schwartz JH, Atkins J, O'Rourke M, Perry MC, Goldberg RM, Mayer RJ, Colacchio TA. Documenting the natural history of patients with resected stage II adenocarcinoma of the colon after random assignment to adjuvant treatment with edrecolomab or observation: results from CALGB 9581. J Clin Oncol. 2011 Aug 10;29(23):3146-52. Epub 2011 Jul 11. link to original article link to PMC article PubMed
  7. Hasegawa K, Saiura A, Takayama T, Miyagawa S, Yamamoto J, Ijichi M, Teruya M, Yoshimi F, Kawasaki S, Koyama H, Oba M, Takahashi M, Mizunuma N, Matsuyama Y, Watanabe T, Makuuchi M, Kokudo N. Adjuvant oral uracil-tegafur with leucovorin for colorectal cancer liver metastases: A randomized controlled trial. PLoS One. 2016 Sep 2;11(9):e0162400. eCollection 2016. link to original article link to PMC article contains verified protocol PubMed

Tegafur, Uracil, Folinic acid

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Variant #1, 300/75

Study Evidence Comparator Efficacy
Shimada et al. 2014 (JCOG0205) Phase III (E) 5-FU & Leucovorin Non-inferior DFS
Hasegawa et al. 2016 Phase III (E) Observation Superior RFS

Preceding treatment

  • JCOG0205: Surgery with D2/D3 lymph node dissection
  • Hasegawa et al. 2016: Surgical resection of colorectal cancer liver metastases, within 8 weeks

Chemotherapy

35-day cycle for 5 cycles

Variant #2, 300/90

Study Evidence Comparator Efficacy
Lembersky et al. 2006 (NSABP C-06) Phase III (E) 5-FU & Leucovorin Seems not superior

Preceding treatment

  • A potentially curative resection of stage II or stage III colon cancer

Chemotherapy

35-day cycle for 5 cycles

References

  1. NSABP C-06: Lembersky BC, Wieand HS, Petrelli NJ, O'Connell MJ, Colangelo LH, Smith RE, Seay TE, Giguere JK, Marshall ME, Jacobs AD, Colman LK, Soran A, Yothers G, Wolmark N. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 2006 May 1;24(13):2059-64. link to original article contains verified protocol PubMed
  2. JCOG0205: Shimada Y, Hamaguchi T, Mizusawa J, Saito N, Kanemitsu Y, Takiguchi N, Ohue M, Kato T, Takii Y, Sato T, Tomita N, Yamaguchi S, Akaike M, Mishima H, Kubo Y, Nakamura K, Fukuda H, Moriya Y. Randomised phase III trial of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients with stage III colorectal cancer who have undergone Japanese D2/D3 lymph node dissection: final results of JCOG0205. Eur J Cancer. 2014 Sep;50(13):2231-40. Epub 2014 Jun 20. link to SD article contains verified protocol PubMed
  3. Hasegawa K, Saiura A, Takayama T, Miyagawa S, Yamamoto J, Ijichi M, Teruya M, Yoshimi F, Kawasaki S, Koyama H, Oba M, Takahashi M, Mizunuma N, Matsuyama Y, Watanabe T, Makuuchi M, Kokudo N. Adjuvant oral uracil-tegafur with leucovorin for colorectal cancer liver metastases: A randomized controlled trial. PLoS One. 2016 Sep 2;11(9):e0162400. eCollection 2016. link to original article link to PMC article contains verified protocol PubMed

Therapy for oligometastatic disease, including perioperative therapy and hyperthermic intra-peritoneal chemotherapy

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Evidence Comparator Efficacy
Nordlinger et al. 2008 (EORTC 40983) Phase III (E) Surgery alone Superior PFS

Note: this is the regimen as described by de Gramont et al. 2000; the manuscript refers to this protocol.

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus, then 600 mg/m2/day IV continuous infusion over 22 hours once per day on days 1 & 2 (total dose per cycle: 2000 mg/m2)
  • Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, before 5-FU
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, concurrent with leucovorin

14-day cycle for 6 cycles before surgery, and 6 cycles after surgery (12 cycles total)

References

  1. EORTC 40983: Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008 Mar 22;371(9617):1007-16. link to original article link to PMC article does not contain protocol PubMed
    1. Update: Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Mauer M, Tanis E, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und–tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectalcancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1208-15. Epub 2013 Oct 11. link to original article PubMed

Hepatic arterial chemotherapy

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Regimen

Study Evidence Comparator Efficacy
Kemeny et al. 1999 Phase III (E) Surgery alone Seems to have superior OS

Of historic interest; unlikely to be completed.

Chemotherapy

Supportive medications

References

  1. Kemeny N, Huang Y, Cohen AM, Shi W, Conti JA, Brennan MF, Bertino JR, Turnbull AD, Sullivan D, Stockman J, Blumgart LH, Fong Y. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med. 1999 Dec 30;341(27):2039-48. link to original article PubMed

Intraperitoneal 5-FU

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Regimen

Study Evidence Comparator Efficacy
Cashin et al. 2016 (SPS-1) Randomized (E) mFOLFOX6 Seems to have superior OS

Preceding treatment

  • Cytoreductive surgery

Chemotherapy

Monthly cycle for 6 cycles

References

  1. SPS-1: Cashin PH, Mahteme H, Spång N, Syk I, Frödin JE, Torkzad M, Glimelius B, Graf W. Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial. Eur J Cancer. 2016 Jan;53:155-62. Epub 2016 Jan 2. link to SD article contains verified protocol PubMed

Intraperitoneal hyperthermic mitomycin

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Regimen

Study Evidence Comparator Efficacy
Verwaal et al. 2003 Phase III (E) 5-FU & LV (modified Laufman regimen) Seems to have superior OS

Preceding treatment

  • Cytoreductive surgery

Chemotherapy

  • Hyperthermic Mitomycin (Mutamycin) 17.5 mg/m2 IP once, then 8.8 mg/m2 every 30 minutes (maximum dose: 70 mg)

One treatment

References

  1. Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003 Oct 15;21(20):3737-43. link to original article PubMed

Surgery alone

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Regimen

Study Evidence Comparator Efficacy
Kemeny et al. 1999 Phase III (C) Hepatic arterial chemotherapy Seems to have inferior OS
Nordlinger et al. 2008 (EORTC 40983) Phase III (E) FOLFOX4 Inferior PFS

No treatment other than surgical resection of oligometastatic disease.

References

  1. Kemeny N, Huang Y, Cohen AM, Shi W, Conti JA, Brennan MF, Bertino JR, Turnbull AD, Sullivan D, Stockman J, Blumgart LH, Fong Y. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med. 1999 Dec 30;341(27):2039-48. link to original article PubMed
  2. EORTC 40983: Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008 Mar 22;371(9617):1007-16. link to original article link to PMC article does not contain protocol PubMed
    1. Update: Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Mauer M, Tanis E, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und–tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectalcancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1208-15. Epub 2013 Oct 11. link to original article PubMed

Advanced or metastatic disease, first-line

Capecitabine monotherapy

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C: Capecitabine

Variant #1, 2000 mg/m2/day

Study Evidence Comparator Efficacy Toxicity
Kwakman et al. 2017 (SALTO) Phase III (C) S-1 Higher incidence of hand-foot syndrome

Note: this trial had a primary toxicity endpoint; this dose was intended for patients at least 70 years old.

Chemotherapy

21-day cycles

Variant #2, 2500 mg/m2/day

Study Evidence Comparator Efficacy Toxicity
Hoff et al. 2001 Phase III (E) 5-FU + Folinic acid Superior ORR
Van Cutsem et al. 2001 Phase III (E) 5-FU + Folinic acid Seems not superior
Tebbutt et al. 2010 (AGITG MAX) Phase III (C) Capecitabine & Bevacizumab Inferior PFS
CBM Inferior PFS
Cunningham et al. 2013 (AVEX) Phase III (C) Capecitabine & Bevacizumab Inferior PFS
Kwakman et al. 2017 (SALTO) Phase III (C) S-1 Higher incidence of hand-foot syndrome

Note: SALTO had a primary toxicity endpoint; this dose was intended for patients less than 70 years old.

Chemotherapy

21-day cycles

References

  1. Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001 Apr 15;19(8):2282-92. link to original article contains verified protocol PubMed
    1. Pooled update: Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. link to original article link to PMC article PubMed
  2. Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P; Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001 Nov 1;19(21):4097-106. link to original article contains verified protocol PubMed
    1. Pooled update: Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. link to original article link to PMC article PubMed
  3. AGITG MAX: Tebbutt NC, Wilson K, Gebski VJ, Cummins MM, Zannino D, van Hazel GA, Robinson B, Broad A, Ganju V, Ackland SP, Forgeson G, Cunningham D, Saunders MP, Stockler MR, Chua Y, Zalcberg JR, Simes RJ, Price TJ. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study. J Clin Oncol. 2010 Jul 1;28(19):3191-8. Epub 2010 Jun 1. link to original article contains verified protocol PubMed
  4. AVEX: Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, Jonker D, Osborne S, Andre N, Waterkamp D, Saunders MP; AVEX study investigators. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label,randomised phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1077-85. Epub 2013 Sep 10. link to original article PubMed
  5. SALTO: Kwakman JJM, Simkens LHJ, van Rooijen JM, van de Wouw AJ, Ten Tije AJ, Creemers GJM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, van Werkhoven E, Punt CJA. Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group. Ann Oncol. 2017 Jun 1;28(6):1288-1293. link to original article contains protocol PubMed

Capecitabine & Bevacizumab

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CB: Capecitabine & Bevacizumab

Variant #1, 1000/7.5

Study Evidence Comparator Efficacy
Cunningham et al. 2013 (AVEX) Phase III (E) Capecitabine Superior PFS

Chemotherapy

21-day cycles

Variant #2, 1250/7.5

Study Evidence Comparator Efficacy
Tebbutt et al. 2010 (AGITG MAX) Phase III (E) Capecitabine Superior PFS
Giessen et al. 2011 (AIO KRK 0110) Phase III (C) CAPIRI-Bev TBD

Note: there are no results for AIO KRK 0110 as of yet; the reference does describe the regimen, however.

