Colon cancer
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10 regimens on this page
20 variants on this page
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Adjuvant therapy
Capecitabine (Xeloda)
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Regimen
Study | Evidence | Comparator |
Twelves et al. 2005 | Phase III | 5-FU & Leucovorin |
- Capecitabine (Xeloda) 1250 mg/m2 PO BID on days 1 to 14
21-day cycles x 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
CapeOx, XELOX
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CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda (Capecitabine), OXaliplatin
Regimen #1
Study | Evidence | Comparator |
Schmoll et al. 2007 | Phase III | 5-FU & Leucovorin |
Note: This is the same trial as described by Haller et al. 2011, but the schedule for Capecitabine (Xeloda) is slightly different.
- 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 cycles x 8 cycles
Regimen #2
Study | Evidence | Comparator |
Haller et al. 2011 | Phase III | 5-FU & Leucovorin |
Note: This is the same trial as described by Schmoll et al. 2007, but the schedule for Capecitabine (Xeloda) is slightly different.
- 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 cycles x 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
- 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
Fluorouracil & Folinic acid
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Regimen #1, 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV)
Study | Evidence | Comparator | |
O'Connell et al. 1997 | Phase III | Observation | |
Haller et al. 2005 (Intergroup 0089) | Phase III | High-dose 5-FU & Folinic acid; 5-FU, Folinic acid & Levamisole |
- 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 x 3 cycles, then 35-day cycles x 3 cycles
Regimen #2, 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV)
Study | Evidence | Comparator | |
Twelves et al. 2005 | Phase III | Capecitabine | |
Schmoll et al. 2007 | Phase III | CapeOx | |
Haller et al. 2011 | Phase III | CapeOx |
- 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 cycles x 6 cycles
Regimen #3, 5-FU & high-dose Leucovorin (Roswell Park regimen/HDLV)
Study | Evidence | Comparator | |
Haller et al. 2005 (Intergroup 0089) | Phase III | Low-dose 5-FU & Folinic acid; 5-FU, Folinic acid & Levamisole | |
Lembersky et al. 2006 (NSABP C-06) | Phase III | Uracil-tegafur & Folinic acid | |
Schmoll et al. 2007 | Phase III | CapeOx | |
Kuebler et al. 2007 (NSABP C-07) | Phase III | FLOX | |
Haller et al. 2011 | Phase III | CapeOx |
- 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 on days 1, 8, 15, 22, 29, 36; 1 hour after start of leucovorin
8-week cycles x 3-4 cycles
Regimen #4
Study | Evidence | Comparator |
André et al. 2004 (MOSAIC) | Phase III | FOLFOX 4 |
To be completed
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
- 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
- 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
- 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
- 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
Fluorouracil, Folinic acid, Levamisole
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Regimen
Study | Evidence | Comparator |
Haller et al. 2005 (Intergroup 0089) | Phase III | High-dose 5-FU & Folinic acid; Low-dose 5-FU & Folinic acid |
Not in routine use; used as a comparator arm and here for reference purposes only.
- 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 cycles x 3 cycles, then 35-day cycles x 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
Regimen
Study | Evidence | Comparator |
Kuebler et al. 2007 (NSABP C-07) | Phase III | 5-FU & Leucovorin |
- Fluorouracil (5-FU) 500 mg/m2 IV bolus 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 Fluorouracil (5-FU)
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once per day on days 1, 15, 29, given prior to 5-FU and leucovorin
8-week cycles x 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
FOLFOX 4
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FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin
Also known as FOLFOX4.
Regimen
Study | Evidence | Comparator |
André et al. 2004 (MOSAIC) | Phase III | 5-FU & Folinic acid |
- Fluorouracil (5-FU) 400 mg/m2 IV bolus, then 600 mg/m2/day IV continuous infusion over 22 hours once per day on days 1 & 2 (both bolus and continuous infusion are given on days 1 & 2)
- Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, before 5-FU
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, concurrent with leucovorin
14-day cycles x 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
- Retrospective: Goldberg RM, Tabah-Fisch I, Bleiberg H, de Gramont A, Tournigand C, Andre T, Rothenberg ML, Green E, Sargent DJ. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol. 2006 Sep 1;24(25):4085-91. link to original article PubMed
mFOLFOX 6
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mFOLFOX: modified FOLinic acid, Fluorouracil, OXaliplatin
Regimen
Study | Evidence | Comparator | |
Allegra et al. 2009 (NSABP C-08) | Phase III | mFOLFOX 6 & Bevacizumab | |
Alberts et al. 2012 | Phase III | mFOLFOX 6 & Cetuximab |
- 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 cycles x 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 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 PubMed
mFOLFOX 6 & Bevacizumab
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FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin
The NCCN, Colon Cancer version 1.2015, does not recommend using bevacizumab as adjuvant therapy outside of a clinical trial.
