Colon cancer
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Section editor | |
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Neeta K. Venepalli, MD, MBA Chicago, IL |
Note: the page has adjuvant and perioperative regimens specific to colon cancer as well as systemic regimens for the more general category of colorectal cancer. Please see the rectal cancer page for regimens specific to rectal cancer.
10 regimens on this page
20 variants on this page
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Guidelines
ESMO
- Early Colon Cancer: ESMO Clinical Practice Guidelines PubMed
- ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. PubMed
- Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. PubMed
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
- Capecitabine (Xeloda) 1250 mg/m2 PO BID on days 1 to 14
21-day cycle for 8 cycles
References
- 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
- Kerr RS, Love S, Segelov E, Johnstone E, Falcon B, Hewett P, Weaver A, Church D, Scudder C, Pearson S, Julier P, Pezzella F, Tomlinson I, Domingo E, Kerr DJ. Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial. Lancet Oncol. 2016 Nov;17(11):1543-1557. link to original article contains protocol PubMed
CapeOx
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CapeOX: Capecitabine, OXaliplatin
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
- Capecitabine (Xeloda) 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 cycle for 8 cycles
Regimen #2
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
- Capecitabine (Xeloda) 1000 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 cycle for 8 cycles
References
- 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
- 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
- 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
- Example orders for 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV) in colon cancer
- Example orders for 5-FU & high-dose Leucovorin (Roswell Park regimen/HDLV) in colon cancer
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
- Folinic acid (Leucovorin) 20 mg/m2 IV push once per day on days 1 to 5, given before before 5-FU
- Fluorouracil (5-FU) 425 mg/m2 IV push once per day on days 1 to 5
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
- Folinic acid (Leucovorin) 20 mg/m2 IV push once per day on days 1 to 5, before 5-FU
- Fluorouracil (5-FU) 425 mg/m2 IV push once per day on days 1 to 5
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 | FOLFOX4 | 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Folinic acid (Leucovorin) 20 mg/m2 IV push once per day on days 1 to 5, before 5-FU
- Fluorouracil (5-FU) 425 mg/m2 IV push once per day on days 1 to 5
- Levamisole (Ergamisol)
28-day cycle for 3 cycles, then 35-day cycle for 3 cycles
References
- 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
- Fluorouracil (5-FU) 500 mg/m2 IV bolus once per day on days 1, 8, 15, 22, 29, 36, to start 1 hour after start of leucovorin
- Folinic acid (Leucovorin) 500 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, given before 5-FU
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once per day on days 1, 15, 29, given first
8-week cycle for 3 cycles
References
- 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
FOLFOX4
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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
André et al. 2004 (MOSAIC) | Phase III (E) | 5-FU & Folinic acid | Seems to have superior OS (*) |
de Gramont et al. 2012 (AVANT) | Phase III (C) | FOLFOX4 & Bevacizumab | Seems not superior |
XELOX & Bevacizumab | Seems not superior | ||
Taieb et al. 2014 (PETACC-8) | Phase III (C) | FOLFOX4 & Cetuximab | Seems not superior |
Reported efficacy for MOSAIC 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 (total dose per cycle: 2000 mg/m2)
- Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, before 5-FU
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, concurrent with leucovorin
14-day cycle for 12 cycles
References
- 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
- 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
- de Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, Cunningham D, Cartwright TH, Hecht JR, Rivera F, Im SA, Bodoky G, Salazar R, Maindrault-Goebel F, Shacham-Shmueli E, Bajetta E, Makrutzki M, Shang A, André T, Hoff PM. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012 Dec;13(12):1225-33. Epub 2012 Nov 16. link to original article contains protocol PubMed
- Taieb J, Tabernero J, Mini E, Subtil F, Folprecht G, Van Laethem JL, Thaler J, Bridgewater J, Petersen LN, Blons H, Collette L, Van Cutsem E, Rougier P, Salazar R, Bedenne L, Emile JF, Laurent-Puig P, Lepage C; PETACC-8 Study Investigators. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Jul;15(8):862-73. Epub 2014 Jun 11. link to original article PubMed
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
- 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 to 2
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
14-day cycle for 12 cycles, to start within 10 weeks of surgery
References
- 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
- 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
- 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
- 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. Some guidelines do not recommend using bevacizumab as adjuvant therapy outside of a clinical trial.
Chemotherapy
- 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 to 2
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
- Bevacizumab (Avastin) 5 mg/kg IV once on day 1
14-day cycle for 12 cycles, to start within 10 weeks of surgery
References
- 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
- 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
- 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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mFOLFOX & Cetuximab: modified FOLinic acid, Fluorouracil, OXaliplatin, Cetuximab
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Alberts et al. 2012 | Phase III | mFOLFOX 6 | Might have inferior DFS |
Some guidelines do not recommend using cetuximab as adjuvant therapy outside of a clinical trial.
