Difference between revisions of "Colon cancer"

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===References===
 
===References===
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# Pfeiffer P, Yilmaz M, Möller S, et al. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21(3):412-420. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30827-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/31999946/ PubMed]
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# Pfeiffer P, Yilmaz M, Möller S, Zitnjak D, Krogh M, Petersen LN, Poulsen LO, Winther SB, Thomsen KG, Ovortrup C. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21(3):412-420. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30827-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/31999946/ PubMed]
  
 
[[Category:Colon cancer regimens]]
 
[[Category:Colon cancer regimens]]
 
[[Category:Disease-specific pages]]
 
[[Category:Disease-specific pages]]
 
[[Category:Colorectal cancers]]
 
[[Category:Colorectal cancers]]

Revision as of 20:59, 21 July 2020

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

10 regimens on this page
20 variants on this page


Guidelines

ASCO

ESMO

Older

Japanese Society for Cancer of the Colon and Rectum

NCCN

SIOG

Adjuvant therapy

Capecitabine monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Twelves et al. 2005 (X-ACT) 1998-2001 Phase III (E-RT-switch-ic) FULV Seems to have superior OS (*)
Kerr et al. 2016 (QUASAR 2) Phase III (C) Capecitabine & Bevacizumab Did not meet primary endpoint of DFS36
Hamaguchi et al. 2017 (JCOG0910) Phase III (C) S-1 Inconclusive whether non-inferior DFS
Tomita et al. 2019 (JFMC37-0801) Phase III (C) Capecitabine x 12 mo Might have inferior DFS

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

Preceding treatment

Chemotherapy

21-day cycle for 8 cycles

References

  1. X-ACT: Twelves C, Wong A, Nowacki MP, Abt M, Burris HA 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005 Jun 30;352(26):2696-704. link to original article contains verified protocol PubMed
    1. Update: Twelves C, Scheithauer W, McKendrick J, Seitz JF, Van Hazel G, Wong A, Díaz-Rubio E, Gilberg F, Cassidy J. Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy. Ann Oncol. 2012 May;23(5):1190-7. Epub 2011 Sep 6. link to original article PubMed
  2. QUASAR 2: Kerr RS, Love S, Segelov E, Johnstone E, Falcon B, Hewett P, Weaver A, Church D, Scudder C, Pearson S, Julier P, Pezzella F, Tomlinson I, Domingo E, Kerr DJ. Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial. Lancet Oncol. 2016 Nov;17(11):1543-1557. link to original article contains protocol PubMed
  3. JCOG0910: Hamaguchi T, Shimada Y, Mizusawa J, Kinugasa Y, Kanemitsu Y, Ohue M, Fujii S, Takiguchi N, Yatsuoka T, Takii Y, Ojima H, Masuko H, Kubo Y, Mishima H, Yamaguchi T, Bando H, Sato T, Kato T, Nakamura K, Fukuda H, Moriya Y. Capecitabine versus S-1 as adjuvant chemotherapy for patients with stage III colorectal cancer (JCOG0910): an open-label, non-inferiority, randomised, phase 3, multicentre trial. Lancet Gastroenterol Hepatol. 2018 Jan;3(1):47-56. Epub 2017 Oct 24. link to original article PubMed
  4. JFMC37-0801: Tomita N, Kunieda K, Maeda A, Hamada C, Yamanaka T, Sato T, Yoshida K, Boku N, Nezu R, Yamaguchi S, Mishima H, Sadahiro S, Muro K, Ishiguro M, Sakamoto J, Saji S, Maehara Y. Phase III randomised trial comparing 6 vs 12-month of capecitabine as adjuvant chemotherapy for patients with stage III colon cancer: final results of the JFMC37-0801 study. Br J Cancer. 2019 Apr;120(7):689-696. Epub 2019 Mar 5. link to original article contains verified protocol PubMed

CapeOx

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CapeOx: Capecitabine & Oxaliplatin
CAPOX: CAPecitabine & OXaliplatin
XELOX: XELoda (Capecitabine) & OXaliplatin