Chemotherapy

21-day cycles

References

  1. AGITG MAX: Tebbutt NC, Wilson K, Gebski VJ, Cummins MM, Zannino D, van Hazel GA, Robinson B, Broad A, Ganju V, Ackland SP, Forgeson G, Cunningham D, Saunders MP, Stockler MR, Chua Y, Zalcberg JR, Simes RJ, Price TJ. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study. J Clin Oncol. 2010 Jul 1;28(19):3191-8. Epub 2010 Jun 1. link to original article PubMed
  2. AIO KRK 0110: Giessen C, von Weikersthal LF, Hinke A, Stintzing S, Kullmann F, Vehling-Kaiser U, Mayerle J, Bangerter M, Denzlinger C, Sieber M, Teschendorf C, Freiberg-Richter J, Schulz C, Modest DP, Moosmann N, Aubele P, Heinemann V. A randomized, phase III trial of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in first-line treatment of metastatic colorectal cancer: the AIO KRK 0110 trial/ML22011 trial. BMC Cancer. 2011 Aug 23;11:367. link to original article contains verified protocol link to PMC article PubMed
  3. AVEX: Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, Jonker D, Osborne S, Andre N, Waterkamp D, Saunders MP; AVEX study investigators. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label,randomised phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1077-85. Epub 2013 Sep 10. link to original article contains protocol PubMed

CapeOx

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CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda, OXaliplatin

Example orders

Variant #1, 850/130

Study Evidence Comparator Efficacy
Hochster et al. 2008 (TREE-1) Phase III (E) bFOL Seems not superior
mFOLFOX6 Seems not superior

Chemotherapy

  • Capecitabine (Xeloda) 850 mg/m2 PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
    • In TREE-2, based on safety data from TREE-1, the initial dose was decreased to 850 mg/m2 PO BID. Patients with a CrCl of 30 to 50 mL/min/1.73m2 received 650 mg/m2 PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
  • Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1

21-day cycles

Variant #2, 1000/70

Study Evidence Comparator Efficacy
Porschen et al. 2007 Phase III (E) FUFOX Inconclusive whether non-inferior

Chemotherapy

21-day cycles

Variant #3, 1000/130

Study Evidence Comparator Efficacy
Díaz-Rubio et al. 2007 Phase III (E) FUOX Seems not superior
Cassidy et al. 2008 (NO16966) Phase III (C) FOLFOX4
FOLFOX4 & Bevacizumab 		Non-inferior PFS
XELOX & Bevacizumab Not reported
Saltz et al. 2008 (NO16966) Phase III (C) FOLFOX4 & Bevacizumab
XELOX & Bevacizumab 		Inferior PFS
FOLFOX4 Not reported
Ducreux et al. 2011 Phase III (E) mFOLFOX6 Non-inferior OS
Maughan et al. 2011 (UK MRC COIN) Phase III (C) CapeOx & Cetuximab Seems not superior (*)
Hoff et al. 2012 (HORIZON-II) Phase III (C) CAPOX & Cediranib
FOLFOX4 & Cediranib
mFOLFOX6 & Cediranib 		Seems to have inferior PFS
Hong et al. 2012 Phase III (C) SOX Non-inferior PFS

Note: Ducreux et al. 2011 gave up to 8 cycles of treatment. NO16966 said that initial treatment could be given up to 16 cycles, but then could continue beyond that for patients who did not have progression of disease. Efficacy for UK MRC COIN is as reported for KRAS wild-type patients.

Chemotherapy

  • Capecitabine (Xeloda) 1000 mg/m2 PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
    • Note: In Saltz et al. 2008 and Hong et al. 2012 capecitabine was described as being given 1000 mg/m2 PO BID on days 1 to 14
  • Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1

21-day cycles (see note)

Subsequent treatment

References

  1. Porschen R, Arkenau HT, Kubicka S, Greil R, Seufferlein T, Freier W, Kretzschmar A, Graeven U, Grothey A, Hinke A, Schmiegel W, Schmoll HJ; AIO Colorectal Study Group. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol. 2007 Sep 20;25(27):4217-23. Epub 2007 Jun 4. link to original article contains verified protocol PubMed
  2. Díaz-Rubio E, Tabernero J, Gómez-España A, Massutí B, Sastre J, Chaves M, Abad A, Carrato A, Queralt B, Reina JJ, Maurel J, González-Flores E, Aparicio J, Rivera F, Losa F, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol. 2007 Sep 20;25(27):4224-30. Epub 2007 Jun 4. link to original article contains verified protocol PubMed
  3. NO16966: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. link to original article contains verified protocol PubMed
    1. Update: Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. link to original article contains verified protocol PubMed
    2. Update: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64. Epub 2011 Jun 14. link to original article link to PMC article PubMed
  4. TREE: Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. link to original article contains verified protocol PubMed
  5. Ducreux M, Bennouna J, Hebbar M, Ychou M, Lledo G, Conroy T, Adenis A, Faroux R, Rebischung C, Bergougnoux L, Kockler L, Douillard JY; GI Group of the French Anti-Cancer Centers. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer. Int J Cancer. 2011 Feb 1;128(3):682-90. link to original article contains verified protocol PubMed
  6. UK MRC COIN: Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP; MRC COIN Trial Investigators. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011 Jun 18;377(9783):2103-14. Epub 2011 Jun 5. link to original article link to PMC article contains verified protocol PubMed
  7. HORIZON II: Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. link to original article contains verified protocol PubMed
  8. Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. link to original article contains protocol PubMed

CapeOx & Bevacizumab

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CapeOX & Bevacizumab: Capecitabine, OXaliplatin, Bevacizumab
CAPOX-B: CAPecitabine, OXaliplatin, Bevacizumab
XELOX & Bevacizumab: XELoda, OXaliplatin, Bevacizumab

Variant #1, 850/130/7.5

Study Evidence Comparator Efficacy
Hochster et al. 2008 (TREE-2) Phase III (E) bFOL & Bevacizumab Seems not superior
mFOLFOX6 & Bevacizumab Seems not superior

Chemotherapy

  • Capecitabine (Xeloda) 850 mg/m2 PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
    • In TREE-2, patients with a CrCl of 30 to 50 mL/min/1.73m2 received 650 mg/m2 PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
  • Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
  • Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycles

Variant #2, 1000/130/7.5 x 6

Study Evidence Comparator Efficacy
Tol et al. 2009 (CAIRO2) Phase III (C) CapeOx, Bevacizumab, Cetuximab Superior PFS
Simkens et al. 2015 (CAIRO3) Non-randomized portion of RCT

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment

Variant #3, 1000/130/7.5, indefinite

Study Evidence Comparator Efficacy
Cassidy et al. 2008 (NO16966) Phase III (E) FOLFOX4
FOLFOX4 & Bevacizumab 		Non-inferior PFS
XELOX Not reported
Saltz et al. 2008 (NO16966) Phase III (E) FOLFOX4
XELOX 		Superior PFS
FOLFOX4 & Bevacizumab Not reported
Yamada et al. 2018 (TRICOLORE) Phase III (C) IRIS & Bevacizumab Non-inferior PFS
Nakayama 2018 (CCOG-1201) Randomized Phase II (C) CAPIRI & Bevacizumab Seems not superior

Note: N016966 specified that initial treatment could be given up to 16 cycles, but then could continue beyond that for patients who did not have progression of disease.

Chemotherapy

  • Capecitabine (Xeloda) 1000 mg/m2 PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
    • Note: In Saltz et al. 2008--the same study as Cassidy et al. 2008--capecitabine was described as being given 1000 mg/m2 PO BID on days 1 to 14
  • Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1, given second
  • Bevacizumab (Avastin) 7.5 mg/kg IV over 30 to 90 minutes once on day 1, given first

21-day cycles

References

  1. NO16966: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. link to original article contains verified protocol PubMed
    1. Update: Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. link to original article contains verified protocol PubMed
    2. Update: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64. Epub 2011 Jun 14. link to original article link to PMC article PubMed
  2. TREE-2: Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. link to original article contains verified protocol PubMed
  3. CAIRO2: Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, Erdkamp FL, Vos AH, van Groeningen CJ, Sinnige HA, Richel DJ, Voest EE, Dijkstra JR, Vink-Börger ME, Antonini NF, Mol L, van Krieken JH, Dalesio O, Punt CJ. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009 Feb 5;360(6):563-72. Erratum in: N Engl J Med. 2010 Dec 23;363(26):2573. link to original article contains verified protocol PubMed
  4. CAIRO3: Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoeven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, Honkoop AH, Mol L, Punt CJ, Koopman M. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015 May 9;385(9980):1843-52. Epub 2015 Apr 7. link to original article contains verified protocol PubMed
    1. Update: Goey KKH, Elias SG, van Tinteren H, Laclé MM, Willems SM, Offerhaus GJA, de Leng WWJ, Strengman E, Ten Tije AJ, Creemers GM, van der Velden A, de Jongh FE, Erdkamp FLG, Tanis BC, Punt CJA, Koopman M. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann Oncol. 2017 Sep 1;28(9):2128-2134. link to original article PubMed
  5. TRICOLORE: Yamada Y, Denda T, Gamoh M, Iwanaga I, Yuki S, Shimodaira H, Nakamura M, Yamaguchi T, Ohori H, Kobayashi K, Tsuda M, Kobayashi Y, Miyamoto Y, Kotake M, Shimada K, Sato A, Morita S, Takahashi S, Komatsu Y, Ishioka C. S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized, open-label, phase III, noninferiority trial. Ann Oncol. 2018 Mar 1;29(3):624-631. link to original article contains verified protocol PubMed
  6. CCOG-1201: Nakayama G, Mitsuma A, Sunagawa Y, Ishigure K, Yokoyama H, Matsui T, Nakayama H, Nakata K, Ishiyama A, Asada T, Umeda S, Ezaka K, Hattori N, Takami H, Kobayashi D, Tanaka C, Kanda M, Yamada S, Koike M, Fujiwara M, Fujii T, Murotani K, Ando Y, Kodera Y. Randomized phase II trial of CapOX plus bevacizumab and capIRI plus bevacizumab as first-line treatment for Japanese patients with metastatic colorectal cancer (CCOG-1201 study). Oncologist. 2018 Aug;23(8):919-927. Epub 2018 Jul 26. link to original article contains protocol PubMed

CAPIRI

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CapeIRI: Capecitabine and IRInotecan
CAPIRI: CAPecitabine and IRInotecan
XELIRI: XELox (Capecitabine) and IRInotecan

Regimen

Study Evidence Comparator Efficacy
Fuchs et al. 2007 (BICC-C) Phase III (E) FOLFIRI Seems to have inferior PFS
mIFL Seems not superior
Moehler et al. 2009 Phase II

Chemotherapy

21-day cycles

References

  1. Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article contains verified protocol PubMed
    1. Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article PubMed
  2. Moehler M, Sprinzl MF, Abdelfattah M, Schimanski CC, Adami B, Godderz W, Majer K, Flieger D, Teufel A, Siebler J, Hoehler T, Galle PR, Kanzler S. Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients. World J Gastroenterol. 2009 Jan 28;15(4):449-56. link to PMC article contains verified protocol link to PMC article PubMed

CAPIRI-Bev

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CAPIRI-Bev: CAPecitabine, IRInotecan, Bevacizumab
XELIRI-Bev: XELoda (Capecitabine), IRInotecan, Bevacizumab

Variant #1, 800/200/7.5

Study Evidence Comparator Efficacy
Giessen et al. 2011 (AIO KRK 0110) Phase III (E) Cape-Bev TBD

Note: there are no results for this trial; the reference does describe the regimen, however.