Chemotherapy
- 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 to 2
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
- Cetuximab (Erbitux) 400 mg/m2 IV over 2 hours once on day 1 of cycle 1, then 250 mg/m2 IV over 60 minutes once on day 8 (cycle 1); for cycles 2 to 12: Cetuximab (Erbitux) 250 mg/m2 IV over 2 hours once per day on days 1 & 8
14-day cycle for 12 cycles, to start within 10 weeks of surgery
References
- 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
- 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
- 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
- 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, 300/75
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
- Tegafur and uracil (UFT) 300 mg/m2/day PO on days 1 to 28
- Folinic acid (Leucovorin) 75 mg/day PO on days 1 to 28
35-day cycle for 5 cycles
Regimen #2, 100/30
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Lembersky et al. 2006 (NSABP C-06) | Phase III | 5-FU & Leucovorin | Seems not superior |
Preceding treatment
- A potentially curative resection of stage II or stage III colon cancer
Chemotherapy
- Tegafur and uracil (UFT) 100 mg/m2 PO Q8H on days 1 to 28
- Folinic acid (Leucovorin) 30 mg PO Q8H on days 1 to 28
- No food for 1 hour before and after each dose of medication.
35-day cycle for 5 cycles
References
- 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
- Hasegawa K, Saiura A, Takayama T, Miyagawa S, Yamamoto J, Ijichi M, Teruya M, Yoshimi F, Kawasaki S, Koyama H, Oba M, Takahashi M, Mizunuma N, Matsuyama Y, Watanabe T, Makuuchi M, Kokudo N. Adjuvant oral uracil-tegafur with leucovorin for colorectal cancer liver metastases: A randomized controlled trial. PLoS One. 2016 Sep 2;11(9):e0162400. eCollection 2016. link to original article link to PMC article contains verified protocol PubMed
Perioperative therapy for oligometastatic disease
FOLFOX4
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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Nordlinger et al. 2008 (EORTC 40983) | Phase III (E) | Surgery alone | Superior PFS |
Note: this is the regimen as described by de Gramont et al. 2000; the manuscript refers to this protocol.
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV bolus, then 600 mg/m2/day IV continuous infusion over 22 hours once per day on days 1 & 2 (total dose per cycle: 2000 mg/m2)
- Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, before 5-FU
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, concurrent with leucovorin
14-day cycle for 6 cycles before surgery, and 6 cycles after surgery (12 cycles total)
References
- Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008 Mar 22;371(9617):1007-16. link to original article link to PMC article does not contain protocol PubMed
- Update: Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Mauer M, Tanis E, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und–tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectalcancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1208-15. Epub 2013 Oct 11. link to original article PubMed
Advanced or metastatic disease, first-line
Capecitabine monotherapy
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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: Some guidelines list 850 to 1250 mg/m2 as the dosage range. No primary reference for the lower monotherapy dosages could be found.
Chemotherapy
- Capecitabine (Xeloda) 1250 mg/m2 PO BID on days 1 to 14
21-day cycles
References
- 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
- 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
- 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
Capecitabine & Bevacizumab
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Regimen #1, 1000/7.5
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Cunningham et al. 2013 (AVEX) | Phase III | Capecitabine | Superior PFS |
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO BID on days 1 to 14
- Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
Regimen #2, 1250/7.5
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
- Capecitabine (Xeloda) 1250 mg/m2 PO BID on days 1 to 14
- Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
References
- 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
- Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, Jonker D, Osborne S, Andre N, Waterkamp D, Saunders MP; AVEX study investigators. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label,randomised phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1077-85. Epub 2013 Sep 10. link to original article contains protocol PubMed
CapeOx
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CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda, OXaliplatin
Example orders
Regimen #1, 1000/130
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Díaz-Rubio et al. 2007 | Phase III | FUOX | Seems not superior |
Cassidy et al. 2008 | Phase III | FOLFOX4 FOLFOX4 & Bevacizumab |
Non-inferior PFS |
XELOX & Bevacizumab | Not reported | ||
Saltz et al. 2008 | Phase III | FOLFOX4 & Bevacizumab XELOX & Bevacizumab |
Inferior PFS |
FOLFOX4 | Not reported | ||
Hoff et al. 2012 (HORIZON-II) | Phase III | CAPOX & Cediranib FOLFOX4 & Cediranib mFOLFOX6 & Cediranib |
Seems to have inferior PFS |
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
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. Patients in Hong et al. 2012 were allowed to continue capecitabine maintenance after 9 cycles.