Regimen
Study | Evidence | Comparator |
Allegra et al. 2009 (NSABP C-08) | Phase III | mFOLFOX 6 |
- 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 cycles x 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 PubMed
mFOLFOX 6 & Cetuximab
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FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin
The NCCN, Colon Cancer version 1.2015, does not recommend using cetuximab as adjuvant therapy outside of a clinical trial.
Regimen
Study | Evidence | Comparator |
Alberts et al. 2012 | Phase III | mFOLFOX 6 |
- 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 1 hour 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 cycles x 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 PubMed
Observation
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Regimen
Study | Evidence | Comparator |
O'Connell et al. 1997 | Phase III | 5-FU & Leucovorin |
No treatment; 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
Uracil-tegafur & Folinic acid
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Regimen
Study | Evidence | Comparator |
Lembersky et al. 2006 (NSABP C-06) | Phase III | 5-FU & Leucovorin |
- Uracil-tegafur (UFT) 100 mg/m2 PO Q8H (total dose of 300 mg/m2/day) on days 1 to 28
- Folinic acid (Leucovorin) 30 mg PO Q8H (total dose of 90 mg/day) on days 1 to 28
- No food for 1 hour before and after each dose of medication.
35-day cycles x 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
Advanced or metastatic disease
Bevacizumab & Capecitabine
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Regimen
Study | Evidence | Comparator |
Cunningham et al. 2013 (AVEX) | Phase III | Capecitabine |
Note: The NCCN, Colon Cancer version 1.2015, lists Capecitabine (Xeloda) 850 to 1250 mg/m2 as the dosage range.
- Capecitabine (Xeloda) 650 to 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
- Abstract: David Cunningham, Istvan Lang, Vito Lorusso, Janja Ocvirk, Dongbok Shin, Derek J. Jonker, Stuart Osborne, Niko Alexander Andre, Daniel Waterkamp, Mark P. Saunders. Bevacizumab (bev) in combination with capecitabine (cape) for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): Results of a randomized international phase III trial (AVEX). 2013 ASCO Gastrointestinal Cancers Symposium abstract 337. link to abstract
Capecitabine (Xeloda)
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Regimen
Study | Evidence | Comparator | |
Hoff et al. 2001 | Phase III | 5-FU + Folinic acid | |
Van Cutsem et al. 2001 | Phase III | 5-FU + Folinic acid | |
Cunningham et al. 2013 (AVEX) | Phase III | Bevacizumab & Capecitabine |
Note: The NCCN, Colon Cancer version 1.2015, lists Capecitabine (Xeloda) 850 to 1250 mg/m2 as the dosage range. No primary reference for the lower monotherapy dosages could be found.