Chemotherapy

21-day cycles

Variant #2, 1000/200/7.5

Study Evidence
Moehler et al. 2009 Phase II

Chemotherapy

21-day cycles

Variant #3, 1000/240/7.5

Study Evidence Comparator Efficacy
Pectasides et al. 2012 Phase III (E) FOLFIRI-Bev Seems not superior

Chemotherapy

21-day cycle for 6 cycles

References

  1. Moehler M, Sprinzl MF, Abdelfattah M, Schimanski CC, Adami B, Godderz W, Majer K, Flieger D, Teufel A, Siebler J, Hoehler T, Galle PR, Kanzler S. Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients. World J Gastroenterol. 2009 Jan 28;15(4):449-56. link to PMC article contains verified protocol link to PMC article PubMed
  2. Giessen C, von Weikersthal LF, Hinke A, Stintzing S, Kullmann F, Vehling-Kaiser U, Mayerle J, Bangerter M, Denzlinger C, Sieber M, Teschendorf C, Freiberg-Richter J, Schulz C, Modest DP, Moosmann N, Aubele P, Heinemann V. A randomized, phase III trial of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in first-line treatment of metastatic colorectal cancer: the AIO KRK 0110 trial/ML22011 trial. BMC Cancer. 2011 Aug 23;11:367. link to original article contains verified protocol link to PMC article PubMed
  3. Pectasides D, Papaxoinis G, Kalogeras KT, Eleftheraki AG, Xanthakis I, Makatsoris T, Samantas E, Varthalitis I, Papakostas P, Nikitas N, Papandreou CN, Pentheroudakis G, Timotheadou E, Koutras A, Sgouros J, Bafaloukos D, Klouvas G, Economopoulos T, Syrigos KN, Fountzilas G. XELIRI-bevacizumab versus FOLFIRI-bevacizumab as first-line treatment in patients with metastatic colorectal cancer: a Hellenic Cooperative Oncology Group phase III trial with collateral biomarker analysis. BMC Cancer. 2012 Jun 29;12:271. link to original article contains verified protocol link to PMC article PubMed

Fluorouracil & Folinic acid

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LV5FU2: LeucoVorin and 5-FU, two days out of the month
sLV5FU2: simplified LeucoVorin and 5-FU, two days out of the month

Example orders

Variant #1, "Roswell Park regimen"

Study Evidence Comparator Efficacy
Kabbinavar et al. 2003 (AVF0780) Randomized Phase II (C) 5-FU, Folinic acid & Bevacizumab Might have inferior OS

Chemotherapy

8-week cycles

Variant #2, "Mayo Clinic regimen"

Study Evidence Comparator Efficacy
de Gramont et al. 1997 Phase III (C) LV5FU2 Inferior PFS
Saltz et al. 2000 (Irinotecan Study Group) Phase III (C) IFL Seems to have inferior OS
Irinotecan Seems not superior
Hoff et al. 2001 Phase III (C) Capecitabine Inferior ORR
Van Cutsem et al. 2001 Phase III (C) Capecitabine Seems not superior
Schilsky et al. 2002 (FUMA3008) Phase III (C) Eniluracil & 5-FU Inconclusive whether non-inferior
Douillard et al. 2002 Phase III (C) UFT & Leucovorin Seems to have equivalent OS
Carmichael et al. 2002 Phase III (C) UFT & Leucovorin Seems not superior

Chemotherapy

28- to 35-day cycles

Variant #3, LV5FU2 ("de Gramont regimen")

Study Evidence Comparator Efficacy
de Gramont et al. 1997 Phase III (E) Mayo Clinic Regimen Superior PFS
Douillard et al. 2000 Phase III (C) IFL
FOLFIRI 		Seems to have inferior OS
de Gramont et al. 2000 Phase III (C) FOLFOX4 Inferior PFS
Maughan et al. 2002 Phase III (C) Lokich regimen Seems not superior
Raltitrexed Seems not superior
Kerr et al. 2003 Phase III (C) IHA LV5FU2 Seems not superior
Maughan et al. 2003 Phase III (C) Intermittent LV5FU2 Seems not superior

Note: Maughan et al. 2003 randomized patients to 12 weeks of treatment with re-treatment upon progression, versus continuous treatment. There was no difference in outcome between the two arms.

Chemotherapy

  • Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, given first
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus, then 600 mg/m2/day IV continuous infusion over 22 hours once per day on days 1 & 2 (both bolus and continuous infusion are given on days 1 & 2)

14-day cycles (see note)

Variant #4, 500/2600

Study Evidence Comparator Efficacy
Douillard et al. 2000 Phase III (C) IFL
FOLFIRI 		Seems to have inferior OS

Chemotherapy

7-day cycles

Variant #5

Study Evidence Comparator Efficacy
Jäger et al. 1996 Phase III (C) 5-FU & High-dose Folinic acid Seems not superior

Chemotherapy

7-day cycles

Variant #6, "modified Laufman"

Study Evidence Comparator Efficacy
Verwaal et al. 2003 Phase III (C) HIPEC Seems to have inferior OS

Chemotherapy

7-day cycle for up to 26 weeks

Variant #7, "modified de Gramont"

Study Evidence
Cheeseman et al. 2002 Non-randomized
Seymour et al. 2007 (MRC FOCUS) Phase III (C)

Note: it is not completely clear from the abstract whether this was the protocol used in MRC FOCUS, although it is alluded to in the Cheeseman et al. 2002 publication. Also, efficacy results for MRC FOCUS are complex and will be added in the future (to be completed).

Chemotherapy

  • Folinic acid (Leucovorin) 350 mg IV over 2 hours once on day 1, given first
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus over 5 minutes once on day 1 after leucovorin, then 1400 mg/m2/day IV continuous infusion over 46 hours on days 1 to 2 (total dose per cycle: 2800 mg/m2)

Supportive medications

14-day cycles

Variant #8 reduced-dose sLV5FU2

Study Evidence Comparator Efficacy Toxicity
Seymour et al. 2011 (MRC FOCUS2) Phase III (C) Capecitabine
CapeOx
OxFU 		Might have inferior PFS (see note) Similar QoL (see note)

Note: efficacy comparison was to oxaliplatin-containing regimens; QoL comparison was to capecitabine-containing regimens.

Chemotherapy

  • Folinic acid (Leucovorin) 175 mg/m2 IV over 2 hours once on day 1
  • Fluorouracil (5-FU) 320 mg/m2 IV bolus once on day 1, then 2240 mg/m2 IV continuous infusion over 46 hours on days 1 to 2 (total dose per cycle: 2560 mg/m2)

14-day cycles

References

  1. Jäger E, Heike M, Bernhard H, Klein O, Bernhard G, Lautz D, Michaelis J, Meyer zum Büschenfelde KH, Knuth Al; Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. J Clin Oncol. 1996 Aug;14(8):2274-9. link to original article contains verified protocol PubMed
  2. de Gramont A, Bosset JF, Milan C, Rougier P, Bouché O, Etienne PL, Morvan F, Louvet C, Guillot T, François E, Bedenne L. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol. 1997 Feb;15(2):808-15. link to original article contains verified protocol PubMed
  3. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-7. link to original article contains verified protocol PubMed
  4. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. link to original article contains verified protocol PubMed
  5. Irinotecan Study Group: Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. link to original article contains verified protocol PubMed
  6. Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001 Apr 15;19(8):2282-92. link to original article contains verified protocol PubMed
    1. Pooled update: Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. link to original article link to PMC article PubMed
  7. Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P; Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001 Nov 1;19(21):4097-106. link to original article contains verified protocol PubMed
    1. Pooled update: Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. link to original article link to PMC article PubMed
  8. FUMA3008: Schilsky RL, Levin J, West WH, Wong A, Colwell B, Thirlwell MP, Ansari RH, Bell WN, White RL, Yates BB, McGuirt PV, Pazdur R. Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. J Clin Oncol. 2002 Mar 15;20(6):1519-26. link to original article contains protocol PubMed
  9. Maughan TS, James RD, Kerr DJ, Ledermann JA, McArdle C, Seymour MT, Cohen D, Hopwood P, Johnston C, Stephens RJ; British MRC Colorectal Cancer Working Party. Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2002 May 4;359(9317):1555-63. link to original article PubMed
  10. Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12;87(4):393-9. link to original article contains verified protocol link to PMC article PubMed
  11. Douillard JY, Hoff PM, Skillings JR, Eisenberg P, Davidson N, Harper P, Vincent MD, Lembersky BC, Thompson S, Maniero A, Benner SE. Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2002 Sep 1;20(17):3605-16. link to original article contains protocol PubMed
  12. Carmichael J, Popiela T, Radstone D, Falk S, Borner M, Oza A, Skovsgaard T, Munier S, Martin C. Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2002 Sep 1;20(17):3617-27. link to original article contains protocol PubMed
  13. AVF0780: Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, Griffing S, Bergsland E. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003 Jan 1;21(1):60-5. link to original article contains verified protocol PubMed
  14. Kerr DJ, McArdle CS, Ledermann J, Taylor I, Sherlock DJ, Schlag PM, Buckels J, Mayer D, Cain D, Stephens RJ; Medical Research Council's colorectal cancer study group; European Organisation for Research and Treatment of Cancer colorectal cancer study group. Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. Lancet. 2003 Feb 1;361(9355):368-73. link to original article contains protocol PubMed
  15. Maughan TS, James RD, Kerr DJ, Ledermann JA, Seymour MT, Topham C, McArdle C, Cain D, Stephens RJ; Medical Research Council Colorectal Cancer Group. Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial. Lancet. 2003 Feb 8;361(9356):457-64. link to original article PubMed
  16. Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003 Oct 15;21(20):3737-43. link to original article PubMed
  17. MRC FOCUS: Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, Smith DB, Shepherd S, Maraveyas A, Ferry DR, Meade AM, Thompson L, Griffiths GO, Parmar MK, Stephens RJ; FOCUS Trial Investigators; National Cancer Research Institute Colorectal Clinical Studies Group. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007 Jul 14;370(9582):143-52. Erratum in: Lancet. 2007 Aug 18;370(9587):566. link to original article PubMed
  18. MRC FOCUS2: Seymour MT, Thompson LC, Wasan HS, Middleton G, Brewster AE, Shepherd SF, O'Mahony MS, Maughan TS, Parmar M, Langley RE; FOCUS2 Investigators; National Cancer Research Institute Colorectal Cancer Clinical Studies Group. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. Lancet. 2011 May 21;377(9779):1749-59. Epub 2011 May 11. link to original article link to PMC article contains verified protocol PubMed

FOLFIRI

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Example orders

Variant #1, 400/2800/180, racemic leucovorin

Study Evidence Comparator Efficacy
Falcone et al. 2007 Phase III (C) FOLFOXIRI Seems to have inferior OS
Fuchs et al. 2007 (BICC-C) Phase III (E) CapeIRI Seems to have superior PFS
mIFL Superior PFS
Van Cutsem et al. 2009 (CRYSTAL) Phase III (C) FOLFIRI & Cetuximab Inferior OS (*)
Sanoff et al. 2018 Randomized Phase II (C) FOLFIRI & Regorafenib Might have inferior PFS

Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.

Chemotherapy

  • Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, given during irinotecan infusion
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours on days 1 & 2, given last (total dose per cycle: 2800 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first together with leucovorin

14-day cycles

Variant #2, 200/2800/180, L-leucovorin

Study Evidence Comparator Efficacy
Van Cutsem et al. 2009 (CRYSTAL) Phase III (C) FOLFIRI & Cetuximab Inferior OS (*)
Carrato et al. 2013 (SUN 1122) Phase III (C) FOLFIRI & Sunitinib Seems not superior

Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.

