Colon cancer

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45 regimens on this page
71 variants on this page

Contents


Guidelines

ESMO

NCCN

Adjuvant therapy

Capecitabine monotherapy

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Regimen

Study Evidence Comparator Efficacy
Twelves et al. 2005 Phase III 5-FU & Leucovorin Non-inferior DFS
Kerr et al. 2016 (QUASAR 2) Phase III Capecitabine & Bevacizumab Seems not superior

Chemotherapy

21-day cycle for 8 cycles

References

  1. Twelves C, Wong A, Nowacki MP, Abt M, Burris H 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
  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; XELOX

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

Example orders

Regimen #1

Study Evidence Comparator Efficacy
Haller et al. 2011 (XELOXA) Phase III 5-FU & Leucovorin Seems to have superior OS

Note: This is the same as described by Schmoll et al. 2007, but the schedule for capecitabine is slightly different.

Chemotherapy

21-day cycle for 8 cycles

Regimen #2, "XELOX"

Study Evidence Comparator Efficacy
Schmoll et al. 2007 (XELOXA) Phase III 5-FU & Leucovorin Seems to have superior OS

Note: This is the same as described by Haller et al. 2011, but the schedule for capecitabine is slightly different.

Chemotherapy

21-day cycle for 8 cycles

References

  1. 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

Fluorouracil & Folinic acid

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Example orders

Regimen #1, 5-FU & high-dose Leucovorin (Roswell Park regimen/HDLV)

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

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

Regimen #2, 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV)

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

Chemotherapy

28-day cycle for 6 cycles

Regimen #3, 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV)

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

Chemotherapy

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

Regimen #4, LV5FU2

Study Evidence Comparator Efficacy
André et al. 2004 (MOSAIC) Phase III FOLFOX 4 Seems to have inferior OS (*)

Reported efficacy is based on 2009 updated results.

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

References

  1. 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. 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 articlePubMed
  4. Twelves C, Wong A, Nowacki MP, Abt M, Burris H 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
  5. 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
  6. 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
  7. 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
  8. 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

Fluorouracil, Folinic acid, Levamisole

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Regimen

Study Evidence Comparator Efficacy
Haller et al. 2005 (Intergroup 0089) Phase III High-dose 5-FU & Folinic acid Seems not superior
Low-dose 5-FU & Folinic acid Seems not superior
5-FU & Levamisole Seems not superior

Not in routine use; used as a comparator arm and here for reference purposes only.

Chemotherapy

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

References

  1. 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

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 5-FU & Leucovorin Superior DFS

Chemotherapy

8-week cycle for 3 cycles

References

  1. 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

FOLFOX 4

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FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin
Also known as FOLFOX4.

Regimen

Study Evidence Comparator Efficacy
André et al. 2004 (MOSAIC) Phase III 5-FU & Folinic acid Seems to have superior OS (*)

Reported efficacy is based on the 2009 update.

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 (both bolus and continuous infusion are given on days 1 & 2)
  • 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. 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 articlePubMed
  2. 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

mFOLFOX 6

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mFOLFOX: modified FOLinic acid, Fluorouracil, OXaliplatin

Example orders

Regimen

Study Evidence Comparator Efficacy
Allegra et al. 2009 (NSABP C-08) Phase III mFOLFOX 6 & Bevacizumab Seems not superior
Alberts et al. 2012 Phase III mFOLFOX 6 & Cetuximab Might have superior DFS

Chemotherapy

14-day cycle for 12 cycles, to start within 10 weeks of surgery

References

  1. 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. 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

mFOLFOX 6 & Bevacizumab

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FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Evidence Comparator Efficacy
Allegra et al. 2009 (NSABP C-08) Phase III mFOLFOX 6 Seems not superior

Note: this was a negative study. The NCCN, Colon Cancer version 1.2015, does not recommend using bevacizumab as adjuvant therapy outside of a clinical trial.

