Colon cancer

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Adjuvant therapy

Capecitabine (Xeloda)

Regimen

21-day cycles x 8 cycles

References

  1. Twelves C, Wong A, Nowacki MP, Abt M, Burris H 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005 Jun 30;352(26):2696-704. link to original article contains verified protocol PubMed

CapeOx (XELOX)

CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda, OXaliplatin

Regimen

21-day cycles x 8 cycles

References

  1. Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A, Maroun J, Price T, Lim R, Van Cutsem E, Park YS, McKendrick J, Topham C, Soler-Gonzalez G, de Braud F, Hill M, Sirzén F, Haller DG. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007 Jan 1;25(1):102-9. link to original article contains verified protocol PubMed

Fluorouracil (5-FU) & Folinic acid (Leucovorin)

Regimen #1, 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV), O'Connell, et al. 1997 & Haller, et al. 2005

28-day cycles x 3 cycles, then 35-day cycles x 3 cycles

Regimen #2, 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV), Twelves, et al. 2005 & Schmoll, et al. 2007

28-day cycles x 6 cycles

Regimen #3, 5-FU & high-dose Leucovorin (Roswell Park regimen/HDLV); Haller, et al. 2005; Lembersky, et al. 2006; Schmoll, et al. 2007; Kuebler, et al. 2007

8-week cycles x 3-4 cycles

References

  1. O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, Wieand HS. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997 Jan;15(1):246-50. link to original article contains verified protocol PubMed
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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

FLOX

FLOX: Fluorouracil, Leucovorin, OXaliplatin

Regimen

8-week cycles x 3 cycles

References

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

FOLFOX 4

Also known as FOLFOX4.

Regimen

14-day cycles x 12 cycles

References

  1. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. link to original article contains verified protocol--regimen was not used in adjuvant setting PubMed
  2. 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
  3. 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
  4. Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. link to original article regimen was not used in adjuvant setting PubMed

mFOLFOX 6

Regimen

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

References

  1. Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Colangelo LH, Lopa SH, Petrelli NJ, Goldberg RM, Atkins JN, Seay TE, Fehrenbacher L, O'Reilly S, Chu L, Azar CA, Wolmark N. Initial safety report of NSABP C-08: A randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol. 2009 Jul 10;27(20):3385-90. Epub 2009 May 4. link to original article contains verified protocol PubMed
  2. Alberts SR, Sargent DJ, Nair S, Mahoney MR, Mooney M, Thibodeau SN, Smyrk TC, Sinicrope FA, Chan E, Gill S, Kahlenberg MS, Shields AF, Quesenberry JT, Webb TA, Farr GH Jr, Pockaj BA, Grothey A, Goldberg RM. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA. 2012 Apr 4;307(13):1383-93. link to original article contains verified protocol PubMed

UFT & leucovorin

Regimen

35-day cycles x 5 cycles

References

  1. Lembersky BC, Wieand HS, Petrelli NJ, O'Connell MJ, Colangelo LH, Smith RE, Seay TE, Giguere JK, Marshall ME, Jacobs AD, Colman LK, Soran A, Yothers G, Wolmark N. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 2006 May 1;24(13):2059-64. link to original article contains verified protocol PubMed

Advanced or metastatic disease

Capecitabine (Xeloda)

Regimen

Note: The NCCN, Colon Cancer version 2.2012, lists Capecitabine (Xeloda) 850-1250 mg/m2 as the dosage range. No primary reference for the lower monotherapy dosages could be found.

21-day cycles

References

  1. Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001 Apr 15;19(8):2282-92. link to original article contains verified protocol PubMed
  2. Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P; Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001 Nov 1;19(21):4097-106. link to original article contains verified protocol PubMed

Capecitabine (Xeloda) & Bevacizumab (Avastin)

Regimen

Note: The NCCN, Colon Cancer version 2.2012, lists Capecitabine (Xeloda) 850-1250 mg/m2 as the dosage range.