Chemotherapy

  • Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given during irinotecan infusion
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours on days 1 & 2, given last (total dose per cycle: 2800 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV once on day 1, given first together with levoleucovorin

14-day cycles

Variant #3, 400/1000/180, bi-weekly

Study Evidence Comparator Efficacy
Douillard et al. 2000 Phase III (E) 5-FU & LV Seems to have superior OS

Chemotherapy

14-day cycles

Variant #4, 500/2300/80, weekly

Study Evidence Comparator Efficacy
Douillard et al. 2000 Phase III (E) 5-FU & LV Seems to have superior OS

Chemotherapy

7-day cycles

Variant #5, 6 out of 7 weeks ("AIO regimen")

Study Evidence Comparator Efficacy
Köhne et al. 2005 (EORTC 40986) Phase III (E) 5-FU & LV Superior PFS

Chemotherapy

7-week cycles

References

  1. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-7. link to original article contains verified protocol PubMed
  2. EORTC 40986: Köhne CH, van Cutsem E, Wils J, Bokemeyer C, El-Serafi M, Lutz MP, Lorenz M, Reichardt P, Rückle-Lanz H, Frickhofen N, Fuchs R, Mergenthaler HG, Langenbuch T, Vanhoefer U, Rougier P, Voigtmann R, Müller L, Genicot B, Anak O, Nordlinger B; European Organisation for Research and Treatment of Cancer Gastrointestinal Group. Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol. 2005 Aug 1;23(22):4856-65. Epub 2005 Jun 6. link to original article contains verified protocol PubMed
  3. Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6. link to original article contains verified protocol PubMed
  4. BICC-C: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article contains verified protocol PubMed
    1. Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article PubMed
  5. CRYSTAL: Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. link to original article contains verified protocol PubMed
    1. Update: Abstract: E. Van Cutsem, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D. Cunningham, I. Celik, C. Kohne. Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome. 2010 ASCO Annual Meeting abstract 3570. link to abstract
    2. Update: Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. link to original article contains verified protocol PubMed
    3. Pooled Update: Bokemeyer C, Cutsem EV, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article PubMed
  6. SUN 1122: Carrato A, Swieboda-Sadlej A, Staszewska-Skurczynska M, Lim R, Roman L, Shparyk Y, Bondarenko I, Jonker DJ, Sun Y, De la Cruz JA, Williams JA, Korytowsky B, Christensen JG, Lin X, Tursi JM, Lechuga MJ, Van Cutsem E. Fluorouracil, leucovorin, and irinotecan plus either sunitinib or placebo in metastatic colorectal cancer: a randomized, phase III trial. J Clin Oncol. 2013 Apr 1;31(10):1341-7. Epub 2013 Jan 28. link to original article contains verified protocol PubMed
  7. Sanoff HK, Goldberg RM, Ivanova A, O'Reilly S, Kasbari SS, Kim RD, McDermott R, Moore DT, Zamboni W, Grogan W, Cohn AL, Bekaii-Saab TS, Leonard G, Ryan T, Olowokure OO, Fernando NH, McCaffrey J, El-Rayes BF, Horgan AM, Sherrill GB, Yacoub GH, O'Neil BH. Multicenter, randomized, double-blind phase 2 trial of FOLFIRI with regorafenib or placebo as second-line therapy for metastatic colorectal cancer. Cancer. 2018 Aug 1;124(15):3118-3126. Epub 2018 Jun 15. link to original article contains verified protocol PubMed

FOLFIRI & Bevacizumab

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FOLFIRI & Bevacizumab: FOLinic acid, Fluorouracil, IRInotecan, Bevacizumab

Variant #1, indefinite

Study Evidence Comparator Efficacy
Fuchs et al. 2007 (BICC-C) Phase III (E) mIFL & Bevacizumab Seems to have superior OS
Yamazaki et al. 2016 (WJOG4407G) Phase III (E) mFOLFOX6 & Bevacizumab Non-inferior PFS
Heinemann et al. 2014 (FIRE-3) Phase III (E) FOLFIRI & Cetuximab Seems not superior

Chemotherapy

  • Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, started during irinotecan infusion
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours on days 1 to 2, given last (total dose per cycle: 2800 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first
  • Bevacizumab (Avastin) 5 mg/kg IV once on day 1
    • In FIRE-3, initial infusion is over 90 minutes, next over 60 minutes, and subsequently over 30 minutes

14-day cycles

Variant #2, limited duration

Study Evidence Comparator Efficacy
Loupakis et al. 2014 (TRIBE) Phase III (C) FOLFOXIRI & Bevacizumab Seems to have inferior OS

Note: Loupakis et al. 2014 listed folinic acid 200 mg/m2 in the body of the paper, whereas the protocol in the supplementary material stated that levoleucovorin 200 mg/m2 was used. We have contacted NEJM regarding this suspected error.

Chemotherapy

14-day cycle for up to 12 cycles

Subsequent treatment

  • Fluorouracil, leucovorin, bevacizumab maintenance

References

  1. BICC-C: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article contains verified protocol PubMed
    1. Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article PubMed
  2. Observational cohort: Bendell JC, Bekaii-Saab TS, Cohn AL, Hurwitz HI, Kozloff M, Tezcan H, Roach N, Mun Y, Fish S, Flick ED, Dalal D, Grothey A. Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-bevacizumab or FOLFIRI-bevacizumab: results from ARIES, a bevacizumab observational cohort study. Oncologist. 2012;17(12):1486-95. link to original article link to PMC article PubMed
  3. FIRE-3: Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31.link to original article PubMed
  4. TRIBE: Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014 Oct 23;371(17):1609-18. link to original article link to protocol in supplementary material contains verified protocol PubMed
    1. Update: Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, Mezi S, Tomasello G, Ronzoni M, Zaniboni A, Tonini G, Carlomagno C, Allegrini G, Chiara S, D'Amico M, Granetto C, Cazzaniga M, Boni L, Fontanini G, Falcone A. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015 Oct;16(13):1306-15. link to original article PubMed
  5. WJOG4407G: Yamazaki K, Nagase M, Tamagawa H, Ueda S, Tamura T, Murata K, Eguchi Nakajima T, Baba E, Tsuda M, Moriwaki T, Esaki T, Tsuji Y, Muro K, Taira K, Denda T, Funai S, Shinozaki K, Yamashita H, Sugimoto N, Okuno T, Nishina T, Umeki M, Kurimoto T, Takayama T, Tsuji A, Yoshida M, Hosokawa A, Shibata Y, Suyama K, Okabe M, Suzuki K, Seki N, Kawakami K, Sato M, Fujikawa K, Hirashima T, Shimura T, Taku K, Otsuji T, Tamura F, Shinozaki E, Nakashima K, Hara H, Tsushima T, Ando M, Morita S, Boku N, Hyodo I. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol. 2016 Aug;27(8):1539-46. Epub 2016 May 13. link to original article PubMed

FOLFIRINOX

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FOLFIRINOX: FOLinic acid, Fluorouracil, IRINotecan, OXaliplatin
FOLFOXIRI: FOLinic acid, Fluorouracil, OXaliplatin, IRInotecan

Regimen

Study Evidence Comparator Efficacy
Falcone et al. 2007 Phase III (E) FOLFIRI Seems to have superior OS

Note: In contrast to Falcone et al. 2007, some guidelines list the dose of folinic acid as 400 mg/m2 IV on day 1. No primary reference could be found for this.

Chemotherapy

14-day cycles

References

  1. Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6. link to original article contains verified protocol PubMed

FOLFIRINOX & Bevacizumab

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FOLFIRINOX & Bevacizumab: FOLinic acid, Fluorouracil, IRINotecan, OXaliplatin, Bevacizumab
FOLFOXIRI & Bevacizumab: FOLinic acid, Fluorouracil, OXaliplatin, IRInotecan, Bevacizumab

Regimen

Study Evidence Comparator Efficacy
Loupakis et al. 2014 (TRIBE) Phase III (E) FOLFIRI & Bevacizumab Seems to have superior OS

Note: Loupakis et al. 2014 listed folinic acid 200 mg/m2 in the body of the paper, whereas the protocol in the supplementary material stated that levoleucovorin 200 mg/m2 was used. We have contacted NEJM regarding this suspected error. Some guidelines list either folinic acid 400 mg/m2 IV once on day 1 or levoleucovorin 200 mg/m2 IV once on day 1 as options.

Chemotherapy

14-day cycle for up to 12 cycles, then followed by maintenance fluorouracil, leucovorin, and bevacizumab given until progression of disease or unacceptable adverse event. Loupakis et al. 2014 did not provide specific details about the maintenance therapy.

References

  1. TRIBE: Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014 Oct 23;371(17):1609-18. link to original article link to protocol in supplementary material contains verified protocol PubMed
    1. Update: Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, Mezi S, Tomasello G, Ronzoni M, Zaniboni A, Tonini G, Carlomagno C, Allegrini G, Chiara S, D'Amico M, Granetto C, Cazzaniga M, Boni L, Fontanini G, Falcone A. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015 Oct;16(13):1306-15. link to original article PubMed

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Variant #1, racemic leucovorin

Study Evidence Comparator Efficacy
de Gramont et al. 2000 Phase III (E) 5-FU & Folinic acid Superior PFS
Goldberg et al. 2003 Phase III (E) IFL Superior OS
IROX Seems not superior
Tournigand et al. 2006 (OPTIMOX1) Phase III (C) FOLFOX7/LV5FU2 Seems not superior
Cassidy et al. 2008 (NO16966) Phase III (C) FOLFOX4 & Bevacizumab Not reported
XELOX
XELOX & Bevacizumab 		Non-inferior PFS
Saltz et al. 2008 (NO16966) Phase III (C) FOLFOX4 & Bevacizumab
XELOX & Bevacizumab 		Inferior PFS
XELOX Not reported
Bokemeyer et al. 2008 (OPUS) Phase III (C) FOLFOX4 & Cetuximab Inferior OS (*)
Douillard et al. 2010 (PRIME) Phase III (C) FOLFOX4 & Panitumumab See note
Hecht et al. 2011 Phase III (C) FOLFOX4 & Vatalanib Seems not superior
Hoff et al. 2012 (HORIZON II) Phase III (C) CAPOX & Cediranib
FOLFOX4 & Cediranib
mFOLFOX6 & Cediranib 		Seems to have inferior PFS

Note: in PRIME, KRAS wild-type patients receiving this regimen seem to have inferior PFS. Conversely, in KRAS mutants, this regimen seems to have superior PFS. Reported efficacy for OPUS is based on the 2012 pooled update and is only for KRAS wild-type tumors.

Chemotherapy

14-day cycles

Variant #2, L-leucovorin

Study Evidence Comparator Efficacy
Hecht et al. 2011 Phase III (C) FOLFOX4 & Vatalanib Seems not superior

Chemotherapy

14-day cycles

References

  1. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. link to original article contains verified protocol PubMed
  2. Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. Epub 2003 Dec 9. link to original article contains verified protocol PubMed
  3. OPTIMOX1: Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, Mineur L, Carola E, Etienne PL, Rivera F, Chirivella I, Perez-Staub N, Louvet C, André T, Tabah-Fisch I, de Gramont A. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006 Jan 20;24(3):394-400. link to original article contains verified protocol PubMed
  4. Retrospective: Goldberg RM, Tabah-Fisch I, Bleiberg H, de Gramont A, Tournigand C, Andre T, Rothenberg ML, Green E, Sargent DJ. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol. 2006 Sep 1;24(25):4085-91. link to original article PubMed content property of HemOnc.org
  5. NO16966: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. link to original article PubMed
    1. Update: Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. link to original article refers to de Gramont et al. 2000 for protocol PubMed
    2. Update: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64. Epub 2011 Jun 14. link to original article link to PMC article PubMed
  6. OPUS: Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29. link to original article contains verified protocol PubMed
    1. Pooled Update: Bokemeyer C, Cutsem EV, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article PubMed
  7. PRIME: Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010 Nov 1;28(31):4697-705. Epub 2010 Oct 4. link to original article PubMed
  8. Hecht JR, Trarbach T, Hainsworth JD, Major P, Jäger E, Wolff RA, Lloyd-Salvant K, Bodoky G, Pendergrass K, Berg W, Chen BL, Jalava T, Meinhardt G, Laurent D, Lebwohl D, Kerr D. Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):1997-2003. Epub 2011 Apr 4. link to original article contains verified protocol PubMed
  9. HORIZON II: Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. link to original article contains verified protocol PubMed

mFOLFOX6

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mFOLFOX6: modified FOLinic acid, Fluorouracil, OXaliplatin
OxMdG: Oxaliplatin Modified de Gramont

Example orders

Variant #1, LCV 200 mg/m2

Study Evidence Comparator Efficacy
Wasan et al. 2017 (SIRFLOX; FOXFIRE-Global) Phase III (C) mFOLFOX6 plus SIRT Seems not superior

Note: Wasan et al. 2017 describes the folinic acid as a flat 200 mg dose, but an earlier description of the SIRFLOX protocol uses 200 mg/m2; the authors were contacted for clarification.