Chemotherapy

14-day cycle for 12 cycles, to start within 10 weeks of surgery

References

  1. 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

mFOLFOX 6 & Cetuximab

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FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin

The NCCN, Colon Cancer version 1.2015, does not recommend using cetuximab as adjuvant therapy outside of a clinical trial.

Regimen

Study Evidence Comparator Efficacy
Alberts et al. 2012 Phase III mFOLFOX 6 Might have inferior DFS

Chemotherapy

14-day cycle for 12 cycles, to start within 10 weeks of surgery

References

  1. 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

MOF

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MOF: MeCCNU (Lomustine), Oncovin (Vincristine), Fluorouracil

Regimen

Study Evidence Comparator Efficacy
Wolmark et al. 1993 (NSABP C-03) Phase III 5-FU & LV Inferior OS

Note: here for historical reference purposes, only.

Chemotherapy

References

  1. 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

Observation

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Regimen

Study Evidence Comparator Efficacy
O'Connell et al. 1997 Phase III 5-FU & Leucovorin Seems to have inferior OS
Hasegawa et al. 2016 Phase III Tegafur, Uracil, Leucovorin Inferior RFS

No treatment after surgery; used as a comparator arm and here for reference purposes only.

References

  1. 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
  2. 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 articlelink to PMC article contains verified protocol PubMed

Tegafur, Uracil, Folinic acid

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Regimen #1

Study Evidence Comparator Efficacy
Hasegawa et al. 2016 Phase III Observation Superior RFS

Note: it is not clear from the manuscript whether doses were split or taken once per day. Treatment started no later than 8 weeks after surgical resection of colorectal cancer liver metastases.

Chemotherapy

35-day cycle for 5 cycles

Regimen #2

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

Treatment preceded by a potentially curative resection of stage II or stage III colon cancer.

Chemotherapy

35-day cycle for 5 cycles

References

  1. 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. 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 articlelink to PMC article contains verified protocol PubMed

Advanced or metastatic disease, first-line

Bevacizumab & Capecitabine

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Regimen #1

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

Chemotherapy

21-day cycles

Regimen #2

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

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

Chemotherapy

21-day cycles

References

  1. 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
  2. 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

Capecitabine monotherapy

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Regimen

Study Evidence Comparator Efficacy
Hoff et al. 2001 Phase III 5-FU + Folinic acid Superior ORR
Van Cutsem et al. 2001 Phase III 5-FU + Folinic acid Seems not superior
Cunningham et al. 2013 (AVEX) Phase III Bevacizumab & Capecitabine Inferior PFS

Note: The NCCN, Colon Cancer version 1.2015, lists Capecitabine (Xeloda) 850 to 1250 mg/m2 as the dosage range. No primary reference for the lower monotherapy dosages could be found.

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
  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
  3. 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

CapeOx (XELOX)

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CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda, OXaliplatin

Example orders

Regimen #1

Study Evidence Comparator Efficacy
Cassidy et al. 2008 Phase III FOLFOX 4
FOLFOX 4 & Bevacizumab
Non-inferior PFS
XELOX & Bevacizumab Not reported
Hong et al. 2012 Phase III SOX Non-inferior PFS

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, given until progression of disease, or unacceptable toxicity; Cassidy et al. 2008 & Saltz et al. 2008 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

Regimen #2

Study Evidence Comparator Efficacy
Hochster et al. 2008 (TREE-1) Phase III 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 Hochster et al. 2008 (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, given until progression of disease or unacceptable toxicity

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 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 PubMed
  3. 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
  4. 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
  5. 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
  6. 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 PubMed
  7. 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 PubMed

CapeOx (XELOX) & Bevacizumab

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CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda, OXaliplatin

Regimen #1

Study Evidence Comparator Efficacy
Cassidy et al. 2008 Phase III FOLFOX 4
FOLFOX 4 & Bevacizumab
Non-inferior PFS
XELOX Not reported

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
  • Bevacizumab (Avastin) 7.5 mg/kg IV over 30 to 90 minutes once on day 1, given before oxaliplatin