21-day cycles

References

  1. Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001 Apr 15;19(8):2282-92. link to original article contains verified protocol--this regimen did not include bevacizumab PubMed
  2. Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P; Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001 Nov 1;19(21):4097-106. link to original article contains verified protocol--this regimen did not include bevacizumab PubMed
  3. 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--this regimen also included treatment with irinotecan PubMed
  4. Pietrantonio F, Biondani P, Pellegrinelli A, Marchianò A, Dotti KF, Buzzoni R, Bartolomeo MD. Hepatic colorectal cancer metastases showing a distinctive pattern of pathological response after metronomic capecitabine and bevacizumab. Med Oncol. 2012 Jan 21. [Epub ahead of print] link to original article contains verified protocol PubMed

CapeOx (XELOX)

CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda, OXaliplatin

Regimen

21-day cycles

References

  1. Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. link to original article contains verified protocol PubMed
  2. 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 (Avastin)

CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda, OXaliplatin

Regimen

21-day cycles

References

  1. Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. link to original article contains verified protocol PubMed
  2. 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

Cetuximab (Erbitux)

Regimen #1, Cunningham, et al. 2004; Lenz, et al. 2006; Jonker et al. 2007

  • Cetuximab (Erbitux) 400 mg/m2 IV over 2 hours on cycle 1 day 1, then 250 mg/m2 IV over 60 minutes on days 8 of cycle 1; then on subsequent cycles, Cetuximab (Erbitux) 250 mg/m2 IV over 60 minutes on days 1 & 8

14-day cycles

Supportive medications:

  • Antihistamine (such as Diphendyramine (Benadryl) 50 mg IV) prior to at least the first infusion cetuximab

Regimen #2, Martín-Martorell, et al. 2008

Note: The NCCN, Colon Cancer version 2.2012, lists this dosage and schedule as an option, although no primary reference could be found for this exact regimen.

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

14-day cycles

Supportive medications:

  • Antihistamine prior to cetuximab

References

  1. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22;351(4):337-45. link to original article contains verified protocol PubMed
  2. Lenz HJ, Van Cutsem E, Khambata-Ford S, Mayer RJ, Gold P, Stella P, Mirtsching B, Cohn AL, Pippas AW, Azarnia N, Tsuchihashi Z, Mauro DJ, Rowinsky EK. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol. 2006 Oct 20;24(30):4914-21. link to original article contains verified protocol PubMed
  3. Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007 Nov 15;357(20):2040-8. link to original article contains verified protocol PubMed
  4. 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

Cetuximab (Erbitux) & Irinotecan (Camptosar)

Regimen #1, Cunningham, et al. 2004 & Sobrero, et al. 2008

21-day cycles

Supportive medications:

  • Antihistamine prior to at least the first infusion of cetuximab

Regimen #2, Cunningham, et al. 2004

  • Cetuximab (Erbitux) 400 mg/m2 IV over 2 hours on cycle 1 day 1, then 250 mg/m2 IV over 60 minutes on days 8, 15, 22, 29, 36 of cycle 1; then on subsequent cycles, Cetuximab (Erbitux) 250 mg/m2 IV over 60 minutes on days 1, 8, 15, 22, 29, 36
  • Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes on days 1, 8, 15, 22

42-day cycles

Supportive medications:

  • Antihistamine prior to at least the first infusion cetuximab

Regimen #3

Note: In contrast to Cunningham, et al. 2004, the NCCN, Colon Cancer version 2.2012, lists Irinotecan (Camptosar) as being given on days 1 & 8 of a 21-day cycle. No primary reference could be found for this.

21-day cycles

Supportive medications:

  • Antihistamine prior to at least the first infusion cetuximab

Regimen #4, Martín-Martorell, et al. 2008

14-day cycles

Supportive medications:

  • Antihistamine prior to cetuximab
  • Dexamethasone & ondansetron prior to irinotecan

References

  1. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22;351(4):337-45. link to original article contains verified protocol PubMed
  2. Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kröning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008 May 10;26(14):2311-9. Epub 2008 Apr 7. link to original article contains verified protocol PubMed
  3. Martín-Martorell P, Roselló S, Rodríguez-Braun E, Chirivella I, Bosch A, Cervantes A. Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial. Br J Cancer. 2008 Aug 5;99(3):455-8. link to original article contains verified protocol PubMed