Regimen #2, 850/130
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 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
Regimen #3, 1000/70
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Porschen et al. 2007 | Phase III | FUFOX | Inconclusive whether non-inferior |
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO BID on days 1 to 14
- Oxaliplatin (Eloxatin) 70 mg/m2 IV over 2 hours once per day on days 1 & 8
21-day cycles, given until progression of disease
References
- Porschen R, Arkenau HT, Kubicka S, Greil R, Seufferlein T, Freier W, Kretzschmar A, Graeven U, Grothey A, Hinke A, Schmiegel W, Schmoll HJ; AIO Colorectal Study Group. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol. 2007 Sep 20;25(27):4217-23. Epub 2007 Jun 4. link to original article contains verified protocol PubMed
- Díaz-Rubio E, Tabernero J, Gómez-España A, Massutí B, Sastre J, Chaves M, Abad A, Carrato A, Queralt B, Reina JJ, Maurel J, González-Flores E, Aparicio J, Rivera F, Losa F, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol. 2007 Sep 20;25(27):4224-30. Epub 2007 Jun 4. link to original article contains verified protocol PubMed
- 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
- 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
- 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
- Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. link to original article contains verified protocol PubMed
- Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. link to original article contains protocol PubMed
CapeOx & Bevacizumab
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CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda, OXaliplatin
Regimen #1, 1000/130/7.5
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Cassidy et al. 2008 | Phase III | FOLFOX4 FOLFOX4 & Bevacizumab |
Non-inferior PFS |
XELOX | Not reported | ||
Saltz et al. 2008 | Phase III | FOLFOX4 XELOX |
Superior PFS |
FOLFOX4 & Bevacizumab | 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; 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, 850/130/7.5
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 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
References
- 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
- 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
- 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
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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
- Capecitabine (Xeloda) 1000 mg/m2 BID on days 1 to 14
- Irinotecan (Camptosar) 250 mg/m2 IV over 90 minutes once on day 1
21-day cycles
References
- 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
- 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
- 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, 800/200/7.5
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
- Capecitabine (Xeloda) 800 mg/m2 PO BID on days 1 to 14
- Irinotecan (Camptosar) 200 mg/m2 IV once on day 1
- Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
Regimen #2, 1000/200/7.5
Study | Evidence |
---|---|
Moehler et al. 2009 | Phase II |
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO BID on days 1 to 14
- Irinotecan (Camptosar) 200 mg/m2 IV once on day 1
- Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
References
- 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
- 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
- Example orders for 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV) in colon cancer
- Example orders for 5-FU & high-dose Leucovorin (Roswell Park regimen/HDLV) in colon cancer
- Example orders for weekly 5-FU & Leucovorin in colon cancer
- Example orders for simplified biweekly 5-FU & leucovorin (sLV5FU2) in colon cancer
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
- Folinic acid (Leucovorin) 500 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
- 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 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
- Folinic acid (Leucovorin) 20 mg/m2 IV push once per day on days 1 to 5, before 5-FU
- Fluorouracil (5-FU) 425 mg/m2 IV push once per day on days 1 to 5
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 | FOLFOX4 | 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
- Folinic acid (Leucovorin) 500 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 2600 mg/m2 IV over 24 hours once on day 1
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
- Folinic acid (Leucovorin) 20 mg/m2 IV over 2 hours once on day 1, given first
- Fluorouracil (5-FU) 500 mg/m2 IV bolus once on day 1, given 1 hour after start of leucovorin
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
- Alternatively, Levoleucovorin (Fusilev) 175 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
- No routine prophylactic antiemetics and antidiarrheal medications were used, but patients could use Metoclopramide (Reglan) prn nausea and Loperamide (Imodium) prn diarrhea.
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 2400 mg/m2 IV continuous infusion over 46 to 48 hours on days 1 to 2 (total dose per cycle: 2800 mg/m2)
14-day cycles
References
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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 |
---|---|---|---|
Falcone et al. 2007 | Phase III | FOLFOXIRI | Seems to have inferior OS |
Fuchs et al. 2007 (BICC-C) | Phase III | CapeIRI | Seems to have superior PFS |
mIFL | Superior PFS | ||
Van Cutsem et al. 2009 (CRYSTAL) | Phase III | FOLFIRI & Cetuximab | Inferior OS (*) |
Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.
Chemotherapy
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, given during irinotecan infusion
- Patient in CRYSTAL could receive Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, instead
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours on days 1 & 2, given last (total dose per cycle: 2800 mg/m2)
- Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first together with leucovorin
14-day cycles
References
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Pooled Update: Bokemeyer C, Cutsem EV, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article PubMed
FOLFIRI & Bevacizumab
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FOLFIRI & Bevacizumab: FOLinic acid, Fluorouracil, IRInotecan, Bevacizumab
Regimen #1, indefinite
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Fuchs et al. 2007 (BICC-C) | Phase III | mIFL & Bevacizumab | Seems to have superior OS |
Yamazaki et al. 2016 (WJOG4407G) | Phase III | mFOLFOX6 & Bevacizumab | Non-inferior PFS |
Chemotherapy
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, started during irinotecan infusion
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours on days 1 to 2, given last (total dose per cycle: 2800 mg/m2)
- Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first
- Bevacizumab (Avastin) 5 mg/kg IV once on day 1
14-day cycles
Regimen #2, limited duration
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 200 mg/m2 in the body of the paper, whereas the protocol in the supplementary material stated that levoleucovorin 200 mg/m2 was used. We have contacted NEJM regarding this suspected error.