Example orders

Regimen variant #1, 3 months

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

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

Regimen variant #2, 6 months

Study Evidence Comparator Comparative Efficacy
Schmoll et al. 2007 (XELOXA) Phase III (E-switch-ic) FULV Seems to have superior OS (*)
Pectasides et al. 2015 Phase III (C) mFOLFOX6 Did not meet primary endpoint of DFS
Snoeren et al. 2017 (HEPATICA) Phase III (C) CapeOx & Bevacizumab Did not meet primary endpoint of DFS
Iveson et al. 2018 (SCOT) Phase III (C) CapeOx x 3 mo Seems to have non-inferior DFS

Note: HEPATICA enrolled patients with resected colorectal liver metastases. Reported efficacy for XELOXA is based on the 2015 update.

Preceding treatment

Chemotherapy

  • Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
    • Some references specify from the evening of day 1 to the morning of day 15 (28 doses per cycle)
  • Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1

21-day cycle for 8 cycles

References

  1. XELOXA: Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A, Maroun J, Price T, Lim R, Van Cutsem E, Park YS, McKendrick J, Topham C, Soler-Gonzalez G, de Braud F, Hill M, Sirzén F, Haller DG. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007 Jan 1;25(1):102-9. link to original article contains verified protocol PubMed
    1. Update: Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011 Apr 10;29(11):1465-71. Epub 2011 Mar 7. link to original article PubMed
    2. Update: Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: Final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015 Nov 10;33(32):3733-40. Epub 2015 Aug 31. link to original article PubMed
  2. Pectasides D, Karavasilis V, Papaxoinis G, Gourgioti G, Makatsoris T, Raptou G, Vrettou E, Sgouros J, Samantas E, Basdanis G, Papakostas P, Bafaloukos D, Kotoula V, Kalofonos HP, Scopa CD, Pentheroudakis G, Fountzilas G. Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or stage III colorectal cancer. BMC Cancer. 2015 May 10;15:384. link to original article contains verified protocol link to PMC article PubMed
  3. HEPATICA: Snoeren N, van Hillegersberg R, Schouten SB, Bergman AM, van Werkhoven E, Dalesio O, Tollenaar RA, Verheul HM, van der Sijp J, Borel Rinkes IH, Voest EE; Hepatica study group. Randomized phase III study to assess efficacy and safety of adjuvant CAPOX with or without bevacizumab in patients after resection of colorectal liver metastases: HEPATICA study. Neoplasia. 2017 Feb;19(2):93-99. Epub 2017 Jan 12. link to original article link to PMC article contains verified protocol PubMed
  4. IDEA: Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018 Mar 29;378(13):1177-1188. link to original article does not contain protocol PubMed NCT01308086
    1. Subgroup analysis: Souglakos J, Boukovinas I, Kakolyris S, Xynogalos S, Ziras N, Athanasiadis A, Androulakis N, Christopoulou A, Vaslamatzis M, Ardavanis A, Emmanouilides C, Bompolaki I, Kourousis C, Makrantonakis P, Christofyllakis C, Athanasiadis E, Kentepozidis N, Karampeazis A, Katopodi U, Anagnosopoulos A, Papadopoulos G, Prinarakis E, Kalisperi A, Mavroudis D, Georgoulias V; Hellenic Oncology Research Group. Three versus six months adjuvant FOLFOX or CAPOX for high risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project. Ann Oncol. 2019 Aug 1;30(8):1304-1310. Epub 2019 Jun 22. link to original article PubMed
  5. SCOT: Iveson TJ, Kerr RS, Saunders MP, Cassidy J, Hollander NH, Tabernero J, Haydon A, Glimelius B, Harkin A, Allan K, McQueen J, Scudder C, Boyd KA, Briggs A, Waterston A, Medley L, Wilson C, Ellis R, Essapen S, Dhadda AS, Harrison M, Falk S, Raouf S, Rees C, Olesen RK, Propper D, Bridgewater J, Azzabi A, Farrugia D, Webb A, Cunningham D, Hickish T, Weaver A, Gollins S, Wasan HS, Paul J. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2018 Apr;19(4):562-578. link to original article contains verified protocol PubMed