21-day cycles, given until progression of disease, or unacceptable toxicity; Cassidy et al. 2008 & Saltz et al. 2008 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

Regimen #2

Study Evidence Comparator Efficacy
Hochster et al. 2008 (TREE-2) Phase III 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 Hochster et al. 2008 (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, given until progression of disease or unacceptable toxicity

References

  1. 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
  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 contains verified protocol PubMed
  3. 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

CAPIRI; XELIRI

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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 FOLFIRI Seems to have inferior PFS
mIFL Seems not superior
Moehler et al. 2009 Phase II

Chemotherapy

3-week 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

Regimen #1

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

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

Chemotherapy

3-week cycles

Regimen #2

Study Evidence
Moehler et al. 2009 Phase II

Chemotherapy

3-week 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

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

Regimen #1, "Roswell Park regimen"

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

Chemotherapy

8-week cycles

Regimen #2, "Mayo Clinic regimen"

Study Evidence Comparator Efficacy
de Gramont et al. 1997 Phase III LV5FU2 Inferior PFS
Saltz et al. 2000 (Irinotecan Study Group) Phase III IFL Seems to have inferior OS
Irinotecan Seems not superior
Hoff et al. 2001 Phase III Capecitabine Inferior ORR
Van Cutsem et al. 2001 Phase III Capecitabine Seems not superior

Chemotherapy

28-day cycles

Regimen #3, LV5FU2

Study Evidence Comparator Efficacy
de Gramont et al. 1997 Phase III Mayo Clinic Regimen Superior PFS
de Gramont et al. 2000 Phase III FOLFOX 4 Inferior PFS

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

Regimen #4

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

Chemotherapy

7-day cycles

Regimen #5

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

Chemotherapy

7-day cycles

Regimen #6, "Modified de Gramont"

Study Evidence
Cheeseman et al. 2002 Non-randomized

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

Regimen #7, sLV5FU2

Study Evidence
André et al. 1999 Non-randomized

Note: this publication actually describes FOLFIRI, which is built on top of the sLV5FU2 backbone; no primary publication has yet been identified.

Chemotherapy

  • Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, given first
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, given after leucovorin, then 1200 mg/m2/day IV continuous infusion over 46 to 48 hours on days 1 to 2 (total dose per cycle: 2400 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 A. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. 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. 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
  4. 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
  5. 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
  6. 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 plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000 Sep 28;343(13):905-14. link to original article contains verified protocol PubMed
  7. 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
  8. 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
  9. 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
  10. 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

FOLFIRI

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Example orders

Regimen

Study Evidence Comparator Efficacy
André et al. 1999 Non-randomized
Fuchs et al. 2007 (BICC-C) Phase III CapeIRI Seems to have superior PFS
mIFL Superior PFS

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 1200 mg/m2/day IV continuous infusion over 46 to 48 hours on days 1 & 2, given last (total dose per cycle: 2400 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

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 PubMed
  2. 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
  3. 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
  4. 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 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. 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

FOLFIRI & Bevacizumab

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Regimen #1

Study Evidence Comparator Efficacy
Fuchs et al. 2007 (BICC-C) Phase III mIFL & Bevacizumab Superior OS

Chemotherapy

14-day cycles

Regimen #2

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

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

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 (TRIBE) did not provide specific details about the maintenance therapy.

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. 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. 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. 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

FOLFIRI & Cetuximab

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Regimen

Study Evidence Comparator Efficacy
Van Cutsem et al. 2009 (CRYSTAL) Phase III FOLFIRI Seems to have superior PFS

Note: the benefit of cetuximab in this trial was limited to patients with KRAS wild-type tumors.

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 1200 mg/m2/day IV continuous infusion over 46 hours on days 1 to 2, given last (total dose per cycle: 2400 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given 1 hour after completion of cetuximab
  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 60 minutes on day 8
    • Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once per day on days 1 & 8
      • Cetuximab is given first and infusion is to finish 1 hour before FOLFIRI begins

14-day cycles, given until progression of disease or unacceptable toxicity

References

  1. 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. 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
  2. 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

FOLFOX 4

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FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin
Also known as FOLFOX4.