Chemotherapy
- Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours on days 1 to 2 (total dose per cycle: 2800 mg/m2)
- Irinotecan (Camptosar) 180 mg/m2 IV over 60 minutes once on day 1
- Bevacizumab (Avastin) 5 mg/kg IV over 30 minutes once on day 1
14-day cycle for up to 12 cycles
Treatment 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
- 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
- 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
- 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
- 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
- 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
- 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
- Yamazaki K, Nagase M, Tamagawa H, Ueda S, Tamura T, Murata K, Eguchi Nakajima T, Baba E, Tsuda M, Moriwaki T, Esaki T, Tsuji Y, Muro K, Taira K, Denda T, Funai S, Shinozaki K, Yamashita H, Sugimoto N, Okuno T, Nishina T, Umeki M, Kurimoto T, Takayama T, Tsuji A, Yoshida M, Hosokawa A, Shibata Y, Suyama K, Okabe M, Suzuki K, Seki N, Kawakami K, Sato M, Fujikawa K, Hirashima T, Shimura T, Taku K, Otsuji T, Tamura F, Shinozaki E, Nakashima K, Hara H, Tsushima T, Ando M, Morita S, Boku N, Hyodo I. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol. 2016 Aug;27(8):1539-46. Epub 2016 May 13. link to original article PubMed
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 | Superior OS |
Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.
Chemotherapy
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, started during irinotecan infusion
- Alternatively, Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours on days 1 to 2, given last (total dose per cycle: 2800 mg/m2)
- Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given 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
References
- 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
- 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
- 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
- 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
- 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
FOLFOX4
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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin
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 | FOLFOX4 & Bevacizumab | Not reported |
XELOX XELOX & Bevacizumab |
Non-inferior PFS | ||
Saltz et al. 2008 | Phase III | FOLFOX4 & Bevacizumab XELOX & Bevacizumab |
Inferior PFS |
XELOX | Not reported | ||
Bokemeyer et al. 2008 (OPUS) | Phase III | FOLFOX4 & Cetuximab | Inferior OS (*) |
Douillard et al. 2010 (PRIME) | Phase III | FOLFOX4 & Panitumumab | See note |
Hoff et al. 2012 (HORIZON II) | Phase III | CAPOX & Cediranib FOLFOX4 & Cediranib mFOLFOX6 & Cediranib |
Seems to have inferior PFS |
Note: in PRIME, KRAS wild-type patients receiving this regimen seem to have inferior PFS. Conversely, in KRAS mutants, this regimen seems to have superior PFS. Reported efficacy for OPUS is based on the 2012 pooled update and is only for KRAS wild-type tumors.
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV bolus, then 600 mg/m2/day IV continuous infusion over 22 hours once per day on days 1 & 2 (total dose per cycle: 2000 mg/m2)
- Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, before 5-FU
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, concurrent with leucovorin
14-day cycles
References
- 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
- 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
- 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
- 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
- Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. link to original article refers to de Gramont et al. 2000 for protocol PubMed
- Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29. link to original article contains verified protocol PubMed
- Pooled Update: Bokemeyer C, Cutsem EV, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article PubMed
- 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
- Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. link to original article contains verified protocol PubMed
mFOLFOX 6
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mFOLFOX: modified FOLinic acid, Fluorouracil, OXaliplatin
OxMdG: Oxaliplatin Modified de Gramont
Example orders
Regimen #1, LCV 200 mg/m2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Wasan et al. 2017 (SIRFLOX; FOXFIRE-Global) | Phase III | mFOLFOX 6 plus SIRT | Seems not superior |
Note: Wasan et al. 2017 describes the folinic acid as a flat 200 mg dose, but an earlier description of the SIRFLOX protocol uses 200 mg/m2; the authors were contacted for clarification.