- 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
- Abstract: David Cunningham, Istvan Lang, Vito Lorusso, Janja Ocvirk, Dongbok Shin, Derek J. Jonker, Stuart Osborne, Niko Alexander Andre, Daniel Waterkamp, Mark P. Saunders. Bevacizumab (bev) in combination with capecitabine (cape) for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): Results of a randomized international phase III trial (AVEX). 2013 ASCO Gastrointestinal Cancers Symposium abstract 337. link to abstract
CapeOx (XELOX)
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CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda, OXaliplatin
Regimen #1, Hochster et al. 2008 (TREE-1)
Study | Evidence | Comparator | |
Cassidy et al. 2008 | Phase III | FOLFOX 4 | |
Saltz et al. 2008 | Phase III | CapeOx & Bevacizumab |
- 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
21-day cycles, given until progression of disease, or unacceptable toxicity; Cassidy et al. 2008 & Saltz et al. 2008 said that initial treatment could be given up to 16 cycles, but then could continue beyond that for patients who did not have progression of disease
Regimen #2
Study | Evidence | Comparator |
Hochster et al. 2008 (TREE-2) | Phase III | CapeOx & Bevacizumab |
- Capecitabine (Xeloda) 850 mg/m2 PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
- In Hochster et al. 2008 (TREE-2), based on safety data from TREE-1, the initial capecitabine dose was decreased to 850 mg/m2 PO BID. Patients with a creatinine clearance of 30 to 50 mL/min received Capecitabine (Xeloda) 650 mg/m2 PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
- Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
21-day cycles, given until progression of disease or unacceptable toxicity
References
- 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. 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
CapeOx (XELOX) & Bevacizumab
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CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda, OXaliplatin
Regimen #1, Cassidy et al. 2008
Study | Evidence | Comparator |
Saltz et al. 2008 | Phase III | CapeOx |
- Capecitabine (Xeloda) 1000 mg/m2 PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
- Note: In Saltz et al. 2008--the same study as Cassidy et al. 2008--capecitabine was described as being given 1000 mg/m2 PO BID on days 1 to 14
- Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
- Bevacizumab (Avastin) 7.5 mg/kg IV over 30 to 90 minutes once on day 1, given before oxaliplatin
21-day cycles, given until progression of disease, or unacceptable toxicity; Cassidy et al. 2008 & Saltz et al. 2008 said that initial treatment could be given up to 16 cycles, but then could continue beyond that for patients who did not have progression of disease
Regimen #2
Study | Evidence | Comparator |
Hochster et al. 2008 (TREE-2) | Phase III | CapeOx |
- Capecitabine (Xeloda) 850 mg/m2 PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
- In Hochster et al. 2008 (TREE-2), patients with a creatinine clearance of 30 to 50 mL/min received Capecitabine (Xeloda) 650 mg/m2 PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
- Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
- Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles, given until progression of disease or unacceptable toxicity
References
- 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. 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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Regimen
Study | Evidence |
Moehler et al. 2009 | Phase II |
To be completed
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 original article contains verified protocol PubMed
CAPIRI-Bev
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Regimen
Study | Evidence |
Moehler et al. 2009 | Phase II |
To be completed
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 original article contains verified protocol PubMed
Cetuximab (Erbitux)
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Regimen #1
Study | Evidence | Comparator | |
Cunningham et al. 2004 | Phase III | Cetuximab & Irinotecan | |
Lenz et al. 2006 | Phase II | ||
BMS white paper 2007 | Phase III | Best supportive care | |
Jonker et al. 2007 | Phase III | Best supportive care | |
Asmis et al. 2011 (NCIC CTG CO.17) | Phase III | Best supportive care | |
Price et al. 2014 (ASPECCT) | Phase III | Panitumumab |
- Cetuximab (Erbitux) 400 mg/m2 IV over 2 hours once on day 1 of cycle 1, then 250 mg/m2 IV over 1 hour once per week
Supportive medications (varies depending on reference):
- 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
Study | Evidence |
Martín-Martorell et al. 2008 | Phase II |
Note: The NCCN, Colon Cancer version 1.2015, lists this dosage and schedule as an option, although no primary reference could be found for this exact regimen. The regimen described by Martín-Martorell et al. 2008 they cited used cetuximab together with irinotecan.
- Cetuximab (Erbitux) 500 mg/m2 IV over 2 hours once on day 1
- If tolerated, subsequent doses of cetuximab 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
- Bristol-Myers Squibb and ImClone. A Phase III Randomized Study of Cetuximab (Erbitux, C225) and Best Supportive Care Versus Best Supportive Care in Patients with Pretreated Metastatic Epidermal Growth Factor Receptor (EGFR)-Positive Colorectal Carcinoma. Final Clinical Study Report for CA225025. 2007 Mar 5. link to original report contains verified protocol
- 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
- 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--see note above PubMed
- 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
Cetuximab & Irinotecan
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Regimen #1
Study | Evidence | Comparator | |
Cunningham et al. 2004 | Phase III | Cetuximab | |
Sobrero et al. 2008 (EPIC) | Phase III | Irinotecan |
- Cetuximab (Erbitux) as follows:
- 400 mg/m2 IV over 2 hours once on day 1 of cycle 1, then 250 mg/m2 IV over 1 hour once per day on days 8 & 15 of cycle 1
- 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15 of subsequent cycles
- 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, Irinotecan (Camptosar) is 300 mg/m2 IV over 90 minutes once on day 1
Supportive medications:
- Antihistamine prior to at least the first infusion of Cetuximab (Erbitux)
21-day cycles
Regimen #2
Study | Evidence | Comparator |
Cunningham et al. 2004 | Phase III | Cetuximab |
- Cetuximab (Erbitux) as follows:
- 400 mg/m2 IV over 2 hours on cycle 1 day 1, then 250 mg/m2 IV over 60 minutes once per day on days 8, 15, 22, 29, 36 of cycle 1
- 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36 of subsequent cycles
- Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1, 8, 15, 22
Supportive medications:
- Antihistamine prior to at least the first infusion of Cetuximab (Erbitux)
42-day cycles
Regimen #3
Note: In contrast to Cunningham et al. 2004, the NCCN, Colon Cancer version 1.2015, lists Irinotecan (Camptosar) as being given on days 1 & 8 of a 21-day cycle. No primary reference could be found for this.