Regimen

Study Evidence Comparator Efficacy
de Gramont et al. 2000 Phase III 5-FU & Folinic acid Superior PFS
Tournigand et al. 2006 (OPTIMOX1) Phase III FOLFOX 7 Seems not superior
Cassidy et al. 2008 Phase III FOLFOX 4 & Bevacizumab Not reported
XELOX
XELOX & Bevacizumab
Non-inferior PFS

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 (both bolus and continuous infusion are given on days 1 & 2)
  • 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 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. 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
  3. 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
  4. 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
  5. 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, B?asin'ska-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

mFOLFOX 6

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FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin

Example orders

Regimen #1

Study Evidence Comparator Efficacy
Cheeseman et al. 2002 Non-randomized
Hochster et al. 2008 (TREE-1) Phase III bFOL Seems not superior
CapeOx Seems not superior

Chemotherapy

14-day cycles

Regimen #2

Study Evidence Comparator Efficacy
See note Phase III See note

Note: Neither of the references cited by the NCCN, Colon Cancer version 1.2015, contained this 400 mg/m2 dosage of leucovorin. The two references listed here (Boccia et al. 2010 & Saltz et al. 2011) contain the 400 mg/m2 dosage, but mFOLFOX 6 is in combination with cetuximab and/or bevacizumab. No primary reference for this dosage of mFOLFOX 6 by itself could be found.

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. 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. Boccia RV, Cosgriff TM, Headley DL, Badarinath S, Dakhil SR. A phase II trial of FOLFOX6 and cetuximab in the first-line treatment of patients with metastatic colorectal cancer. Clin Colorectal Cancer. 2010 Apr;9(2):102-7. link to original article contains protocol PubMed
  4. 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 protocol PubMed
  5. 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 PubMed

FOLFOX 7 & sLV5FU2

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

Regimen

Study Evidence Comparator Efficacy
Tournigand et al. 2006 (OPTIMOX1) Phase III FOLFOX 4 Seems not superior

FOLFOX 7 portion

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

Simplified LV5FU2 (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

FOLFOX & Bevacizumab

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FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin

Example orders

Regimen #1, mFOLFOX 6 & Bevacizumab

Study Evidence Comparator Efficacy
Hochster et al. 2008 (TREE-2) Phase III bFOL & Bevacizumab Seems not superior
CapeOx & Bevacizumab Seems not superior
Saltz et al. 2011 Phase III FOLFOX, Bevacizumab & Cetuximab Seems not superior
Schmoll et al. 2012 (HORIZON III) Phase III mFOLFOX6 & Cediranib Seems not superior
Yamada et al. 2013 (SOFT) Phase III SOX & Bevacizumab Seems to have non-inferior PFS

Chemotherapy

14-day cycles

Regimen #2, FOLFOX 4 & Bevacizumab

Study Evidence
Emmanouilides et al. 2007 Phase II

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 600 mg/m2/day IV continuous infusion over 22 hours; both bolus and continuous infusion given on days 1 & 2
  • 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. 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
  3. 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
  4. 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 protocol PubMed
  5. 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
  6. 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
  7. 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

FOLFOX & Panitumumab

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FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin

Regimen #1, FOLFOX 4 & Panitumumab

Study Evidence Comparator Efficacy
Douillard et al. 2010 (PRIME) Phase III FOLFOX 4 See note

Note: in KRAS wild-type patients, this regimen seems to have superior PFS. Conversely, in KRAS mutants, this regimen seems to have inferior PFS.

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 600 mg/m2/day IV continuous infusion over 22 hours; both bolus and continuous infusion given on days 1 & 2
  • 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
  • Panitumumab (Vectibix) 6 mg/kg IV once on day 1, given first
    • Infusion times are 1 hour for cycle 1, then if tolerated, 30 minutes for cycle 2 and later

Regimen #2, mFOLFOX 6 & Panitumumab

Note: The two references cited by the NCCN, Colon Cancer version 1.2015, contained different regimens. No primary reference for this regimen could be found.