Chemotherapy

14-day cycles

Variant #2, LCV 350 mg/m2

Study Evidence Comparator Efficacy
Cheeseman et al. 2002 Non-randomized
Hochster et al. 2008 (TREE-1) Phase III (E) bFOL Seems not superior
CapeOx Seems not superior
Maughan et al. 2011 (UK MRC COIN) Phase III (C) mFOLFOX6 & Cetuximab Seems not superior (*)
Wasan et al. 2017 (FOXFIRE) Phase III (C) OxMdG plus SIRT Seems not superior

Note: Efficacy for UK MRC COIN is as reported for KRAS wild-type patients.

Chemotherapy

14-day cycles

Variant #3, LCV 400 mg/m2

Study Evidence Comparator Efficacy
Hoff et al. 2012 (HORIZON II) Phase III (C) CAPOX & Cediranib
FOLFOX4 & Cediranib
mFOLFOX6 & Cediranib 		Seems to have inferior PFS

Chemotherapy

14-day cycles

Variant #4, levoleucovorin

Study Evidence Comparator Efficacy
Maughan et al. 2011 (UK MRC COIN) Phase III (C) mFOLFOX6 & Cetuximab Seems not superior (*)
Wasan et al. 2017 (FOXFIRE) Phase III (C) OxMdG plus SIRT Seems not superior

Note: Efficacy for UK MRC COIN is as reported for KRAS wild-type patients.

Chemotherapy

14-day cycles

References

  1. Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12;87(4):393-9. link to original article contains verified protocol link to PMC article PubMed
  2. TREE-1: Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. link to original article contains verified protocol PubMed
  3. UK MRC COIN: Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP; MRC COIN Trial Investigators. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011 Jun 18;377(9783):2103-14. Epub 2011 Jun 5. link to original article link to PMC article contains verified protocol PubMed
  4. HORIZON II: Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. link to original article contains verified protocol PubMed
  5. SIRFLOX: van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M, Perez D, Robinson BA, Strickland AH, Ferguson T, Rodríguez J, Kröning H, Wolf I, Ganju V, Walpole E, Boucher E, Tichler T, Shacham-Shmueli E, Powell A, Eliadis P, Isaacs R, Price D, Moeslein F, Taieb J, Bower G, Gebski V, Van Buskirk M, Cade DN, Thurston K, Gibbs P. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2016 May 20;34(15):1723-31. Epub 2016 Feb 22. link to original article PubMed
    1. Pooled update: Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A, van Hazel G, Sharma RA; FOXFIRE/SIRFLOX/FOXFIRE-Global trial investigators. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. Epub 2017 Aug 3. link to original article contains verified protocol PubMed

FOLFOX 7 & sLV5FU2

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FOLFOX 7 & sLV5FU2: FOLinic acid, Fluorouracil, OXaliplatin and simplified LeucoVorin, 5-FU, 2-weekly (every 2 weeks)

Regimen

Study Evidence Comparator Efficacy
Tournigand et al. 2006 (OPTIMOX1) Phase III (E) FOLFOX4 Seems not superior

Chemotherapy, FOLFOX 7 portion

14-day cycle for 6 cycles, until progression of disease or unacceptable toxicity, then proceed to sLV5FU2

Chemotherapy, sLV5FU2 portion

14-day cycle for 12 cycles, until progression of disease or unacceptable toxicity, then resume FOLFOX 7 for 6 additional cycles as described above

References

  1. Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, Mineur L, Carola E, Etienne PL, Rivera F, Chirivella I, Perez-Staub N, Louvet C, André T, Tabah-Fisch I, de Gramont A. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006 Jan 20;24(3):394-400. link to original article contains verified protocol PubMed

FOLFOX4 & Bevacizumab

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FOLFOX4 & Bevacizumab: FOLinic acid, Fluorouracil, OXaliplatin, Bevacizumab
FOLFOX-B: FOLinic acid, Fluorouracil, OXaliplatin, Bevacizumab

Regimen

Study Evidence Comparator Efficacy
Emmanouilides et al. 2007 Phase II
Saltz et al. 2008 (NO16966) Phase III (E) FOLFOX4
XELOX 		Superior PFS
XELOX & Bevacizumab Not reported

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus, then 600 mg/m2/day IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m2)
  • Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
  • Bevacizumab (Avastin) 5 mg/kg IV once on day 1, given first
    • Infusion times are 2 hours for cycle 1, 1 hour for cycle 2, then 30 minutes for cycles 3 and later

14-day cycles

References

  1. Emmanouilides C, Sfakiotaki G, Androulakis N, Kalbakis K, Christophylakis C, Kalykaki A, Vamvakas L, Kotsakis A, Agelaki S, Diamandidou E, Touroutoglou N, Chatzidakis A, Georgoulias V, Mavroudis D, Souglakos J. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. BMC Cancer. 2007 May 30;7:91. link to original article link to PMC article PubMed
  2. Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. link to original article refers to de Gramont et al. 2000 for protocol PubMed

mFOLFOX6 & Bevacizumab

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FOLFOX-B: FOLinic acid, Fluorouracil, OXaliplatin, Bevacizumab

Example orders

Variant #1, standard leucovorin

Study Evidence Comparator Efficacy
Hochster et al. 2008 (TREE-2) Phase III (E) bFOL & Bevacizumab Seems not superior
CapeOx & Bevacizumab Seems not superior
Hecht et al. 2008 (PACCE) Phase III (C) mFOLFOX6 & Bevacizumab & Panitumumab Superior PFS
Saltz et al. 2011 Phase III (C) FOLF-CB Seems not superior
Schmoll et al. 2012 (HORIZON III) Phase III (C) mFOLFOX6 & Cediranib Seems not superior
Yamada et al. 2013 (SOFT) Phase III (C) SOX & Bevacizumab Seems to have non-inferior PFS
Yamazaki et al. 2016 (WJOG4407G) Phase III (E) FOLFIRI & Bevacizumab Non-inferior PFS

This was the most common oxaliplatin-based reigimen used in PACCE.

Chemotherapy

14-day cycles

Variant #2, racemic L-leucovorin

Study Evidence Comparator Efficacy
Yamada et al. 2018 (TRICOLORE) Phase III (C) IRIS & Bevacizumab Non-inferior PFS

Chemotherapy

14-day cycles

References

  1. TREE-2: Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. link to original article contains verified protocol PubMed
  2. PACCE: Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, Marshall J, Cohn A, McCollum D, Stella P, Deeter R, Shahin S, Amado RG. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):672-80. Epub 2008 Dec 29. link to original article PubMed
  3. Saltz L, Badarinath S, Dakhil S, Bienvenu B, Harker WG, Birchfield G, Tokaz LK, Barrera D, Conkling PR, O'Rourke MA, Richards DA, Reidy D, Solit D, Vakiani E, Capanu M, Scales A, Zhan F, Boehm KA, Asmar L, Cohn A. Phase III trial of cetuximab, bevacizumab, and 5-fluorouracil/leucovorin vs FOLFOX-bevacizumab in colorectal cancer. Clin Colorectal Cancer. 2012 Jun;11(2):101-11. Epub 2011 Nov 4. link to original article contains verified protocol PubMed
  4. HORIZON III: Schmoll HJ, Cunningham D, Sobrero A, Karapetis CS, Rougier P, Koski SL, Kocakova I, Bondarenko I, Bodoky G, Mainwaring P, Salazar R, Barker P, Mookerjee B, Robertson J, Van Cutsem E. Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III). J Clin Oncol. 2012 Oct 10;30(29):3588-95. Epub 2012 Sep 10. link to original article PubMed
  5. Observational cohort: Bendell JC, Bekaii-Saab TS, Cohn AL, Hurwitz HI, Kozloff M, Tezcan H, Roach N, Mun Y, Fish S, Flick ED, Dalal D, Grothey A. Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-bevacizumab or FOLFIRI-bevacizumab: results from ARIES, a bevacizumab observational cohort study. Oncologist. 2012;17(12):1486-95. Epub 2012 Sep 26. link to original article link to PMC article PubMed
  6. SOFT: Yamada Y, Takahari D, Matsumoto H, Baba H, Nakamura M, Yoshida K, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1278-86. Epub 2013 Nov 11. Erratum in: Lancet Oncol. 2014 Jan;15(1):e4. link to original article PubMed
  7. SIRFLOX: van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M, Perez D, Robinson BA, Strickland AH, Ferguson T, Rodríguez J, Kröning H, Wolf I, Ganju V, Walpole E, Boucher E, Tichler T, Shacham-Shmueli E, Powell A, Eliadis P, Isaacs R, Price D, Moeslein F, Taieb J, Bower G, Gebski V, Van Buskirk M, Cade DN, Thurston K, Gibbs P. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2016 May 20;34(15):1723-31. Epub 2016 Feb 22. link to original article PubMed
  8. WJOG4407G: Yamazaki K, Nagase M, Tamagawa H, Ueda S, Tamura T, Murata K, Eguchi Nakajima T, Baba E, Tsuda M, Moriwaki T, Esaki T, Tsuji Y, Muro K, Taira K, Denda T, Funai S, Shinozaki K, Yamashita H, Sugimoto N, Okuno T, Nishina T, Umeki M, Kurimoto T, Takayama T, Tsuji A, Yoshida M, Hosokawa A, Shibata Y, Suyama K, Okabe M, Suzuki K, Seki N, Kawakami K, Sato M, Fujikawa K, Hirashima T, Shimura T, Taku K, Otsuji T, Tamura F, Shinozaki E, Nakashima K, Hara H, Tsushima T, Ando M, Morita S, Boku N, Hyodo I. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol. 2016 Aug;27(8):1539-46. Epub 2016 May 13. link to original article PubMed
  9. TRICOLORE: Yamada Y, Denda T, Gamoh M, Iwanaga I, Yuki S, Shimodaira H, Nakamura M, Yamaguchi T, Ohori H, Kobayashi K, Tsuda M, Kobayashi Y, Miyamoto Y, Kotake M, Shimada K, Sato A, Morita S, Takahashi S, Komatsu Y, Ishioka C. S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized, open-label, phase III, noninferiority trial. Ann Oncol. 2018 Mar 1;29(3):624-631. link to original article contains verified protocol PubMed

IFL

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IFL: Irinotecan, Fluorouracil, Leucovorin (Folinic acid)
mIFL: modified Irinotecan, Fluorouracil, Leucovorin (Folinic acid)

Regimen

Study Evidence Comparator Efficacy
Saltz et al. 2000 (Irinotecan Study Group) Phase III (E) 5-FU & Folinic acid Seems to have superior OS
Irinotecan Might have superior OS
Goldberg et al. 2003 Phase III (C) FOLFOX4 Inferior OS
IROX Seems to have inferior OS
Hurwitz et al. 2004 (AVF2107) Phase III (C) FL & Bevacizumab Not reported
IFL & Bevacizumab Inferior OS
Fuchs et al. 2007 (BICC-C) Phase III (E) CapeIRI Seems not superior
FOLFIRI Inferior PFS
Guan et al. 2011 (ARTIST) Phase III (C) mIFL & Bevacizumab Seems to have inferior OS

Note: 5-FU in ARTIST was given over 6 to 8 hours.