Fluorouracil & Levoleucovorin

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Regimen variant #1, 370/25, weekly

Study Years of enrollment Evidence Comparator Comparative Efficacy
Gray et al. 2000 (QUASAR) 1994-1997 Phase III (C) 1. FULV; HDLV Did not meet primary endpoint of OS
2. FULV & Levamisole; LDLV
3. FULV & Levamisole; HDLV 		Might have superior OS

Preceding treatment

Chemotherapy

7-day cycle for 30 cycles

Regimen variant #2, 1850/125, q4wk

Study Years of enrollment Evidence Comparator Comparative Efficacy
Gray et al. 2000 (QUASAR) 1994-1997 Phase III (C) 1. FULV; HDLV Did not meet primary endpoint of OS
2. FULV & Levamisole; LDLV
3. FULV & Levamisole; HDLV 		Might have superior OS

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

References

  1. QUASAR: Gray RG, Kerr DJ, McConkey CC, Williams NS, Hills RK; QUASAR Collaborative Group. Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. Lancet. 2000 May 6;355(9215):1588-96. link to original article contains verified protocol PubMed
    1. Update: Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ; Quasar Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007 Dec 15;370(9604):2020-9. link to original article PubMed

FLOX

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FLOX: Fluorouracil, Leucovorin, OXaliplatin

Example orders

Regimen

Study Evidence Comparator Comparative Efficacy
Kuebler et al. 2007 (NSABP C-07) Phase III (E-esc) FULV Superior DFS

Preceding treatment

Chemotherapy

8-week cycle for 3 cycles

References

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

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
André et al. 2004 (MOSAIC) 1998-2001 Phase III (E-RT-esc) FULV Seems to have superior OS (*)
de Gramont et al. 2012 (AVANT) Phase III (C) 1. FOLFOX4 & Bevacizumab Did not meet primary endpoint of DFS
2. XELOX & Bevacizumab Did not meet primary endpoint of DFS
Taieb et al. 2014 (PETACC-8) Phase III (C) FOLFOX4 & Cetuximab Did not meet primary endpoint of DFS
Grothey et al. 2018 (IDEA) 2007-2015 Phase III (C) FOLFOX4 x 6 Inconclusive whether non-inferior DFS36

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

Preceding treatment

Chemotherapy

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

14-day cycle for 12 cycles

References

  1. MOSAIC: André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004 Jun 3;350(23):2343-51. link to original article contains verified protocol PubMed
    1. Update: André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009 Jul 1;27(19):3109-16. Epub 2009 May 18. link to original article PubMed
    2. Update: André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, Scriva A, Hickish T, Tabernero J, Van Laethem JL, Banzi M, Maartense E, Shmueli E, Carlsson GU, Scheithauer W, Papamichael D, Möehler M, Landolfi S, Demetter P, Colote S, Tournigand C, Louvet C, Duval A, Fléjou JF, de Gramont A. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol. 2015 Dec 10;33(35):4176-87. Epub 2015 Nov 2. link to original article PubMed
  2. AVANT: de Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, Cunningham D, Cartwright TH, Hecht JR, Rivera F, Im SA, Bodoky G, Salazar R, Maindrault-Goebel F, Shacham-Shmueli E, Bajetta E, Makrutzki M, Shang A, André T, Hoff PM. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012 Dec;13(12):1225-33. Epub 2012 Nov 16. link to original article contains protocol PubMed
  3. PETACC-8: Taieb J, Tabernero J, Mini E, Subtil F, Folprecht G, Van Laethem JL, Thaler J, Bridgewater J, Petersen LN, Blons H, Collette L, Van Cutsem E, Rougier P, Salazar R, Bedenne L, Emile JF, Laurent-Puig P, Lepage C; PETACC-8 Study Investigators. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Jul;15(8):862-73. Epub 2014 Jun 11. link to original article PubMed
  4. IDEA: Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018 Mar 29;378(13):1177-1188. link to original article does not contain protocol PubMed NCT01308086
    1. Subgroup analysis: Souglakos J, Boukovinas I, Kakolyris S, Xynogalos S, Ziras N, Athanasiadis A, Androulakis N, Christopoulou A, Vaslamatzis M, Ardavanis A, Emmanouilides C, Bompolaki I, Kourousis C, Makrantonakis P, Christofyllakis C, Athanasiadis E, Kentepozidis N, Karampeazis A, Katopodi U, Anagnosopoulos A, Papadopoulos G, Prinarakis E, Kalisperi A, Mavroudis D, Georgoulias V; Hellenic Oncology Research Group. Three versus six months adjuvant FOLFOX or CAPOX for high risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project. Ann Oncol. 2019 Aug 1;30(8):1304-1310. Epub 2019 Jun 22. link to original article PubMed