Chemotherapy

14-day cycles

References

  1. 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, B?asin'ska-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
    1. Biomarker analysis: Douillard JY, Oliner KS, Siena S, 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, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013 Sep 12;369(11):1023-34. link to original article PubMed

FOLFOXIRI

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FOLFOXIRI: FOLinic acid, Fluorouracil, OXaliplatin, IRInotecan

Regimen

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

Note: In contrast to Falcone et al. 2007, the NCCN, Colon Cancer version 1.2015, listed the dose of Folinic acid (Leucovorin) 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

FOLFOXIRI & Bevacizumab

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FOLFOXIRI: FOLinic acid, Fluorouracil, OXaliplatin, IRInotecan

Regimen

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

Note: Loupakis et al. 2014 listed Folinic acid (Leucovorin) 200 mg/m2 in the body of the paper, whereas the protocol in the supplementary material stated that Levoleucovorin (Fusilev) 200 mg/m2 was used. We have contacted NEJM regarding this suspected error. The NCCN, Colon Cancer version 1.2015, listed either Folinic acid (Leucovorin) 400 mg/m2 IV once on day 1 or Levoleucovorin (Fusilev) 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. 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

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 5-FU & Folinic acid Seems to have superior OS
Irinotecan Might have superior OS
Hurwitz et al. 2004 Phase III IFL & Bevacizumab Inferior OS

Chemotherapy

6-week cycles

References

  1. 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 plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000 Sep 28;343(13):905-14. link to original article contains verified protocol PubMed
  2. 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
  3. 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

IFL & Bevacizumab

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

Regimen, mIFL & Bevacizumab

Study Evidence Comparator Efficacy
Fuchs et al. 2007 (BICC-C) Phase III FOLFIRI+Bev Inferior OS

Chemotherapy

21-day cycles

References

  1. 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. 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

Irinotecan monotherapy

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Example orders

Regimen

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

Chemotherapy

42-day cycles

References

  1. 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 plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000 Sep 28;343(13):905-14. 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
Tveit et al. 2012 (NORDIC-VII) Phase III Nordic FLOX & Cetuximab Seems not superior

Chemotherapy

2-week cycle for 8 cycles

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 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 articlePubMed

Advanced or metastatic disease, refractory

CAPIRI; XELIRI

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

Regimen

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

Chemotherapy

3-week 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

Cetuximab monotherapy

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Example orders

Regimen #1, standard dose

Study Evidence Comparator Efficacy
Cunningham et al. 2004 Phase III Cetuximab & Irinotecan Inferior TTP
Lenz et al. 2006 Phase II
Jonker et al. 2007 (NCIC CTG CO.17) Phase III Best supportive care Superior OS
Price et al. 2014 (ASPECCT) Phase III Panitumumab Non-inferior OS

Chemotherapy

  • Cetuximab (Erbitux) 400 mg/m2 IV over 2 hours once on day 1 of cycle 1, then 250 mg/m2 IV over 1 hour once per week

Supportive medications (varies depending on reference):

Given until progression of disease or unacceptable toxicity

Regimen #2, escalated dose

Note: The NCCN lists this dosage and schedule as an option, although no primary reference could be found for this exact regimen. Several regimens describe this dose of cetuximab used in combination with irinotecan.