Chemotherapy

42-day cycles

References

  1. Irinotecan Study Group: Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. link to original article contains verified protocol PubMed
  2. Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. Epub 2003 Dec 9. link to original article contains verified protocol PubMed
  3. AVF2107: Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. link to original article contains verified protocol PubMed
  4. BICC-C: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article contains verified protocol PubMed
    1. Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article PubMed
  5. ARTIST: Guan ZZ, Xu JM, Luo RC, Feng FY, Wang LW, Shen L, Yu SY, Ba Y, Liang J, Wang D, Qin SK, Wang JJ, He J, Qi C, Xu RH. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer. 2011 Oct;30(10):682-9. link to PMC article contains verified protocol PubMed

IFL & Bevacizumab

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IFL & Bevacizumab: Irinotecan, Fluorouracil, Leucovorin (Folinic acid), Bevacizumab
mIFL & Bevacizumab: modified Irinotecan, Fluorouracil, Leucovorin (Folinic acid), Bevacizumab

Variant #1, IFL

Study Evidence Comparator Efficacy
Hurwitz et al. 2004 (AVF2107) Phase III (E) FL & Bevacizumab Not reported
IFL Superior OS
Fuchs et al. 2007 (BICC-C) Phase III (E) FOLFIRI+Bev Seems to have inferior OS

Chemotherapy

21-day cycles

Variant #2, mIFL

Study Evidence Comparator Efficacy
Guan et al. 2011 (ARTIST) Phase III (E) mIFL Seems to have superior OS

Chemotherapy

42-day cycles

References

  1. AVF2107: Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. link to original article PubMed
  2. BICC-C: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article contains verified protocol PubMed
    1. Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article PubMed
  3. ARTIST: Guan ZZ, Xu JM, Luo RC, Feng FY, Wang LW, Shen L, Yu SY, Ba Y, Liang J, Wang D, Qin SK, Wang JJ, He J, Qi C, Xu RH. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer. 2011 Oct;30(10):682-9. link to PMC article contains verified protocol PubMed

Irinotecan monotherapy

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Example orders

Regimen

Study Evidence Comparator Efficacy
Saltz et al. 2000 (Irinotecan Study Group) Phase III (E) 5-FU & Folinic acid Seems not superior
IFL Might have inferior OS

Chemotherapy

42-day cycles

References

  1. Irinotecan Study Group: Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. link to original article contains verified protocol PubMed

IRIS & Bevacizumab

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IRIS & Bevacizumab: IRInotecan, S-1, Bevacizumab

Variant #1, q3wk

Study Evidence Comparator Efficacy
Yamada et al. 2018 (TRICOLORE) Phase III (E) CapeOx & Bevacizumab
mFOLFOX6 & Bevacizumab 		Non-inferior PFS

Chemotherapy

21-day cycles

Variant #2, q4wk

Study Evidence Comparator Efficacy
Yamada et al. 2018 (TRICOLORE) Phase III (E) CapeOx & Bevacizumab
mFOLFOX6 & Bevacizumab 		Non-inferior PFS

Chemotherapy

28-day cycles

References

  1. TRICOLORE: Yamada Y, Denda T, Gamoh M, Iwanaga I, Yuki S, Shimodaira H, Nakamura M, Yamaguchi T, Ohori H, Kobayashi K, Tsuda M, Kobayashi Y, Miyamoto Y, Kotake M, Shimada K, Sato A, Morita S, Takahashi S, Komatsu Y, Ishioka C. S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized, open-label, phase III, noninferiority trial. Ann Oncol. 2018 Mar 1;29(3):624-631. link to original article contains verified protocol PubMed

IROX

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IROX: IRinotecan & OXaliplatin

Regimen

Study Evidence Comparator Efficacy
Goldberg et al. 2003 Phase III (E) FOLFOX4 Seems not superior
IFL Seems to have superior OS

Chemotherapy

21-day cycles

References

  1. Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. Epub 2003 Dec 9. link to original article contains verified protocol PubMed

Nordic FLOX

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FLOX: Fluorouracil, Leucovorin, OXaliplatin

Example orders

Regimen

Study Evidence Comparator Efficacy
Sørbye et al. 2004 Phase II
Tveit et al. 2012 (NORDIC-VII) Phase III (C) Nordic FLOX & Cetuximab Seems not superior

Chemotherapy

14-day cycle for 8 cycles (NORDIC-VII) or indefinitely (Sørbye et al. 2004)

References

  1. Sørbye H, Glimelius B, Berglund A, Fokstuen T, Tveit KM, Braendengen M, Øgreid D, Dahl O. Multicenter phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):31-8. link to original article contains protocol PubMed
  2. Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, Sigurdsson F, Kure E, Ikdahl T, Skovlund E, Fokstuen T, Hansen F, Hofsli E, Birkemeyer E, Johnsson A, Starkhammar H, Yilmaz MK, Keldsen N, Erdal AB, Dajani O, Dahl O, Christoffersen T. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012 May 20;30(15):1755-62. Epub 2012 Apr 2. link to original article contains verified protocol PubMed
    1. Update: Guren TK, Thomsen M, Kure EH, Sorbye H, Glimelius B, Pfeiffer P, Österlund P, Sigurdsson F, Lothe IMB, Dalsgaard AM, Skovlund E, Christoffersen T, Tveit KM. Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study. Br J Cancer. 2017 May 9;116(10):1271-1278. Epub 2017 Apr 11. link to PMC article PubMed

S-1 monotherapy

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Regimen

Study Evidence Comparator Efficacy Toxicity
Kwakman et al. 2017 (SALTO) Phase III (E) Capecitabine Lower incidence of hand-foot syndrome

Note: this trial had a primary toxicity endpoint.

Chemotherapy

21-day cycles

References

  1. Kwakman JJM, Simkens LHJ, van Rooijen JM, van de Wouw AJ, Ten Tije AJ, Creemers GJM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, van Werkhoven E, Punt CJA. Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group. Ann Oncol. 2017 Jun 1;28(6):1288-1293. link to original article contains protocol PubMed

SOX

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SOX: S-1 & OXaliplatin

Regimen

Study Evidence Comparator Efficacy
Hong et al. 2012 Phase III (E) CapeOX Non-inferior PFS

Chemotherapy

21-day cycle for up to 9 cycles

Subsequent treatment

References

  1. Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. link to original article contains protocol PubMed

Maintenance after first-line therapy

Capecitabine monotherapy

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Regimen

Study Evidence Comparator Efficacy
Hong et al. 2012 Non-randomized portion of RCT
Luo et al. 2016 Phase III (E) Observation Superior PFS

Preceding treatment

Chemotherapy

21-day cycles

References

  1. Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. link to original article contains protocol PubMed
  2. Luo HY, Li YH, Wang W, Wang ZQ, Yuan X, Ma D, Wang FH, Zhang DS, Lin DR, Lin YC, Jia J, Hu XH, Peng JW, Xu RH. Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety. Ann Oncol. 2016 Jun;27(6):1074-81. Epub 2016 Mar 2. link to original article contains verified protocol PubMed

Capecitabine & Bevacizumab

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CAP-B: CAPecitabine & Bevacizumab

Regimen

Study Evidence Comparator Efficacy
Simkens et al. 2015 (CAIRO3) Phase III (E) Observation Superior PFS2

Preceding treatment

Chemotherapy

21-day cycles

References

  1. CAIRO3: Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoeven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, Honkoop AH, Mol L, Punt CJ, Koopman M. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015 May 9;385(9980):1843-52. Epub 2015 Apr 7. link to original article contains verified protocol PubMed
    1. Update: Goey KKH, Elias SG, van Tinteren H, Laclé MM, Willems SM, Offerhaus GJA, de Leng WWJ, Strengman E, Ten Tije AJ, Creemers GM, van der Velden A, de Jongh FE, Erdkamp FLG, Tanis BC, Punt CJA, Koopman M. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann Oncol. 2017 Sep 1;28(9):2128-2134. link to original article PubMed

Observation

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Regimen

Study Evidence Comparator Efficacy
Simkens et al. 2015 (CAIRO3) Phase III (C) CAP-B Inferior PFS2
Luo et al. 2016 Phase III (C) Capecitabine Inferior PFS

No further treatment after first-line induction.

Preceding treatment

References

  1. CAIRO3: Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoeven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, Honkoop AH, Mol L, Punt CJ, Koopman M. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015 May 9;385(9980):1843-52. Epub 2015 Apr 7. link to original article contains verified protocol PubMed
    1. Update: Goey KKH, Elias SG, van Tinteren H, Laclé MM, Willems SM, Offerhaus GJA, de Leng WWJ, Strengman E, Ten Tije AJ, Creemers GM, van der Velden A, de Jongh FE, Erdkamp FLG, Tanis BC, Punt CJA, Koopman M. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann Oncol. 2017 Sep 1;28(9):2128-2134. link to original article PubMed
  2. Luo HY, Li YH, Wang W, Wang ZQ, Yuan X, Ma D, Wang FH, Zhang DS, Lin DR, Lin YC, Jia J, Hu XH, Peng JW, Xu RH. Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety. Ann Oncol. 2016 Jun;27(6):1074-81. Epub 2016 Mar 2. link to original article contains verified protocol PubMed

S-1 monotherapy

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Regimen

Study Evidence
Hong et al. 2012 Non-randomized portion of RCT

Preceding treatment

Chemotherapy

21-day cycles

References

  1. Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. link to original article contains protocol PubMed

Advanced or metastatic disease, second-line therapy

CapeOx

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CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda, OXaliplatin

Example orders

Regimen

Study Evidence Comparator Efficacy
Rothenberg et al. 2008 Phase III (E) FOLFOX4 Non-inferior PFS

Chemotherapy

21-day cycles

References

  1. Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, Gollins S, Siu LL, Laguerre S, Cunningham D. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008 Oct;19(10):1720-6. Epub 2008 Jun 10. link to original article contains verified protocol PubMed

CAPIRI

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CapeIRI: Capecitabine and IRInotecan
CAPIRI: CAPecitabine and IRInotecan
XELIRI: XELox (Capecitabine) and IRInotecan
mXELIRI: modified XELox (Capecitabine) and IRInotecan

Variant #1, "standard"

Study Evidence Comparator Efficacy
Lim et al. 2015 Phase III (C) XELIRI & Simvastatin Seems not superior

Chemotherapy

21-day cycles

Variant #2, "modified"

Study Evidence Comparator Efficacy
Xu et al. 2018 (AXEPT) Phase III (E) FOLFIRI Non-inferior OS

Chemotherapy

21-day cycles

References

  1. Lim SH, Kim TW, Hong YS, Han SW, Lee KH, Kang HJ, Hwang IG, Lee JY, Kim HS, Kim ST, Lee J, Park JO, Park SH, Park YS, Lim HY, Jung SH, Kang WK. A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer. Br J Cancer. 2015 Nov 17;113(10):1421-6. Epub 2015 Oct 27. link to original article contains verified protocol link to PMC article PubMed
  2. AXEPT: Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. link to original article contains verified protocol PubMed

CAPIRI-Bev

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CAPIRI-Bev: CAPecitabine, IRInotecan, Bevacizumab
mXELIRI & Bevacizumab: modified XELox (Capecitabine), IRInotecan, Bevacizumab

Regimen

Study Evidence Comparator Efficacy
Xu et al. 2018 (AXEPT) Phase III (E) FOLFIRI & Bevacizumab Non-inferior OS

Chemotherapy

21-day cycles

References

  1. AXEPT: Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. link to original article contains verified protocol PubMed

FOLFIRI

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Example orders

Variant #1, lower-dose leucovorin

Study Evidence Comparator Efficacy
Lim et al. 2015 Phase III (C) FOLFIRI & Simvastatin Seems not superior

Chemotherapy

  • Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once on day 1, given after irinotecan
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2/day IV continuous infusion over 46 hours on days 1 & 2, given last (total dose per cycle: 2800 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1, given first

14-day cycles

Variant #2, higher-dose leucovorin

Study Evidence Comparator Efficacy
Peeters et al. 2010 Phase III (C) FOLFIRI & Panitumumab Inferior PFS (*)
Van Cutsem et al. 2012 (VELOUR) Phase III (C) FOLFIRI & Ziv-aflibercept Inferior OS
Masi et al. 2015 (BEBYP) Phase III (C) FOLFIRI & Bevacizumab Seems to have inferior OS
Tabernero et al. 2015 (RAISE) Phase III (C) FOLFIRI & Ramucirumab Seems to have inferior OS
Xu et al. 2018 (AXEPT) Phase III (C) CAPIRI Non-inferior OS

Note: BEBYP does not provide dosing details; this is the most commonly used variant of FOLFIRI. Efficacy reported for Peeters et al. 2010 is for wild-type KRAS, only.