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours on days 1 to 2 (total dose per cycle: 2800 mg/m2)
- Folinic acid (Leucovorin) 200 mg/m2 IV once on day 1
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
14-day cycles
Regimen #2, OxMdG with leucovorin
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Wasan et al. 2017 (FOXFIRE) | Phase III | OxMdG plus SIRT | Seems not superior |
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours on days 1 to 2 (total dose per cycle: 2800 mg/m2)
- Folinic acid (Leucovorin) 350 mg IV over 2 hours once on day 1
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
14-day cycles
Regimen #3, OxMdG with levoleucovorin
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Wasan et al. 2017 (FOXFIRE) | Phase III | OxMdG plus SIRT | Seems not superior |
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours on days 1 to 2 (total dose per cycle: 2800 mg/m2)
- Levoleucovorin (Fusilev) 175 mg IV over 2 hours once on day 1
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
14-day cycles
Regimen #4, LCV 400 mg/m2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Hoff et al. 2012 (HORIZON II) | Phase III | CAPOX & Cediranib FOLFOX4 & Cediranib mFOLFOX6 & Cediranib |
Seems to have inferior PFS |
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 on days 1 to 2 (total dose per cycle: 2800 mg/m2)
- Folinic acid (Leucovorin) 400 mg/m2 IV once on day 1
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
14-day cycles
Regimen #5, LCV 350 mg/m2
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
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours on days 1 to 2 (total dose per cycle: 2800 mg/m2)
- Folinic acid (Leucovorin) 350 mg/m2 IV over 2 hours once on day 1
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
14-day cycles
References
- 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
- 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
- Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. link to original article contains verified protocol PubMed
- Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A; FOXFIRE trial investigators; SIRFLOX trial investigators; FOXFIRE-Global trial investigators, van Hazel G, Sharma RA. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. Epub 2017 Aug 3. link to original article contains verified protocol PubMed
FOLFOX 7 & sLV5FU2
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FOLFOX: 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 | FOLFOX4 | Seems not superior |
FOLFOX 7 portion
- Fluorouracil (5-FU) 1200 mg/m2/day IV continuous infusion over 46 hours on days 1 to 2 (total dose per cycle: 2400 mg/m2)
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, given first
- Alternatively, Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given first
- Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
14-day cycle for 6 cycles, until progression of disease or unacceptable toxicity, then proceed to sLV5FU2
Simplified LV5FU2 (sLV5FU2) portion
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, given second; then Fluorouracil (5-FU) 1500 mg/m2/day IV continuous infusion over 46 hours on days 1 to 2 (total dose per cycle: 3000 mg/m2)
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, given first
- Alternatively, Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given first
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
- 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-B: FOLinic acid, Fluorouracil, OXaliplatin, Bevacizumab
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 | FOLF-CB | 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 |
Yamazaki et al. 2016 (WJOG4407G) | Phase III | FOLFIRI & Bevacizumab | Non-inferior PFS |
Chemotherapy
- 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 to 2 (total dose per cycle: 2800 mg/m2)
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
- Bevacizumab (Avastin) 5 mg/kg IV once on day 1
14-day cycles
Regimen #2, FOLFOX4 & Bevacizumab
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Emmanouilides et al. 2007 | Phase II | ||
Saltz et al. 2008 | Phase III | FOLFOX4 XELOX |
Superior PFS |
XELOX & Bevacizumab | Not reported |
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV bolus, then 600 mg/m2/day IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m2)
- Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
- Bevacizumab (Avastin) 5 mg/kg IV once on day 1, given first
- Infusion times are 2 hours for cycle 1, 1 hour for cycle 2, then 30 minutes for cycles 3 and later
14-day cycles
References
- 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
- Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. link to original article refers to de Gramont et al. 2000 for protocol PubMed
- 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
- Saltz L, Badarinath S, Dakhil S, Bienvenu B, Harker WG, Birchfield G, Tokaz LK, Barrera D, Conkling PR, O'Rourke MA, Richards DA, Reidy D, Solit D, Vakiani E, Capanu M, Scales A, Zhan F, Boehm KA, Asmar L, Cohn A. Phase III trial of cetuximab, bevacizumab, and 5-fluorouracil/leucovorin vs. FOLFOX-bevacizumab in colorectal cancer. Clin Colorectal Cancer. 2012 Jun;11(2):101-11. Epub 2011 Nov 4. link to original article contains verified protocol PubMed
- 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
- 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
- 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
- Yamazaki K, Nagase M, Tamagawa H, Ueda S, Tamura T, Murata K, Eguchi Nakajima T, Baba E, Tsuda M, Moriwaki T, Esaki T, Tsuji Y, Muro K, Taira K, Denda T, Funai S, Shinozaki K, Yamashita H, Sugimoto N, Okuno T, Nishina T, Umeki M, Kurimoto T, Takayama T, Tsuji A, Yoshida M, Hosokawa A, Shibata Y, Suyama K, Okabe M, Suzuki K, Seki N, Kawakami K, Sato M, Fujikawa K, Hirashima T, Shimura T, Taku K, Otsuji T, Tamura F, Shinozaki E, Nakashima K, Hara H, Tsushima T, Ando M, Morita S, Boku N, Hyodo I. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol. 2016 Aug;27(8):1539-46. Epub 2016 May 13. link to original article PubMed
FOLFOX & Cetuximab
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FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Bokemeyer et al. 2008 (OPUS) | Phase III | FOLFOX4 | Superior OS (*) |
Reported efficacy is based on the 2012 pooled update and is only for KRAS wild-type tumors.
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV bolus, then 600 mg/m2/day IV continuous infusion over 22 hours once per day on days 1 & 2 (total dose per cycle: 2000 mg/m2)
- Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, before 5-FU
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, concurrent with leucovorin
- Cetuximab (Erbitux) as follows:
- Cycle 1 day 1: 400 mg/m2 IV over 2 hours once, given first
- Thereafter: 250 mg/m2 IV over 60 minutes once per week, given first
14-day cycles
References
- Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29. link to original article contains verified protocol PubMed
- Pooled Update: Bokemeyer C, Cutsem EV, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article PubMed
FOLFOX & Panitumumab
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FOLFOX & Panitumumab: FOLinic acid, Fluorouracil, OXaliplatin, Panitumumab
Regimen #1, FOLFOX4 & Panitumumab
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Douillard et al. 2010 (PRIME) | Phase III | FOLFOX4 | 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: No primary reference for this regimen could be found.