Chemotherapy

  • Cetuximab (Erbitux) 500 mg/m2 IV over 2 hours once on day 1
    • If tolerated, subsequent doses can be given over 1 hour

Supportive medications

14-day cycles

References

  1. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22;351(4):337-45. link to original article contains verified protocol PubMed
  2. Lenz HJ, Van Cutsem E, Khambata-Ford S, Mayer RJ, Gold P, Stella P, Mirtsching B, Cohn AL, Pippas AW, Azarnia N, Tsuchihashi Z, Mauro DJ, Rowinsky EK. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol. 2006 Oct 20;24(30):4914-21. 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. Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Zhang K, Murugappan S, Sidhu R. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014 May;15(6):569-79. Epub 2014 Apr 14. link to original article PubMed

Cetuximab & Irinotecan

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Regimen #1

Study Evidence Comparator Efficacy
Cunningham et al. 2004 Phase III Cetuximab Superior TTP
Sobrero et al. 2008 (EPIC) Phase III Irinotecan Superior PFS

Chemotherapy

  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 1 hour once per day on days 8 & 15
    • Subsequent cycles: 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
  • Irinotecan (Camptosar) 350 mg/m2 IV over 90 minutes once on day 1
    • If aged 70 years old or more, ECOG performance status 2 or more, or prior pelvic radiation: 300 mg/m2 IV over 90 minutes once on day 1

Supportive medications

21-day cycles

Regimen #2

Study Evidence Comparator Efficacy
Cunningham et al. 2004 Phase III Cetuximab Superior TTP

Chemotherapy

  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 60 minutes once per day on days 8, 15, 22, 29, 36
    • Subsequent cycles: 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36
  • Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1, 8, 15, 22

Supportive medications

42-day cycles

Regimen #3

Note: In contrast to Cunningham et al. 2004, the NCCN, Colon Cancer version 1.2015, lists Irinotecan (Camptosar) as being given on days 1 & 8 of a 21-day cycle. No primary reference could be found for this.

Chemotherapy

  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 60 minutes once per day on days 8 & 15
    • Subsequent cycles: 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
  • Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1 & 8

Supportive medications

21-day cycles

Regimen #4, escalated dose

Study Evidence
Martín-Martorell et al. 2008 Phase II

Chemotherapy

Supportive medications

14-day cycles

References

  1. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22;351(4):337-45. link to original article contains verified protocol PubMed
  2. 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
  3. Martín-Martorell P, Roselló S, Rodríguez-Braun E, Chirivella I, Bosch A, Cervantes A. Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial. Br J Cancer. 2008 Aug 5;99(3):455-8. link to original article contains verified protocol link to PMC article PubMed
  4. Van Cutsem E, Tejpar S, Vanbeckevoort D, Peeters M, Humblet Y, Gelderblom H, Vermorken JB, Viret F, Glimelius B, Gallerani E, Hendlisz A, Cats A, Moehler M, Sagaert X, Vlassak S, Schlichting M, Ciardiello F. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol. 2012 Aug 10;30(23):2861-8. Epub 2012 Jul 2.link to original article PubMed

FOLFIRI

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Example orders

Regimen #1

Study Evidence Comparator Efficacy
Lim et al. 2015 Phase III 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

Regimen #2

Study Evidence Comparator Efficacy
André et al. 1999 Non-randomized
Peeters et al. 2010 Phase III FOLFIRI & Panitumumab Inferior PFS
Tabernero et al. 2015 (RAISE) Phase III FOLFIRI & Ramucirumab Seems to have inferior OS

Note: efficacy 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 1200 mg/m2/day IV continuous infusion over 46 to 48 hours on days 1 & 2, given last (total dose per cycle: 2400 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
  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. 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 PubMed
  4. 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
  5. 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

FOLFIRI & Panitumumab

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Regimen

Study Evidence Comparator Efficacy
Peeters et al. 2010 Phase III FOLFIRI Superior PFS

Note: efficacy is for wild-type KRAS, only.