Fluorouracil (5-FU) & Folinic acid (Leucovorin)

Regimen #1, de Gramont, et al. 2000

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus, 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 before 5-FU on days 1 & 2

14-day cycles

Regimen #2, 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV), Hoff, et al. 2001 & Van Cutsem, et al. 2001

28-day cycles

Regimen #3, 5-FU & high-dose Leucovorin (Roswell Park regimen/HDLV), Kabbinavar, et al. 2003

8-week cycles

Regimen #4, Jäger, et al. 1996

7-day cycles

Regimen #5, simplified biweekly (sLV5FU2), André, et al. 1999

14-day cycles

Regimen #6, Douillard, et al. 2000

7-day cycles

References

  1. Jäger E, Heike M, Bernhard H, Klein O, Bernhard G, Lautz D, Michaelis J, Meyer zum Büschenfelde KH, Knuth A. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. J Clin Oncol. 1996 Aug;14(8):2274-9. link to original article contains verified protocol PubMed
  2. 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
  3. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-7. link to original article contains verified protocol PubMed
  4. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. link to original article contains verified protocol PubMed
  5. 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
  6. 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
  7. 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

Regimen

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day IV continuous infusion over 46-48 hours on days 1-2, 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
  • Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours, started during irinotecan infusion on day 1
  • Irinotecan (Camptosar) 180 mg/m2 IV over 30-90 minutes on day 1, given first

14-day cycles

References

  1. André T, Louvet C, Maindrault-Goebel F, Couteau C, Mabro M, Lotz JP, Gilles-Amar V, Krulik M, Carola E, Izrael V, de Gramont A. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer. 1999 Sep;35(9):1343-7. link to original article contains verified protocol PubMed
  2. 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
  3. Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article PubMed
  4. 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 & Bevacizumab (Avastin)

Regimen

14-day cycles

References

  1. Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article contains verified protocol PubMed
  2. 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

FOLFIRI & Cetuximab (Erbitux)

Regimen

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day IV continuous infusion over 46-48 hours on days 1-2, given last
  • Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours, started during irinotecan infusion on day 1
  • Irinotecan (Camptosar) 180 mg/m2 IV over 30-90 minutes on day 1, given first
  • Cetuximab (Erbitux) 400 mg/m2 IV over 2 hours 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) 250 mg/m2 IV over 60 minutes on days 1 & 8
    • Alternate schedule as described in Martín-Martorell, et al. 2008: Cetuximab (Erbitux) 500 mg/m2 IV over 2 hours on day 1

14-day cycles

Supportive medications:

  • Antihistamine prior to at least the first infusion of cetuximab

References

  1. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22;351(4):337-45. link to original article contains verified protocol PubMed
  2. Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kröning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008 May 10;26(14):2311-9. Epub 2008 Apr 7. link to original article contains verified protocol--regimen was only for cetuximab and irinotecan; regimen did not involve Fluorouracil (5-FU) or Folinic acid (Leucovorin) PubMed
  3. Martín-Martorell P, Roselló S, Rodríguez-Braun E, Chirivella I, Bosch A, Cervantes A. Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial. Br J Cancer. 2008 Aug 5;99(3):455-8. link to original article contains verified protocol--regimen was only for cetuximab and irinotecan; regimen did not involve Fluorouracil (5-FU) or Folinic acid (Leucovorin) PubMed

FOLFIRI & Panitumumab (Vectibix)

Regimen

14-day cycles

References

  1. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010 Nov 1;28(31):4706-13. Epub 2010 Oct 4. link to original article contains verified protocol PubMed

FOLFOX 4

Also known as FOLFOX4.

Regimen

14-day cycles

References

  1. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. link to original article contains verified protocol PubMed
  2. Goldberg RM, 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
  3. Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. link to original article PubMed

mFOLFOX 6

Regimen #1, Cheeseman, et al. 2002 & Hochster, et al. 2008

14-day cycles

Regimen #2, Boccia, et al. 2010 & Saltz, et al. 2011

Note: Neither of the references cited by the NCCN, Colon Cancer version 2.2012, contained this 400 mg/m2 dosage of leucovorin. The two references listed here 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.