- Cetuximab (Erbitux) 400 mg/m2 IV over 2 hours on cycle 1 day 1, then 250 mg/m2 IV over 60 minutes once per day on days 8 & 15 of cycle 1; then on subsequent cycles, Cetuximab (Erbitux) 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
- Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1 & 8
Supportive medications:
- Antihistamine prior to at least the first infusion of Cetuximab (Erbitux)
21-day cycles
Regimen #4, Martín-Martorell et al. 2008
Study | Evidence |
Martín-Martorell et al. 2008 | Phase II |
- Cetuximab (Erbitux) 500 mg/m2 IV over 2 hours once on day 1
- If tolerated, subsequent doses of cetuximab can be given over 1 hour
- Irinotecan (Camptosar) 180 mg/m2 IV over 30 minutes once on day 1
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 PubMed
Fluorouracil & Folinic acid
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Regimen #1
Study | Evidence | Comparator |
de Gramont et al. 2000 | Phase III | FOLFOX 4 |
- Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, given first before 5-FU
- 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 #2 "Modified de Gramont"
Study | Evidence |
Cheeseman et al. 2002 | Non-randomized |
- Folinic acid (Leucovorin) 350 mg IV over 2 hours once on day 1, given first
- Instead of Folinic acid (Leucovorin), an alternative is 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 (total dose of 2800 mg/m2) IV continuous infusion over 46 hours on days 1 to 2
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 #3 "Mayo Clinic regimen"
Study | Evidence | Comparator | |
Saltz et al. 2000 (Irinotecan Study Group) | Phase III | FOLFIRI Irinotecan | |
Hoff et al. 2001 | Phase III | Capecitabine | |
Van Cutsem et al. 2001 | Phase III | Capecitabine |
- 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 #4 "Roswell Park regimen"
Study | Evidence | Comparator |
Kabbinavar et al. 2003 | Randomized Phase II, >20 per arm | 5-FU, Folinic acid & Bevacizumab |
- 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 #5
Study | Evidence | Comparator |
Jäger et al. 1996 | Phase III | 5-FU & High-dose Folinic acid |
- 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, 1 hour after start of leucovorin
7-day cycles
Regimen #6, André et al. 1999 (simplified biweekly (sLV5FU2))
- 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 after leucovorin, then 1200 mg/m2/day (total dose of 2400 mg/m2) IV continuous infusion over 46 to 48 hours on days 1 to 2
14-day cycles
Regimen #7
Study | Evidence | Comparator |
Douillard et al. 2000 | Phase III | IFL |
- 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
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
- 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 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
Regimen #1
Study | Evidence | Comparator | |
André et al. 1999 | Non-randomized | ||
Fuchs et al. 2007 (BICC-C) | Phase III | FOLFIRI & Bevacizumab | |
Peeters et al. 2010 | Phase III | FOLFIRI & Panitumumab |
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, given during irinotecan infusion
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 1200 mg/m2/day (total dose of 2400 mg/m2) IV continuous infusion over 46 to 48 hours on days 1 to 2, given last
- In André et al. 1999, the continuous infusion dose of Fluorouracil (5-FU) 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
Regimen #2
Study | Evidence | Comparator | |
Saltz et al. 2000 (Irinotecan Study Group) | Phase III | 5-FU & Folinic acid Irinotecan | |
Hurwitz et al. 2004 | Phase III | FOLFIRI & Bevacizumab |
- Folinic acid (Leucovorin) 20 mg/m2 IV bolus 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
- Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1, 8, 15, 22
6-week 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
- 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
- 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
- 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
- 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
- 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
FOLFIRI & Bevacizumab
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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan
Regimen #1
Study | Evidence | Comparator |
Fuchs et al. 2007 (BICC-C) | Phase III | FOLFIRI |
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, started during irinotecan infusion
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 1200 mg/m2/day (total dose of 2400 mg/m2) IV continuous infusion over 46 to 48 hours on days 1 to 2, given last
- 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
Study | Evidence | Comparator |
Loupakis et al. 2014 (TRIBE) | Phase III | FOLFOXIRI & Bevacizumab |
Note: Loupakis et al. 2014 listed Folinic acid (Leucovorin) 200 mg/m2 in the body of the paper, whereas the protocol in the supplementary material stated that Levoleucovorin (Fusilev) 200 mg/m2 was used. We have contacted NEJM regarding this suspected error.