mFOLFOX6

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mFOLFOX6: modified FOLinic acid, Fluorouracil, OXaliplatin

Example orders

Regimen variant #1, 3 months

Study Evidence Comparator Comparative Efficacy
Iveson et al. 2018 (SCOT) Phase III (E-de-esc) mFOLFOX6 x 6 mo Seems to have non-inferior DFS

Preceding treatment

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 2800 mg/m2)
  • Folinic acid (Leucovorin) 350 mg/m2 IV over 2 hours once on day 1, given first, with oxaliplatin
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first, with folinic acid

14-day cycle for 6 cycles

Regimen variant #2, 6 months (LCV 200 mg/m2)

Study Evidence Comparator Comparative Efficacy
Pectasides et al. 2015 Phase III (C) CAPOX Did not meet primary endpoint of DFS

Preceding treatment

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours, given second (total dose per cycle: 2800 mg/m2)
  • Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once on day 1, given first, with oxaliplatin
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first, with folinic acid

14-day cycle for 12 cycles

Regimen variant #3, 6 months (LCV 350 mg/m2)

Study Evidence Comparator Comparative Efficacy
Iveson et al. 2018 (SCOT) Phase III (C) mFOLFOX6 x 3 mo Seems to have non-inferior DFS

Preceding treatment

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours, given second (total dose per cycle: 2800 mg/m2)
  • Folinic acid (Leucovorin) 350 mg/m2 IV over 2 hours once on day 1, given first, with oxaliplatin
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first, with folinic acid

14-day cycle for 12 cycles

Regimen variant #4, 6 months (LCV 400 mg/m2)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Allegra et al. 2009 (NSABP C-08) Phase III (C) mFOLFOX6 & Bevacizumab Did not meet primary endpoint of DFS
Grothey et al. 2018 (IDEA) 2007-2015 Phase III (C) mFOLFOX6 x 3 mo Inconclusive whether non-inferior DFS36
André et al. 2018 (IDEA France) Phase III (C) mFOLFOX6 x 3 mo Seems to have superior DFS

Preceding treatment

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours, given second (total dose per cycle: 2800 mg/m2)
  • Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, given first, with oxaliplatin
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first, with folinic acid