Chemotherapy

  • Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, given during irinotecan infusion
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours on days 1 & 2, given last (total dose per cycle: 2800 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first together with leucovorin

14-day cycles

Variant #3, levo-leucovorin

Study Evidence Comparator Efficacy
Xu et al. 2018 (AXEPT) Phase III (C) CAPIRI Non-inferior OS

Chemotherapy

  • Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given during irinotecan infusion
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours on days 1 & 2, given last (total dose per cycle: 2800 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1, given first together with levo-leucovorin

14-day cycles

References

  1. Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15;22(2):229-37. Epub 2003 Dec 2. link to original article PubMed
  2. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010 Nov 1;28(31):4706-13. Epub 2010 Oct 4. link to original article contains verified protocol PubMed
  3. VELOUR: Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012 Oct 1;30(28):3499-506. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Tabernero J, Van Cutsem E, Lakomý R, Prausová J, Ruff P, van Hazel GA, Moiseyenko VM, Ferry DR, McKendrick JJ, Soussan-Lazard K, Chevalier S, Allegra CJ. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014 Jan;50(2):320-31. link to original article PubMed
  4. BEBYP: Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-30. Epub 2015 Jan 18. link to original article does not contain protocol PubMed
  5. RAISE: Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F; RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 May;16(5):499-508. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. link to original article contains verified protocol PubMed
  6. Lim SH, Kim TW, Hong YS, Han SW, Lee KH, Kang HJ, Hwang IG, Lee JY, Kim HS, Kim ST, Lee J, Park JO, Park SH, Park YS, Lim HY, Jung SH, Kang WK. A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer. Br J Cancer. 2015 Nov 17;113(10):1421-6. Epub 2015 Oct 27. link to original article contains verified protocol link to PMC article PubMed
  7. AXEPT: Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. link to original article contains verified protocol PubMed

FOLFIRI & Bevacizumab

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FOLFIRI & Bevacizumab: FOLinic acid, Fluorouracil, IRInotecan, Bevacizumab

Variant #1

Study Evidence Comparator Efficacy
Bennouna et al. 2012 (ML18147) Phase III (E) FOLFIRI Superior OS
Masi et al. 2015 (BEBYP) Phase III (E) FOLFIRI Seems to have superior OS
Xu et al. 2018 (AXEPT) Phase III (C) mXELIRI & Bevacizumab Non-inferior OS

Note: the abstract of ML18147 does not specify the exact type of chemotherapy; patients had to be previously bevacizumab-exposed. BEBYP does not provide dosing details; this is the most commonly used variant of FOLFIRI.

Chemotherapy

14-day cycles

Variant #2, levo-leucovorin

Study Evidence Comparator Efficacy
Xu et al. 2018 (AXEPT) Phase III (C) mXELIRI & Bevacizumab Non-inferior OS

Chemotherapy

14-day cycles

References

  1. ML18147: Bennouna J, Sastre J, Arnold D, Österlund P, Greil R, Van Cutsem E, von Moos R, Viéitez JM, Bouché O, Borg C, Steffens CC, Alonso-Orduña V, Schlichting C, Reyes-Rivera I, Bendahmane B, André T, Kubicka S; ML18147 Study Investigators. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013 Jan;14(1):29-37. Epub 2012 Nov 16. link to original article PubMed
  2. BEBYP: Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-30. Epub 2015 Jan 18. link to original article does not contain protocol PubMed
  3. AXEPT: Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. link to original article contains verified protocol PubMed

FOLFIRI & Ramucirumab

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FOLFIRI & Ramucirumab: FOLinic acid, Fluorouracil, IRInotecan & Ramucirumab

Regimen

FDA-recommended dose
Study Evidence Comparator Efficacy
Tabernero et al. 2015 (RAISE) Phase III (E) FOLFIRI Seems to have superior OS

Chemotherapy

  • Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, either given third or concurrently with irinotecan
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus over 2 to 4 minutes once on day 1, then 2400 mg/m2 IV continuous infusion over 48 hours on days 1 to 2, given last (total dose per cycle: 2800 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1, given second
  • Ramucirumab (Cyramza) 8 mg/kg IV over 60 minutes once on day 1, given first

14-day cycles

References

  1. RAISE: Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F; RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 May;16(5):499-508. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. link to original article contains verified protocol PubMed

FOLFIRI & Ziv-aflibercept

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FOLFIRI & Ziv-aflibercept: FOLinic acid, Fluorouracil, IRInotecan, Ziv-aflibercept

Regimen

Study Evidence Comparator Efficacy
Van Cutsem et al. 2012 (VELOUR) Phase III (E) FOLFIRI Superior OS

Chemotherapy

Supportive medications

14-day cycles

References

  1. VELOUR: Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012 Oct 1;30(28):3499-506. link to original article PubMed
    1. Subgroup analysis: Tabernero J, Van Cutsem E, Lakomý R, Prausová J, Ruff P, van Hazel GA, Moiseyenko VM, Ferry DR, McKendrick JJ, Soussan-Lazard K, Chevalier S, Allegra CJ. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014 Jan;50(2):320-31. link to original article contains verified protocol PubMed

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Evidence Comparator Efficacy
Rothenberg et al. 2003 Phase III (E) LV5FU2
Oxaliplatin 		Superior TTP
Rothenberg et al. 2008 Phase III (E) XELOX Non-inferior PFS

Chemotherapy

14-day cycles

References

  1. Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, Hart LL, Gupta S, Garay CA, Burger BG, Le Bail N, Haller DG. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol. 2003 Jun 1;21(11):2059-69. link to original article contains verified protocol PubMed
  2. Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, Gollins S, Siu LL, Laguerre S, Cunningham D. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008 Oct;19(10):1720-6. Epub 2008 Jun 10. link to original article refers to de Gramont et al. 2000 protocol PubMed

mFOLFOX6

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mFOLFOX6: modified FOLinic acid, Fluorouracil, OXaliplatin

Example orders

Regimen

Study Evidence Comparator Efficacy
Masi et al. 2015 (BEBYP) Phase III (C) mFOLFOX6 & Bevacizumab Seems to have inferior OS

Note: BEBYP does not provide dosing details; this is the most commonly used variant of mFOLFOX6.

Chemotherapy

14-day cycles

References

  1. BEBYP: Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-30. Epub 2015 Jan 18. link to original article does not contain protocol PubMed

mFOLFOX6 & Bevacizumab

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mFOLFOX6 & Bevacizumab: modified FOLinic acid, Fluorouracil, OXaliplatin, Bevacizumab

Regimen

Study Evidence Comparator Efficacy
Masi et al. 2015 (BEBYP) Phase III (E) mFOLFOX6 Seems to have superior OS

Note: BEBYP does not provide dosing details; this is the most commonly used variant of mFOLFOX6.

Chemotherapy

14-day cycles

References

  1. BEBYP: Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-30. Epub 2015 Jan 18. link to original article does not contain protocol PubMed

Irinotecan monotherapy

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Example orders

Variant #1, 125 mg/m2, 4 weeks out of 6

Study Evidence Comparator Efficacy
Fuchs et al. 2003 Phase III (E) Irinotecan every 3 weeks Seems not superior

Note: In contrast to what is described here, some guidelines list irinotecan as being given on days 1 & 8 of a 21-day cycle. No primary reference could be found for this.

Chemotherapy

42-day cycles

Variant #2, 250 mg/m2 q3wk

Study Evidence Comparator Efficacy
Haller et al. 2008 Phase III (C) IROX Inferior OS

This starting dose was intended for patients who were at least 65 years old, had prior abdomen/pelvic radiation, or had elevated bilirubin. Dose escalations in the absence of grade 2 or higher toxicities were allowed.

Chemotherapy

21-day cycles

Variant #3, 300 mg/m2 q3wk

Study Evidence Comparator Efficacy
Rougier et al. 1998 Phase III (E) Continuous 5-FU Seems to have superior OS
Fuchs et al. 2003 Phase III (E) Irinotecan 4 weeks out of 6 Seems not superior
Sobrero et al. 2008 (EPIC) Phase III (C) Irinotecan & Cetuximab Seems not superior
Kim et al. 2009 (N9841) Phase III (C) FOLFOX4 Non-inferior OS
Seymour et al. 2013 (PICCOLO) Phase III (C) Irinotecan & Panitumumab Seems not superior

Note: This was the lower bound of the dosing range described by Rougier et al. 1998. In some trials, this starting dose was intended for patients who were at least 70 years old, had ECOG performance status 2 or more, or had prior pelvic radiation. Patients in N9841 had not previously received irinotecan or oxaliplatin.

Chemotherapy

21-day cycles

Variant #4, 350 mg/m2 q3wk

Study Evidence Comparator Efficacy
Rougier et al. 1998 Phase III (E) Continuous 5-FU Seems to have superior OS
Fuchs et al. 2003 Phase III (E) Irinotecan 4 weeks out of 6 Seems not superior
Sobrero et al. 2008 (EPIC) Phase III (C) Irinotecan & Cetuximab Seems not superior
Haller et al. 2008 Phase III (C) IROX Inferior OS
Kim et al. 2009 (N9841) Phase III (C) FOLFOX4 Non-inferior OS
Seymour et al. 2013 (PICCOLO) Phase III (C) Irinotecan & Cyclosporine
Irinotecan & Panitumumab 		Seems not superior

Note: This was the upper bound of the dosing range described by Rougier et al. 1998. Patients in N9841 had not previously received irinotecan or oxaliplatin.

Chemotherapy

Supportive medications

21-day cycles

References

  1. Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Awad L, Herait P, Jacques C. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1407-12. Erratum in: Lancet 1998 Nov 14;352(9140):1634. link to original article contains protocol PubMed
  2. Fuchs CS, Moore MR, Harker G, Villa L, Rinaldi D, Hecht JR. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003 Mar 1;21(5):807-14. link to original article contains verified protocol PubMed
  3. EPIC: Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kröning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008 May 10;26(14):2311-9. Epub 2008 Apr 7. link to original article contains verified protocol PubMed
  4. Haller DG, Rothenberg ML, Wong AO, Koralewski PM, Miller WH Jr, Bodoky G, Habboubi N, Garay C, Olivatto LO. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008 Oct 1;26(28):4544-50. link to original article contains verified protocol PubMed
  5. N9841: Kim GP, Sargent DJ, Mahoney MR, Rowland KM Jr, Philip PA, Mitchell E, Mathews AP, Fitch TR, Goldberg RM, Alberts SR, Pitot HC. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol. 2009 Jun 10;27(17):2848-54. Epub 2009 Apr 20. link to original article link to PMC article contains verified protocol PubMed
  6. PICCOLO: Seymour MT, Brown SR, Middleton G, Maughan T, Richman S, Gwyther S, Lowe C, Seligmann JF, Wadsley J, Maisey N, Chau I, Hill M, Dawson L, Falk S, O'Callaghan A, Benstead K, Chambers P, Oliver A, Marshall H, Napp V, Quirke P. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013 Jul;14(8):749-59. Epub 2013 May 29. link to original article link to PMC article contains verified protocol PubMed

IRIS

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IRIS IRInotecan & S-1

Regimen

Study Evidence Comparator Efficacy
Muro et al. 2010 (FIRIS) Phase III (E) FOLFIRI Non-inferior PFS