Chemotherapy
- 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 to 2
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
- Panitumumab (Vectibix) 6 mg/kg IV over 60 minutes once on day 1
14-day cycles
References
- 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
- 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, some guidelines list the dose of folinic acid as 400 mg/m2 IV on day 1. No primary reference could be found for this.
Chemotherapy
- Fluorouracil (5-FU) 1600 mg/m2/day (3200 mg/m2 total dose) IV continuous infusion over 48 hours on days 1 to 2
- Folinic acid (Leucovorin) 200 mg/m2 IV once on day 1
- Oxaliplatin (Eloxatin) 85 mg/m2 IV once on day 1
- Irinotecan (Camptosar) 165 mg/m2 IV once on day 1
14-day cycles
References
- 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 200 mg/m2 in the body of the paper, whereas the protocol in the supplementary material stated that levoleucovorin 200 mg/m2 was used. We have contacted NEJM regarding this suspected error. Some guidelines list either folinic acid 400 mg/m2 IV once on day 1 or levoleucovorin 200 mg/m2 IV once on day 1 as options.
Chemotherapy
- Fluorouracil (5-FU) 1600 mg/m2/day IV continuous infusion over 48 hours on days 1 to 2, given fourth (total dose per cycle: 3200 mg/m2)
- Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given third, together with oxaliplatin
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given third, together with leucovorin
- Irinotecan (Camptosar) 165 mg/m2 IV over 60 minutes once on day 1, given second
- Bevacizumab (Avastin) 5 mg/kg IV over 30 minutes once on day 1, given first
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
- 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
- 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 | FL & Bevacizumab | Not reported |
IFL & Bevacizumab | Inferior OS | ||
Fuchs et al. 2007 (BICC-C) | Phase III | CapeIRI | Seems not superior |
FOLFIRI | Inferior PFS |
Chemotherapy
- Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1, 8, 15, 22
- Fluorouracil (5-FU) 500 mg/m2 IV bolus once per day on days 1, 8, 15, 22
- Folinic acid (Leucovorin) 20 mg/m2 IV bolus once per day on days 1, 8, 15, 22
42-day cycles
References
- 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
- 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
- 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
- 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 |
---|---|---|---|
Hurwitz et al. 2004 | Phase III | FL & Bevacizumab | Not reported |
IFL | Superior OS | ||
Fuchs et al. 2007 (BICC-C) | Phase III | FOLFIRI+Bev | Seems to have inferior OS |
Chemotherapy
- Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1 & 8
- Fluorouracil (5-FU) 500 mg/m2 IV bolus once per day on days 1 & 8
- Folinic acid (Leucovorin) 20 mg/m2 IV bolus once per day on days 1 & 8
- Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
References
- 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
- 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
- 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
- Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1, 8, 15, 22
42-day cycles
References
- 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
- Fluorouracil (5-FU) 500 mg/m2 IV bolus once per day on days 1 & 2
- Folinic acid (Leucovorin) 60 mg/m2 IV bolus once per day on days 1 & 2, given 30 minutes after 5-FU
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 30 to 90 minutes once on day 1, given first
14-day cycle for 8 cycles
References
- 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
- 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
- Update: Guren TK, Thomsen M, Kure EH, Sorbye H, Glimelius B, Pfeiffer P, Österlund P, Sigurdsson F, Lothe IMB, Dalsgaard AM, Skovlund E, Christoffersen T, Tveit KM. Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study. Br J Cancer. 2017 May 9;116(10):1271-1278. Epub 2017 Apr 11. link to PMC article PubMed
SOX
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SOX: S-1 & OXaliplatin
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Hong et al. 2012 | Phase III | CapeOX | Non-inferior PFS |
Chemotherapy
- Tegafur, gimeracil, oteracil (S-1) 40 mg/m2 PO BID on days 1 to 14
- Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
21-day cycle for up to 9 cycles
Patients were allowed to continue maintenance S-1.
References
- Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. link to original article contains protocol PubMed
Maintenance after first-line therapy
Capecitabine monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Hong et al. 2012 | Non-randomized portion of RCT | ||
Luo et al. 2016 | Phase III | Observation | Superior PFS |
Preceding treatment
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO BID on days 1 to 14
21-day cycles
References
- Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. link to original article contains protocol PubMed
- Luo HY, Li YH, Wang W, Wang ZQ, Yuan X, Ma D, Wang FH, Zhang DS, Lin DR, Lin YC, Jia J, Hu XH, Peng JW, Xu RH. Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety. Ann Oncol. 2016 Jun;27(6):1074-81. Epub 2016 Mar 2. link to original article contains verified protocol PubMed
Observation
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Luo et al. 2016 | Phase III | Capecitabine | Inferior PFS |
No further treatment after first-line induction.