14-day cycle for 12 cycles

References

  1. NSABP C-08: Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Colangelo LH, Lopa SH, Petrelli NJ, Goldberg RM, Atkins JN, Seay TE, Fehrenbacher L, O'Reilly S, Chu L, Azar CA, Wolmark N. Initial safety report of NSABP C-08: A randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol. 2009 Jul 10;27(20):3385-90. Epub 2009 May 4. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Colangelo LH, Atkins JN, Seay TE, Fehrenbacher L, Goldberg RM, O'Reilly S, Chu L, Azar CA, Lopa S, Wolmark N. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011 Jan 1;29(1):11-6. link to original article link to PMC article PubMed
    2. Update: Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Lopa SH, Wolmark N. Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J Clin Oncol. 2013 Jan 20;31(3):359-64. link to original article link to PMC article PubMed
  2. Pectasides D, Karavasilis V, Papaxoinis G, Gourgioti G, Makatsoris T, Raptou G, Vrettou E, Sgouros J, Samantas E, Basdanis G, Papakostas P, Bafaloukos D, Kotoula V, Kalofonos HP, Scopa CD, Pentheroudakis G, Fountzilas G. Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or stage III colorectal cancer. BMC Cancer. 2015 May 10;15:384. link to original article contains verified protocol link to PMC article PubMed
  3. IDEA: Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018 Mar 29;378(13):1177-1188. link to original article does not contain protocol PubMed NCT01308086
    1. Subgroup analysis: Souglakos J, Boukovinas I, Kakolyris S, Xynogalos S, Ziras N, Athanasiadis A, Androulakis N, Christopoulou A, Vaslamatzis M, Ardavanis A, Emmanouilides C, Bompolaki I, Kourousis C, Makrantonakis P, Christofyllakis C, Athanasiadis E, Kentepozidis N, Karampeazis A, Katopodi U, Anagnosopoulos A, Papadopoulos G, Prinarakis E, Kalisperi A, Mavroudis D, Georgoulias V; Hellenic Oncology Research Group. Three versus six months adjuvant FOLFOX or CAPOX for high risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project. Ann Oncol. 2019 Aug 1;30(8):1304-1310. Epub 2019 Jun 22. link to original article PubMed
  4. IDEA France: André T, Vernerey D, Mineur L, Bennouna J, Desrame J, Faroux R, Fratte S, Hug de Larauze M, Paget-Bailly S, Chibaudel B, Bez J, Dauba J, Louvet C, Lepere C, Dupuis O, Becouarn Y, Mabro M, Egreteau J, Bouche O, Deplanque G, Ychou M, Galais MP, Ghiringhelli F, Dourthe LM, Bachet JB, Khalil A, Bonnetain F, de Gramont A, Taieb J; PRODIGE investigators, GERCOR, Fédération Française de Cancérologie Digestive, UNICANCER. Three versus 6 months of oxaliplatin-based adjuvant chemotherapy for patients with stage III colon cancer: disease-free survival results from a randomized, open-label, International Duration Evaluation of Adjuvant (IDEA) France, phase III trial. J Clin Oncol. 2018 May 20;36(15):1469-1477. Epub 2018 Apr 5. link to original article PubMed
  5. SCOT: Iveson TJ, Kerr RS, Saunders MP, Cassidy J, Hollander NH, Tabernero J, Haydon A, Glimelius B, Harkin A, Allan K, McQueen J, Scudder C, Boyd KA, Briggs A, Waterston A, Medley L, Wilson C, Ellis R, Essapen S, Dhadda AS, Harrison M, Falk S, Raouf S, Rees C, Olesen RK, Propper D, Bridgewater J, Azzabi A, Farrugia D, Webb A, Cunningham D, Hickish T, Weaver A, Gollins S, Wasan HS, Paul J. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2018 Apr;19(4):562-578. link to original article contains verified protocol PubMed

mFOLFOX6 (L-Leucovorin)

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mFOLFOX6: modified L-FOLinic acid, Fluorouracil, OXaliplatin

Example orders

Regimen variant #1, 3 months

Study Evidence Comparator Comparative Efficacy
Iveson et al. 2018 (SCOT) Phase III (E-de-esc) mFOLFOX6 x 6 mo Seems to have non-inferior DFS

Preceding treatment

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 2800 mg/m2)
  • Levoleucovorin (Fusilev) 175 mg/m2 IV over 2 hours once on day 1, given first, with oxaliplatin
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first, with L-folinic acid

14-day cycle for 6 cycles

Regimen variant #2, 6 months

Study Evidence Comparator Comparative Efficacy
Iveson et al. 2018 (SCOT) Phase III (C) mFOLFOX6 x 3 mo Seems to have non-inferior DFS

Preceding treatment

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours, given second (total dose per cycle: 2800 mg/m2)
  • Levoleucovorin (Fusilev) 175 mg/m2 IV over 2 hours once on day 1, given first, with oxaliplatin
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first, with folinic acid