Chemotherapy

28-day cycles

References

  1. FIRIS: Muro K, Boku N, Shimada Y, Tsuji A, Sameshima S, Baba H, Satoh T, Denda T, Ina K, Nishina T, Yamaguchi K, Takiuchi H, Esaki T, Tokunaga S, Kuwano H, Komatsu Y, Watanabe M, Hyodo I, Morita S, Sugihara K. Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study). Lancet Oncol. 2010 Sep;11(9):853-60. Epub 2010 Aug 12. link to SD article contains verified protocol PubMed

IROX

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IROX: IRinotecan & OXaliplatin

Regimen

Study Evidence Comparator Efficacy
Haller et al. 2008 Phase III (E) Irinotecan Superior OS

Chemotherapy

21-day cycles

References

  1. Haller DG, Rothenberg ML, Wong AO, Koralewski PM, Miller WH Jr, Bodoky G, Habboubi N, Garay C, Olivatto LO. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008 Oct 1;26(28):4544-50. link to original article contains verified protocol PubMed

Advanced or metastatic disease, third-line therapy

FOLFIRI

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Example orders

Regimen

Study Evidence
André et al. 1999 Non-randomized

Chemotherapy

  • Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, given during irinotecan infusion
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours on days 1 & 2, given last (total dose per cycle: 2800 mg/m2)
    • In André et al. 1999, the continuous infusion dose could be increased from 1200 mg/m2/day to 1500 mg/m2/day if there were no toxicities higher than grade 1
  • Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first together with leucovorin

14-day cycles

References

  1. André T, Louvet C, Maindrault-Goebel F, Couteau C, Mabro M, Lotz JP, Gilles-Amar V, Krulik M, Carola E, Izrael V, de Gramont A. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer; GERCOR. Eur J Cancer. 1999 Sep;35(9):1343-7. link to original article contains verified protocol PubMed

Advanced or metastatic disease, subsequent lines of therapy

Note: these are trials that are for lines other than first-line; trials restricted to second-line or third-line therapy are to be found in the sections above.

Best supportive care

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Regimen

Study Evidence Comparator Efficacy
Cunningham et al. 1998 Phase III (C) Irinotecan Inferior OS
Van Cutsem et al. 2007 Phase III (C) Panitumumab Inferior PFS
Jonker et al. 2007 (NCIC CTG CO.17) Phase III (C) Cetuximab Inferior OS
Kim et al. 2016 (20100007) Phase III (C) Panitumumab Inferior OS

No treatment except for supportive care.

References

  1. Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1413-8. link to original article contains verified protocol PubMed
  2. Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1;25(13):1658-64. link to original article contains verified protocol PubMed
  3. Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007 Nov 15;357(20):2040-8. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Asmis TR, Powell E, Karapetis CS, Jonker DJ, Tu D, Jeffery M, Pavlakis N, Gibbs P, Zhu L, Dueck DA, Whittom R, Langer C, O'Callaghan CJ. Comorbidity, age and overall survival in cetuximab-treated patients with advanced colorectal cancer (ACRC)--results from NCIC CTG CO.17: a phase III trial of cetuximab versus best supportive care. Ann Oncol. 2011 Jan;22(1):118-26. Epub 2010 Jul 5. link to original article contains verified protocol PubMed
  4. 20100007: Kim TW, Elme A, Kusic Z, Park JO, Udrea AA, Kim SY, Ahn JB, Valencia RV, Krishnan S, Bilic A, Manojlovic N, Dong J, Guan X, Lofton-Day C, Jung AS, Vrdoljak E. A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer. Br J Cancer. 2016 Nov 8;115(10):1206-1214. Epub 2016 Oct 13. link to original article link to PMC article PubMed

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Variant #1, racemic leucovorin

Study Evidence Comparator Efficacy
Giantonio et al. 2007 (ECOG E3200) Phase III (C) FOLFOX4 & Bevacizumab Inferior OS
Bevacizumab Not reported
Kim et al. 2009 (N9841) Phase III (E) Irinotecan Non-inferior OS
Van Cutsem et al. 2011 Phase III (C) FOLFOX4 & Vatalanib Seems not superior

Note: patients in N9841 had not previously received irinotecan or oxaliplatin; patients in Van Cutsem et al. 2011 had not previously received oxaliplatin.

Chemotherapy

14-day cycles

Variant #2, L-leucovorin

Study Evidence Comparator Efficacy
Van Cutsem et al. 2011 Phase III (C) FOLFOX4 & Vatalanib Seems not superior

Note: these patients had not previously received oxaliplatin.

Chemotherapy

14-day cycles

References

  1. ECOG E3200: Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd; Eastern Cooperative Oncology Group Study E3200. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007 Apr 20;25(12):1539-44. link to original article contains verified protocol PubMed
  2. N9841: Kim GP, Sargent DJ, Mahoney MR, Rowland KM Jr, Philip PA, Mitchell E, Mathews AP, Fitch TR, Goldberg RM, Alberts SR, Pitot HC. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol. 2009 Jun 10;27(17):2848-54. Epub 2009 Apr 20. link to original article link to PMC article contains verified protocol PubMed
  3. Van Cutsem E, Bajetta E, Valle J, Köhne CH, Hecht JR, Moore M, Germond C, Berg W, Chen BL, Jalava T, Lebwohl D, Meinhardt G, Laurent D, Lin E. Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):2004-10. Epub 2011 Apr 4. link to original article contains verified protocol PubMed

FOLFOX4 & Bevacizumab

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FOLFOX4 & Bevacizumab: FOLinic acid, Fluorouracil, OXaliplatin, Bevacizumab

Regimen

Study Evidence Comparator Efficacy
Giantonio et al. 2007 (ECOG E3200) Phase III (E) FOLFOX4 Superior OS
Bevacizumab Not reported

Chemotherapy

14-day cycles

References

  1. ECOG E3200: Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd; Eastern Cooperative Oncology Group Study E3200. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007 Apr 20;25(12):1539-44. link to original article contains verified protocol PubMed

Irinotecan monotherapy

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Example orders

Regimen

Study Evidence Comparator Efficacy
Cunningham et al. 1998 Phase III (E) Supportive care Superior OS

Chemotherapy

Supportive medications

21-day cycles

References

  1. Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1413-8. link to original article contains verified protocol PubMed

Pembrolizumab monotherapy

Pembrolizumab (Keytruda) for unresectable or metastatic colon cancer

Placebo

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Regimen

Study Evidence Comparator Efficacy
Yoshino et al. 2012 Randomized Phase II (C) Trifluridine and tipiracil Inferior OS
Grothey et al. 2013 (CORRECT) Phase III (C) Regorafenib Inferior OS
Li et al. 2015 (CONCUR) Phase III (C) Regorafenib Inferior OS
Mayer et al. 2015 (RECOURSE) Phase III (C) Trifluridine and tipiracil Inferior OS
Hickish et al. 2017 Phase III (C) MABp1 Inferior primary endpoint
Xu et al. 2017 (TERRA) Phase III (C) Trifluridine and tipiracil Seems to have inferior OS
Jonker et al. 2018 (NCIC CTG CO.23) Phase III (C) Napabucasin Seems not superior
Li et al. 2018 (FRESCO) Phase III (C) Fruquintinib Inferior OS

No active antineoplastic treatment.

References

  1. Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, Tsuji A, Yamaguchi K, Muro K, Sugimoto N, Tsuji Y, Moriwaki T, Esaki T, Hamada C, Tanase T, Ohtsu A. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2012 Oct;13(10):993-1001. Epub 2012 Aug 28. link to original article contains protocol PubMed
  2. CORRECT: Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. link to original article contains verified protocol PubMed
  3. CONCUR: Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L, Yeh KH, Bi F, Cheng Y, Le AT, Lin JK, Liu T, Ma D, Kappeler C, Kalmus J, Kim TW; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):619-29. Epub 2015 May 13. link to original article PubMed
  4. RECOURSE: Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14;372(20):1909-19. link to original article contains verified protocol PubMed
  5. Hickish T, Andre T, Wyrwicz L, Saunders M, Sarosiek T, Kocsis J, Nemecek R, Rogowski W, Lesniewski-Kmak K, Petruzelka L, Apte RN, Mohanty P, Stecher M, Simard J, de Gramont A. MABp1 as a novel antibody treatment for advanced colorectal cancer: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2017 Feb;18(2):192-201. Epub 2017 Jan 14. link to original article PubMed
  6. TERRA: Xu J, Kim TW, Shen L, Sriuranpong V, Pan H, Xu R, Guo W, Han SW, Liu T, Park YS, Shi C, Bai Y, Bi F, Ahn JB, Qin S, Li Q, Wu C, Ma D, Lin D, Li J. Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: The TERRA study. J Clin Oncol. 2018 Feb 1;36(4):350-358. Epub 2017 Dec 7. link to original article contains verified protocol PubMed
  7. NCIC CTC CO.23: Jonker DJ, Nott L, Yoshino T, Gill S, Shapiro J, Ohtsu A, Zalcberg J, Vickers MM, Wei AC, Gao Y, Tebbutt NC, Markman B, Price T, Esaki T, Koski S, Hitron M, Li W, Li Y, Magoski NM, Li CJ, Simes J, Tu D, O'Callaghan CJ. Napabucasin versus placebo in refractory advanced colorectal cancer: a randomised phase 3 trial. Lancet Gastroenterol Hepatol. 2018 Apr;3(4):263-270. Epub 2018 Feb 1. link to original article PubMed
  8. FRESCO: Li J, Qin S, Xu RH, Shen L, Xu J, Bai Y, Yang L, Deng Y, Chen ZD, Zhong H, Pan H, Guo W, Shu Y, Yuan Y, Zhou J, Xu N, Liu T, Ma D, Wu C, Cheng Y, Chen D, Li W, Sun S, Yu Z, Cao P, Chen H, Wang J, Wang S, Wang H, Fan S, Hua Y, Su W. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018 Jun 26;319(24):2486-2496. link to original article PubMed

Regorafenib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Grothey et al. 2013 (CORRECT) Phase III (E) Best supportive care Superior OS
Li et al. 2015 (CONCUR) Phase III (E) Best supportive care Superior OS

Chemotherapy

  • Regorafenib (Stivarga) 160 mg PO once per day on days 1 to 21, taken with a low-fat (less than 30% fat) breakfast

28-day cycles

References

  1. CORRECT: Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. link to original article contains verified protocol PubMed
  2. CONCUR: Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L, Yeh KH, Bi F, Cheng Y, Le AT, Lin JK, Liu T, Ma D, Kappeler C, Kalmus J, Kim TW; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):619-29. Epub 2015 May 13. link to original article PubMed

Trifluridine and tipiracil monotherapy

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Regimen

Study Evidence Comparator Efficacy
Yoshino et al. 2012 Randomized Phase II (E) Placebo Superior OS
Mayer et al. 2015 (RECOURSE) Phase III (E) Placebo Superior OS
Xu et al. 2017 (TERRA) Phase III (E) Placebo Seems to have superior OS

Chemotherapy

28-day cycles

References

  1. Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, Tsuji A, Yamaguchi K, Muro K, Sugimoto N, Tsuji Y, Moriwaki T, Esaki T, Hamada C, Tanase T, Ohtsu A. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2012 Oct;13(10):993-1001. Epub 2012 Aug 28. link to original article contains verified protocol PubMed
  2. RECOURSE: Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14;372(20):1909-19. link to original article contains verified protocol PubMed
  3. TERRA: Xu J, Kim TW, Shen L, Sriuranpong V, Pan H, Xu R, Guo W, Han SW, Liu T, Park YS, Shi C, Bai Y, Bi F, Ahn JB, Qin S, Li Q, Wu C, Ma D, Lin D, Li J. Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: The TERRA study. J Clin Oncol. 2018 Feb 1;36(4):350-358. Epub 2017 Dec 7. link to original article contains verified protocol PubMed
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