Preceding treatment
References
- Luo HY, Li YH, Wang W, Wang ZQ, Yuan X, Ma D, Wang FH, Zhang DS, Lin DR, Lin YC, Jia J, Hu XH, Peng JW, Xu RH. Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety. Ann Oncol. 2016 Jun;27(6):1074-81. Epub 2016 Mar 2. link to original article contains verified protocol PubMed
S-1 monotherapy
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Regimen
Study | Evidence |
---|---|
Hong et al. 2012 | Non-randomized portion of RCT |
Preceding treatment
- SOX x 9
Chemotherapy
- Tegafur, gimeracil, oteracil (S-1) 40 mg/m2 PO BID on days 1 to 14
21-day cycles
References
- Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. link to original article contains protocol PubMed
Advanced or metastatic disease, subsequent lines
Best supportive care
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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 |
Kim et al. 2016 | Phase III | Panitumumab | Inferior OS |
No treatment except for supportive care.
References
- 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
- 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
- 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
- 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
- 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
CAPIRI
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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
- Capecitabine (Xeloda) 1000 mg/m2 BID on days 1 to 14
- Irinotecan (Camptosar) 250 mg/m2 IV over 90 minutes once on day 1
21-day cycles
References
- 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 60 minutes once per week
Supportive medications
- Varies depending on reference
- Antihistamine (such as Diphenhydramine (Benadryl) 50 mg IV) prior to at least the first infusion Cetuximab (Erbitux)
Given until progression of disease or unacceptable toxicity
Regimen #2, escalated dose
Note: 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
- Antihistamine prior to Cetuximab (Erbitux)
14-day cycles
References
- 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
- 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
- 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
- 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
- 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
FOLFIRI
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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan
Example orders
Regimen #1, lower-dose leucovorin
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, higher-dose leucovorin
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
André et al. 1999 | Non-randomized | ||
Peeters et al. 2010 | Phase III | FOLFIRI & Panitumumab | Inferior PFS |
Van Cutsem et al. 2012 (VELOUR) | Phase III | FOLFIRI & Ziv-aflibercept | Inferior OS |
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 2400 mg/m2 IV continuous infusion over 46 to 48 hours on days 1 & 2, given last (total dose per cycle: 2800 mg/m2)
- In André et al. 1999, the continuous infusion dose could be increased from 1200 mg/m2/day to 1500 mg/m2/day if there were no toxicities higher than grade 1
- Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first together with leucovorin
14-day cycles
References
- 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
- 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
- Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012 Oct 1;30(28):3499-506. link to original article contains verified protocol PubMed
- 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
- 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
- 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
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, started during irinotecan infusion on day 1
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours on days 1 to 2, given last (total dose per cycle: 2800 mg/m2)
- Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first
- Panitumumab (Vectibix) 6 mg/kg IV over 60 minutes once on day 1
14-day cycles
References
- 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 2400 mg/m2 IV continuous infusion over 48 hours on days 1 to 2, given last (total dose per cycle: 2800 mg/m2)
- Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1, given second
- Ramucirumab (Cyramza) 8 mg/kg IV over 60 minutes once on day 1, given first
14-day cycles
References
- 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
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, given after ziv-aflibercept
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours on days 1 to 2, given last (total dose per cycle: 2800 mg/m2)
- Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1, given after ziv-aflibercept
- Ziv-aflibercept (Zaltrap) 4 mg/kg IV over 60 minutes once on day 1, given first
Supportive medications
- "Premedication with Atropine (Atropen) and anti-emetics was permitted. Granulocyte-colony stimulating factor (G-CSF) was used according to the American Society of Clinical Oncology guidelines (2006)."
14-day cycles
References
- 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
- 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, 250 mg/m2 q3wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Haller et al. 2008 | Phase III (C) | IROX | Inferior OS |
This starting dose was intended for patients who were at least 65 years old, had prior abdomen/pelvic radiation, or had elevated bilirubin. Dose escalations in the absence of grade 2 or higher toxicities were allowed.
Chemotherapy
- Irinotecan (Camptosar) 250 mg/m2 IV over 90 minutes once on day 1
21-day cycles
Regimen #2, 300 mg/m2 q3wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Fuchs et al. 2003 | Phase III | Irinotecan 4 weeks out of 6 | Seems not superior |
Sobrero et al. 2008 (EPIC) | Phase III (C) | Irinotecan & Cetuximab | Seems not superior |
Seymour et al. 2013 (PICCOLO) | Phase III (C) | Irinotecan & Panitumumab | Seems not superior |
This starting dose was intended for patients who were at least 70 years old, had ECOG performance status 2 or more, or had prior pelvic radiation.