14-day cycle for 12 cycles

References

  1. SCOT: Iveson TJ, Kerr RS, Saunders MP, Cassidy J, Hollander NH, Tabernero J, Haydon A, Glimelius B, Harkin A, Allan K, McQueen J, Scudder C, Boyd KA, Briggs A, Waterston A, Medley L, Wilson C, Ellis R, Essapen S, Dhadda AS, Harrison M, Falk S, Raouf S, Rees C, Olesen RK, Propper D, Bridgewater J, Azzabi A, Farrugia D, Webb A, Cunningham D, Hickish T, Weaver A, Gollins S, Wasan HS, Paul J. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2018 Apr;19(4):562-578. link to original article contains verified protocol PubMed

FULV

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FULV: 5-FU & LeucoVorin (Folinic acid)
LV5FU2: LeucoVorin (Folinic acid) & 5-FU for 2 days

Example orders

Regimen variant #1, 500/200, 6 out of 8 weeks

Study Evidence Comparator Comparative Efficacy
Papadimitriou et al. 2011 Phase III (C) IFL Did not meet primary endpoint of DFS36

Preceding treatment

Chemotherapy

8-week cycle for 4 cycles

Regimen variant #2, 500/500, 6 out of 8 weeks

Study Evidence Comparator Comparative Efficacy
Wolmark et al. 1993 (NSABP C-03) Phase III (E-de-esc) MOF Superior OS
Wolmark et al. 1999 (NSABP C-04) Phase III (E-switch-ooc) 1. 5-FU & Levamisole Might have superior OS
2. FULV & Levamisole Did not meet primary endpoints of DFS/OS
Haller et al. 2005 (Intergroup 0089) Phase III (E-esc) 1. FULV; low-dose Did not meet primary endpoint of OS
2. LDLV & Levamisole Did not meet primary endpoint of OS
3. 5-FU & Levamisole Did not meet primary endpoint of OS
Lembersky et al. 2006 (NSABP C-06) Phase III (C) Tegafur, Uracil, Folinic acid Did not meet primary endpoints of DFS/OS
Schmoll et al. 2007 (XELOXA) Phase III (C) CapeOx Seems to have inferior OS
Kuebler et al. 2007 (NSABP C-07) Phase III (C) FLOX Inferior DFS
Saltz et al. 2007 (CALGB 89803) Phase III (C) IFL Did not meet primary endpoints of DFS/OS

Note: this is often called the "Roswell Park regimen" but the original regimen described by Petrelli et al. 1987 & 1989 used a 5-FU dose of 600 mg/m2.

Preceding treatment

Chemotherapy

  • Fluorouracil (5-FU) 500 mg/m2 IV bolus once per day on days 1, 8, 15, 22, 29, 36, given second, 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 first

8-week cycle for 3 to 6 cycles

Regimen variant #3, 600/500, 6 out of 8 weeks ("Roswell Park regimen")

Study Evidence Comparator Comparative Efficacy
Fountzilas et al. 2000 Phase III (C) FULV & IFN alfa-2a Did not meet primary endpoint of OS

Preceding treatment

Chemotherapy

  • Fluorouracil (5-FU) 600 mg/m2 IV bolus once per day on days 1, 8, 15, 22, 29, 36, given second, 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 first

8-week cycle for 4 cycles

Regimen variant #4, 1850/2500 ("NCI schedule")

Study Evidence Comparator Comparative Efficacy
Wolmark et al. 1998 (NSABP C-05) Phase III (C) FULV & Interferon alfa Did not meet primary endpoints of DFS/OS

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

Regimen variant #5, 2000/400 ("de Gramont regimen"/LV5FU2)

Study Years of enrollment Evidence Comparator Comparative Efficacy
André et al. 2003 (GERCOR C96.1) Phase III (C) FULV; monthly Did not meet primary endpoint of DFS
André et al. 2004 (MOSAIC) 1998-2001 Phase III (C) FOLFOX4 Seems to have inferior OS (*)
Ychou et al. 2009 (FFCD 9802) 1998-2002 Phase III (C) IFL Did not meet primary endpoint of DFS
Van Cutsem et al. 2009 (PETACC-3) Phase III (C) IFL Did not meet primary endpoint of DFS

Reported efficacy for MOSAIC is based on the 2009 update.