- Levoleucovorin (Fusilev) 200 mg/m2 IV over 120 minutes once on day 1
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 1200 mg/m2/day (total dose of 2400 mg/m2) IV continuous infusion over 46 hours on days 1 to 2
- 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 cycles x up to 12 cycles, then followed by maintenance fluorouracil, leucovorin, and bevacizumab given until progression of disease or unacceptable adverse event. Loupakis et al. 2014 (TRIBE) did not provide specific details about the maintenance therapy.
References
- 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
- 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 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
FOLFIRI & Cetuximab
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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan
Regimen
Study | Evidence | Comparator |
Van Cutsem et al. 2009 (CRYSTAL) | Phase III | FOLFIRI |
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, started during irinotecan infusion on day 1
- Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1 can be used instead of Folinic acid (Leucovorin)
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 1200 mg/m2/day (total dose of 2400 mg/m2) IV continuous infusion over 46 hours on days 1 to 2, given last
- Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given 1 hour after completion of cetuximab
- Cetuximab (Erbitux) 400 mg/m2 IV over 2 hours once on cycle 1 day 1, then 250 mg/m2 IV over 60 minutes on day 8 of cycle 1; then on subsequent cycles, Cetuximab (Erbitux) is 250 mg/m2 IV over 60 minutes once per day on days 1 & 8; cetuximab is given first and infusion is to finish 1 hour before FOLFIRI begins
14-day cycles, given until progression of disease or unacceptable toxicity
References
- 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
FOLFIRI & Panitumumab
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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan
Regimen
Study | Evidence | Comparator |
Peeters et al. 2010 | Phase III | FOLFIRI |
- 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 1200 mg/m2/day (total dose of 2400 mg/m2) IV continuous infusion over 46 to 48 hours on days 1 to 2, given last
- 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 |
Tabernero et al. 2015 (RAISE) | Phase III | FOLFIRI |
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, either given third or concurrently with irinotecan
- Fluorouracil (5-FU) 400 mg/m2 IV bolus over 2 to 4 minutes once on day 1, then 1200 mg/m2/day (total dose of 2400 mg/m2) IV continuous infusion over 48 hours on days 1 to 2, given last
- Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1, given second
- Ramucirumab (Cyramza) 8 mg/kg IV over 60 minutes once on day 1, given first
14-day cycles, given until progression of disease, or unacceptable toxicity
References
- 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 Apr 10. link to original article contains verified protocol PubMed
FOLFIRI & Ziv-aflibercept
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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan
Regimen
Study | Evidence | Comparator |
Tabernero et al. 2014 (VELOUR) | Phase III | FOLFIRI |
- 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 1200 mg/m2/day (total dose of 2400 mg/m2) IV continuous infusion over 46 hours on days 1 to 2, given last
- 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 1 hour 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, given until progression of disease or unacceptable toxicity
References
- 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
FOLFOX 4
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FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin
Also known as FOLFOX4.