14-day cycles

References

  1. Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12;87(4):393-9. link to original article contains verified protocol PubMed
  2. Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. link to original article contains verified protocol PubMed
  3. Boccia RV, Cosgriff TM, Headley DL, Badarinath S, Dakhil SR. A phase II trial of FOLFOX6 and cetuximab in the first-line treatment of patients with metastatic colorectal cancer. Clin Colorectal Cancer. 2010 Apr;9(2):102-7. link to original article contains protocol PubMed
  4. Saltz L, Badarinath S, Dakhil S, Bienvenu B, Harker WG, Birchfield G, Tokaz LK, Barrera D, Conkling PR, O'Rourke MA, Richards DA, Reidy D, Solit D, Vakiani E, Capanu M, Scales A, Zhan F, Boehm KA, Asmar L, Cohn A. Phase III Trial of Cetuximab, Bevacizumab, and 5-Fluorouracil/Leucovorin vs. FOLFOX-Bevacizumab in Colorectal Cancer. Clin Colorectal Cancer. 2011 Nov 4. [Epub ahead of print] link to original article contains protocol PubMed

FOLFOX & Bevacizumab (Avastin)

Regimen #1, mFOLFOX 6 & Bevacizumab (Avastin), Saltz, et al. 2011

14-day cycles

Regimen #2, FOLFOX 4 & Bevacizumab (Avastin), Emmanouilides, et al. 2007

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus 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 on days 1 & 2
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours on day 1
  • Bevacizumab (Avastin) 5 mg/kg IV 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

  1. Emmanouilides C, Sfakiotaki G, Androulakis N, Kalbakis K, Christophylakis C, Kalykaki A, Vamvakas L, Kotsakis A, Agelaki S, Diamandidou E, Touroutoglou N, Chatzidakis A, Georgoulias V, Mavroudis D, Souglakos J. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. BMC Cancer. 2007 May 30;7:91. link to original article PubMed
  2. 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. 2011 Nov 4. [Epub ahead of print] link to original article contains protocol PubMed

FOLFOX & Panitumumab (Vectibix)

Regimen #1, FOLFOX 4 & Panitumumab (Vectibix), Douillard, et al. 2010

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus 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 on days 1 & 2
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours on day 1
  • Panitumumab (Vectibix) 6 mg/kg IV 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 (Vectibix)

Note: The two references cited by the NCCN, Colon Cancer version 2.2012, contained different regimens. No primary reference for this regimen could be found.

14-day cycles

References

  1. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, B?asin'ska-Morawiec M, Šmakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010 Nov 1;28(31):4697-705. Epub 2010 Oct 4. link to original article PubMed

FOLFOXIRI

FOLFOXIRI: FOLinic acid, Fluorouracil, OXaliplatin, IRInotecan

Regimen

Note: In contrast to Falcone, et al. 2007, the NCCN, Colon Cancer version 2.2012, listed the dose of Folinic acid (Leucovorin) as 400 mg/m2 IV on day 1. No primary reference could be found for this.

14-day cycles

References

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

Irinotecan (Camptosar)

Regimen #1, Cunningham, et al. 1998 & Fuchs, et al. 2003

21-day cycles

Supportive medications (varied depending on reference):

  • "Standard regimens of antiemetics, atropine, and intensive loperamide," but no prophylactic atropine allowed on cycle 1 day 1

Regimen #2, weekly irinotecan, Fuchs, et al. 2003

Note: In contrast to Fuchs, et al. 2003, the NCCN, Colon Cancer version 2.2012, listed Irinotecan (Camptosar) as being given on days 1 & 8 of a 21-day cycle. No primary reference could be found for this.

42-day cycles

References

  1. Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1413-8. link to original article contains verified protocol PubMed
  2. Fuchs CS, Moore MR, Harker G, Villa L, Rinaldi D, Hecht JR. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003 Mar 1;21(5):807-14. link to original article contains verified protocol PubMed

IROX

IROX: IRinotecan, OXaliplatin

Regimen

21-day cycles

References

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

Panitumumab (Vectibix)

Regimen

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

References

  1. Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1;25(13):1658-64. link to original article contains verified protocol PubMed
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