Chemotherapy

14-day cycles

References

  1. 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

FOLFIRI & Ramucirumab

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Regimen

Study Evidence Comparator Efficacy
Tabernero et al. 2015 (RAISE) Phase III 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 1200 mg/m2/day IV continuous infusion over 48 hours on days 1 to 2, given last (total dose per cycle: 2400 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, given until progression of disease, or unacceptable toxicity

References

  1. 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: FOLinic acid, Fluorouracil, IRInotecan

Regimen

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

Chemotherapy

Supportive medications

14-day cycles, given until progression of disease or unacceptable toxicity

References

  1. 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

Irinotecan monotherapy

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Example orders

Regimen #1

Study Evidence Comparator Efficacy
Cunningham et al. 1998 Phase III Supportive care Superior OS
Fuchs et al. 2003 Phase III Irinotecan weekly Seems not superior

Chemotherapy

Supportive medications

21-day cycles

Regimen #2

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

Note: In contrast to Fuchs et al. 2003, the NCCN, Colon Cancer version 1.2015, listed Irinotecan (Camptosar) as being given on days 1 & 8 of a 21-day cycle. No primary reference could be found for this.

Chemotherapy

42-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
  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. 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 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 PubMed

IROX

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IROX: IRinotecan, OXaliplatin

Regimen

Study Evidence Comparator Efficacy
Haller et al. 2008 Phase III 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

Observation

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Regimen

Study Evidence Comparator Efficacy
Cunningham et al. 1998 Phase III Irinotecan Inferior OS
Van Cutsem et al. 2007 Phase III Panitumumab Inferior PFS
Jonker et al. 2007 (NCIC CTG CO.17) Phase III Cetuximab Inferior OS
Grothey et al. 2013 (CORRECT) Phase III Regorafenib Inferior OS
Li et al. 2015 (CONCUR) Phase III Regorafenib Inferior OS
Mayer et al. 2015 (RECOURSE) Phase III Trifluridine and tipiracil Inferior OS
Kim et al. 2016 Phase III 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. 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
  5. 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
  6. 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
  7. 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

Panitumumab monotherapy

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Example orders

Regimen

Study Evidence Comparator Efficacy
Van Cutsem et al. 2007 Phase III Best supportive care Superior PFS
Price et al. 2014 (ASPECCT) Phase III Cetuximab Non-inferior OS
Kim et al. 2016 Phase III Best supportive care Superior OS

Chemotherapy

14-day cycles, given until progression of disease or unacceptable toxicity

References

  1. 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
  2. Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Zhang K, Murugappan S, Sidhu R. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014 May;15(6):569-79. Epub 2014 Apr 14. link to original article PubMed
  3. 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

Pembrolizumab monotherapy

Source: Pembrolizumab (Keytruda) for unresectable or metastatic colon cancer

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Regimen #1

Study Evidence
Le et al. (KEYNOTE-164) Phase II

This variant of the regimen is being listed despite lack of a published trial and results because this is the FDA-approved, recommended pembrolizumab dose and schedule in the package insert.

Immunotherapy

21-day cycles

Regimen #2

Study Evidence
Le et al. 2015 Phase II

Note: this study only demonstrated a clear benefit for mismatch repair-deficient colorectal cancers. Please be aware that the FDA-approved, recommended pembrolizumab dose in the package insert is 200 mg for adults, 2 mg/kg (maximum dose 200 mg) for children, given every 3 weeks.

Immunotherapy

14-day cycles

References

  1. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20. Epub 2015 May 30. link to original article contains protocol PubMed
  2. Abstract: Dung T. Le, Takayuki Yoshino, Dirk Jäger, Thierry Andre, Johanna C. Bendell, Ruixue Wang... SoonMo Peter Kang, Minori Koshiji, Luis A. Diaz. KEYNOTE-164: Phase II study of pembrolizumab (MK-3475) for patients with previously treated, microsatellite instability-high advanced colorectal carcinoma. J Clin Oncol abstract TPS787 and abstract TPS3631; NCT02460198 at ClinicalTrials.gov

Regorafenib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Grothey et al. 2013 (CORRECT) Phase III Best supportive care Superior OS
Li et al. 2015 (CONCUR) Phase III 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, given until progression of disease or unacceptable toxicity

References

  1. 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. 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
Mayer et al. 2015 (RECOURSE) Phase III Placebo Superior OS

Chemotherapy

28-day cycles, given until progression of disease or unacceptable toxicity

References

  1. 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