Regimen #1
Study | Evidence | Comparator | |
de Gramont et al. 2000 | Phase III | 5-FU & Folinic acid | |
Tournigand et al. 2006 (OPTIMOX1) | Phase III | FOLFOX 7 | |
Cassidy et al. 2008 | Phase III | CapeOx |
- Fluorouracil (5-FU) 400 mg/m2 IV bolus, then 600 mg/m2/day IV continuous infusion over 22 hours once per day on days 1 & 2 (both bolus and continuous infusion are given on days 1 & 2)
- Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, before 5-FU
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, concurrent with leucovorin
14-day cycles
References
- 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
- 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
mFOLFOX 6
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FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin
Regimen #1
Study | Evidence | Comparator | |
Cheeseman et al. 2002 | Non-randomized | ||
Hochster et al. 2008 (TREE) | Phase III | CapeOx |
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 1200 mg/m2/day (total dose of 2400 mg/m2) IV continuous infusion over 46 hours on days 1 to 2
- 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
Regimen #2
Study | Evidence | Comparator |
See note | Phase III | See note |
Note: Neither of the references cited by the NCCN, Colon Cancer version 1.2015, contained this 400 mg/m2 dosage of leucovorin. The two references listed here (Boccia et al. 2010 & Saltz et al. 2011) contain the 400 mg/m2 dosage, but mFOLFOX 6 is in combination with cetuximab and/or bevacizumab. No primary reference for this dosage of mFOLFOX 6 by itself could be found.
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 1200 mg/m2/day (total dose of 2400 mg/m2) 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 cycles
Example orders
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 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
- Boccia RV, Cosgriff TM, Headley DL, Badarinath S, Dakhil SR. A phase II trial of FOLFOX6 and cetuximab in the first-line treatment of patients with metastatic colorectal cancer. Clin Colorectal Cancer. 2010 Apr;9(2):102-7. link to original article contains protocol PubMed
- Saltz L, Badarinath S, Dakhil S, Bienvenu B, Harker WG, Birchfield G, Tokaz LK, Barrera D, Conkling PR, O'Rourke MA, Richards DA, Reidy D, Solit D, Vakiani E, Capanu M, Scales A, Zhan F, Boehm KA, Asmar L, Cohn A. Phase III Trial of Cetuximab, Bevacizumab, and 5-Fluorouracil/Leucovorin vs. FOLFOX-Bevacizumab in Colorectal Cancer. Clin Colorectal Cancer. 2012 Jun;11(2):101-11. Epub 2011 Nov 4. link to original article contains protocol PubMed
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 |
Tournigand et al. 2006 (OPTIMOX1) | Phase III | FOLFOX 4 |
FOLFOX 7
- Fluorouracil (5-FU) 1200 mg/m2/day (total dose per cycle of 2400 mg/m2) IV continuous infusion over 46 hours on days 1 to 2
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, given first
- Alternatively, instead of Folinic acid (Leucovorin), one can use: 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 cycles x 6 cycles, until progression of disease or unacceptable toxicity, then proceed to sLV5FU2
Simplified LV5FU2 (sLV5FU2)
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, given second; then Fluorouracil (5-FU) 1500 mg/m2/day (total dose per cycle of 3000 mg/m2) IV continuous infusion over 46 hours on days 1 to 2
- Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, given first
- Alternatively, instead of Folinic acid (Leucovorin), one can use: Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given first
14-day cycles x 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: FOLinic acid, Fluorouracil, OXaliplatin
Regimen #1 (mFOLFOX 6 & Bevacizumab)
Study | Evidence | Comparator |
Saltz et al. 2011 | Phase III | FOLFOX, Bevacizumab & Cetuximab |
- 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 cycles
Regimen #2 (FOLFOX 4 & Bevacizumab)
Study | Evidence |
Emmanouilides et al. 2007 | Phase II |
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 600 mg/m2/day IV continuous infusion over 22 hours; both bolus and continuous infusion given on days 1 & 2
- Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
- Bevacizumab (Avastin) 5 mg/kg IV once on day 1, given first
- Infusion times for bevacizumab 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 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 protocol 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 PubMed
FOLFOX & Panitumumab
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FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin
Regimen #1 (FOLFOX 4 & Panitumumab)
Study | Evidence | Comparator |
Douillard et al. 2010 | Phase III | FOLFOX 4 |
- 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 for panitumumab are 1 hour for cycle 1, then if tolerated, 30 minutes for cycle 2 and later
Regimen #2 (mFOLFOX 6 & Panitumumab)
Note: The two references cited by the NCCN, Colon Cancer version 1.2015, contained different regimens. No primary reference for this regimen could be found.
- 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
FOLFOXIRI
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FOLFOXIRI: FOLinic acid, Fluorouracil, OXaliplatin, IRInotecan
Regimen
Study | Evidence | Comparator |
Falcone et al. 2007 | Phase III | FOLFIRI |
Note: In contrast to Falcone et al. 2007, the NCCN, Colon Cancer version 1.2015, listed the dose of Folinic acid (Leucovorin) as 400 mg/m2 IV on day 1. No primary reference could be found for this.