Chemotherapy
- Irinotecan (Camptosar) 300 mg/m2 IV over 90 minutes once on day 1
21-day cycles
Regimen #3, 350 mg/m2 q3wk
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Cunningham et al. 1998 | Phase III (E) | Supportive care | Superior OS |
Fuchs et al. 2003 | Phase III | Irinotecan 4 weeks out of 6 | Seems not superior |
Sobrero et al. 2008 (EPIC) | Phase III (C) | Irinotecan & Cetuximab | Seems not superior |
Haller et al. 2008 | Phase III (C) | IROX | Inferior OS |
Seymour et al. 2013 (PICCOLO) | Phase III (C) | Irinotecan & Panitumumab | Seems not superior |
Chemotherapy
- Irinotecan (Camptosar) 350 mg/m2 IV over 90 minutes once on day 1
Supportive medications
- (varied depending on reference):
- "Standard regimens of antiemetics, Atropine (Atropen), and intensive Loperamide (Imodium)," but no prophylactic Atropine (Atropen) allowed on cycle 1 day 1
21-day cycles
Regimen #4, 4 weeks on, 2 weeks off
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Fuchs et al. 2003 | Phase III | Irinotecan every 3 weeks | Seems not superior |
Note: In contrast to what is described here, some guidelines list irinotecan as being given on days 1 & 8 of a 21-day cycle. No primary reference could be found for this.
Chemotherapy
- Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1, 8, 15, 22
42-day cycles
References
- 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
- 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
- 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
- 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
- Seymour MT, Brown SR, Middleton G, Maughan T, Richman S, Gwyther S, Lowe C, Seligmann JF, Wadsley J, Maisey N, Chau I, Hill M, Dawson L, Falk S, O'Callaghan A, Benstead K, Chambers P, Oliver A, Marshall H, Napp V, Quirke P. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013 Jul;14(8):749-59. Epub 2013 May 29. link to original article link to PMC article contains verified protocol PubMed
Irinotecan & Cetuximab
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Regimen #1, q3wk irinotecan
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Cunningham et al. 2004 | Phase III | Cetuximab | Superior TTP |
Sobrero et al. 2008 (EPIC) | Phase III | Irinotecan | Seems not superior |
Chemotherapy
- 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
- 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
Supportive medications
- Antihistamine prior to at least the first infusion of Cetuximab (Erbitux)
21-day cycles
Regimen #2, irinotecan 4 weeks on, 2 weeks off
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Cunningham et al. 2004 | Phase III | Cetuximab | Superior TTP |
Chemotherapy
- Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1, 8, 15, 22
- 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
Supportive medications
- Antihistamine prior to at least the first infusion of Cetuximab (Erbitux)
42-day cycles
Regimen #3, irinotecan 2 weeks on, 1 week off
Note: In contrast to Cunningham et al. 2004, some guidelines list irinotecan as being given on days 1 & 8 of a 21-day cycle. No primary reference could be found for this.
Chemotherapy
- Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1 & 8
- 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
Supportive medications
- Antihistamine prior to at least the first infusion of Cetuximab (Erbitux)
21-day cycles
Regimen #4, escalated dose cetuximab
Study | Evidence |
---|---|
Martín-Martorell et al. 2008 | Phase II |
Chemotherapy
- Irinotecan (Camptosar) 180 mg/m2 IV over 30 minutes once on day 1
- 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
- Antihistamine prior to Cetuximab (Erbitux)
- Dexamethasone (Decadron) & Ondansetron (Zofran) prior to Irinotecan (Camptosar)
14-day cycles
References
- 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
- 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
- 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
- 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
IROX
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IROX: IRinotecan, OXaliplatin
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Haller et al. 2008 | Phase III | Irinotecan | Superior OS |
Chemotherapy
- Irinotecan (Camptosar) 200 mg/m2 IV over 30 to 90 minutes once on day 1, given second
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first
21-day cycles
References
- 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
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
- Panitumumab (Vectibix) 6 mg/kg IV over 60 minutes once on day 1
14-day cycles
References
- 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
- 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
- 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
Pembrolizumab (Keytruda) for unresectable or metastatic colon cancer
Placebo
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Yoshino et al. 2012 | Randomized Phase II | Trifluridine and tipiracil | 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 |
Hickish et al. 2017 | Phase III | MABp1 | Inferior primary endpoint |
No active antineoplastic treatment.
References
- Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, Tsuji A, Yamaguchi K, Muro K, Sugimoto N, Tsuji Y, Moriwaki T, Esaki T, Hamada C, Tanase T, Ohtsu A. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2012 Oct;13(10):993-1001. Epub 2012 Aug 28. link to original article contains protocol PubMed
- 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
- 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
- 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
- Hickish T, Andre T, Wyrwicz L, Saunders M, Sarosiek T, Kocsis J, Nemecek R, Rogowski W, Lesniewski-Kmak K, Petruzelka L, Apte RN, Mohanty P, Stecher M, Simard J, de Gramont A. MABp1 as a novel antibody treatment for advanced colorectal cancer: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2017 Feb;18(2):192-201. Epub 2017 Jan 14. link to original article PubMed
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
References
- 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
- 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
- Trifluridine and tipiracil (Lonsurf) 35 mg/m2 PO twice per day, used within 1 hour after the morning and evening meals on days 1 to 5, 8 to 12
28-day cycles
References
- 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