- 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 |
Loupakis et al. 2014 (TRIBE) | Phase III | FOLFIRI & Bevacizumab |
Note: Loupakis et al. 2014 listed Folinic acid (Leucovorin) 200 mg/m2 in the body of the paper, whereas the protocol in the supplementary material stated that Levoleucovorin (Fusilev) 200 mg/m2 was used. We have contacted NEJM regarding this suspected error. The NCCN, Colon Cancer version 1.2015, listed either Folinic acid (Leucovorin) 400 mg/m2 IV once on day 1 or Levoleucovorin (Fusilev) 200 mg/m2 IV once on day 1 as options.
- Fluorouracil (5-FU) 1600 mg/m2/day (total dose per cycle: 3200 mg/m2) IV continuous infusion over 48 hours on days 1 to 2, given fourth
- Levoleucovorin (Fusilev) 200 mg/m2 IV over 120 minutes once on day 1, given third, together with oxaliplatin
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 120 minutes 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 x 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
Irinotecan (Camptosar)
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Regimen #1
Study | Evidence | Comparator | |
Cunningham et al. 1998 | Phase III | Supportive care | |
Fuchs et al. 2003 | Phase III | Irinotecan weekly |
- 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, Irinotecan (Camptosar) is 300 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 #2
Study | Evidence | Comparator | |
Saltz et al. 2000 (Irinotecan Study Group) | Phase III | 5-FU & Folinic acid;FOLFIRI | |
Fuchs et al. 2003 | Phase III | Irinotecan every 3 weeks |
Note: In contrast to Saltz et al. 2000 & Fuchs et al. 2003, the NCCN, Colon Cancer version 1.2015, listed Irinotecan (Camptosar) as being given on days 1 & 8 of a 21-day cycle. No primary reference could be found for this.
- 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
- 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
- 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
- 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
IROX
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IROX: IRinotecan, OXaliplatin
Regimen
Study | Evidence | Comparator |
Haller et al. 2008 | Phase III | Irinotecan |
- Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first
- Irinotecan (Camptosar) 200 mg/m2 IV over 30 to 90 minutes once on day 1, given second
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
Observation
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Regimen
Study | Evidence | Comparator | |
Cunningham et al. 1998 | Phase III | Irinotecan | |
BMS white paper 2007 | Phase III | Cetuximab | |
Van Cutsem et al. 2007 | Phase III | Panitumumab | |
Jonker et al. 2007 | Phase III | Cetuximab | |
Asmis et al. 2011 (NCIC CTG CO.17) | Phase III | Cetuximab | |
Grothey et al. 2013 (CORRECT) | Phase III | Regorafenib | |
Mayer et al. 2015 (RECOURSE) | Phase III | Trifluridine and tipiracil |
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
- Bristol-Myers Squibb and ImClone. A Phase III Randomized Study of Cetuximab (Erbitux, C225) and Best Supportive Care Versus Best Supportive Care in Patients with Pretreated Metastatic Epidermal Growth Factor Receptor (EGFR)-Positive Colorectal Carcinoma. Final Clinical Study Report for CA225025. 2007 Mar 5. link to original report contains verified protocol
- 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
- 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
- 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
- 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
Panitumumab (Vectibix)
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Regimen
Study | Evidence | Comparator |
Van Cutsem et al. 2008 | Phase III | Best supportive care |
Price et al. 2014 (ASPECCT) | Phase III | Cetuximab |
- Panitumumab (Vectibix) 6 mg/kg IV over 60 minutes once on day 1
14-day cycles, given until progression of disease or unacceptable toxicity
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
Regorafenib (Stivarga)
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Regimen
Study | Evidence | Comparator |
Grothey et al. 2013 (CORRECT) | Phase III | Best supportive care |
Li et al. 2015 (CONCUR) | Phase III | Best supportive care |
- Regorafenib (Stivarga) 160 mg PO once per day on days 1 to 21, taken with a low-fat (<30% fat) breakfast
28-day cycles, given until progression of disease or unacceptable toxicity
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 (Lonsurf)
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Regimen
Study | Evidence | Comparator |
Mayer et al. 2015 (RECOURSE) | Phase III | Placebo |
- 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, given until progression of disease or unacceptable toxicity
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