Preceding treatment

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given second (total dose per cycle: 2000 mg/m2)
  • Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, given first

14-day cycle for 12 cycles

Regimen variant #6, 2125/100 ("Mayo Clinic regimen")

Study Years of enrollment Evidence Comparator Comparative Efficacy
Twelves et al. 2005 (X-ACT) 1998-2001 Phase III (C) Capecitabine Seems to have inferior OS (*)
Schmoll et al. 2007 (XELOXA) Phase III (C) XELOX Seems to have inferior OS
Popov et al. 2008 (PETACC-1) Phase III (C) Raltitrexed Inconclusive whether non-inferior RFS/OS
Köhne et al. 2013 (PETACC-2) Phase III (C) 1. LV5FU2
2. AIO regimen
3. TTD regimen 		Did not meet primary endpoint of OS60

Note: efficacy for X-ACT is based on the 2011 update. Dosing details for PETACC-1 could not be confirmed from the abstract.

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

Regimen variant #7, 2125/100, with cycle elongation ("Mayo Clinic regimen")

Study Evidence Comparator Comparative Efficacy
O'Connell et al. 1997 Phase III (E-esc) Observation Seems to have superior OS
Punt et al. 2002 (Study 157-002) Phase III (C) 1. FULV & Edrecolomab Did not meet primary endpoint of OS
2. Edrecolomab Seems to have superior OS
Haller et al. 2005 (Intergroup 0089) Phase III (E-de-esc) 1. FULV; high-dose Did not meet primary endpoint of OS
2. LDLV & Levamisole Did not meet primary endpoint of OS
3. 5-FU & Levamisole Did not meet primary endpoint of OS
Fields et al. 2009 (Study 157-001) Phase III (C) FULV & Edrecolomab Did not meet primary endpoint of OS

Preceding treatment

Chemotherapy

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

Regimen variant #8, 2800/400 (LV5FUs)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ychou et al. 2009 2001-2006 Phase III (C) FOLFIRI Did not meet primary endpoint of DFS

Preceding treatment

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 2800 mg/m2)
  • Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, given first

14-day cycle for 12 cycles

References

  1. NSABP C-03: Wolmark N, Rockette H, Fisher B, Wickerham DL, Redmond C, Fisher ER, Jones J, Mamounas EP, Ore L, Petrelli NJ, Spurr CL, Dimitrov N, Romond EH, Sutherland CM, Kardinal CG, DeFusco PA, Jochimsen P. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol. 1993 Oct;11(10):1879-87. link to original article contains verified protocol PubMed
    1. Pooled update: Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. link to original article link to PMC article PubMed
  2. O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, Wieand HS. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997 Jan;15(1):246-50. link to original article contains verified protocol PubMed
    1. Pooled update: Erlichman C, O'Connell M, Kahn M, Marsoni S, Torri V, Tardio B, Zaniboni A, Pancera G, Martignoni G, Labianca R, Barni A, Seitz JF, Milan C, Bedenne L, Giovannini M, Letreut YP, Skillings J, Shepard L, Zee B, Petrioli R, Francini G; International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol. 1999 May;17(5):1356-63. link to original article PubMed
  3. NSABP C-05: Wolmark N, Bryant J, Smith R, Grem J, Allegra C, Hyams D, Atkins J, Dimitrov N, Oishi R, Prager D, Fehrenbacher L, Romond E, Colangelo L, Fisher B. Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst. 1998 Dec 2;90(23):1810-6. link to original article PubMed
    1. Pooled update: Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. link to original article link to PMC article PubMed
  4. NSABP C-04: Wolmark N, Rockette H, Mamounas E, Jones J, Wieand S, Wickerham DL, Bear HD, Atkins JN, Dimitrov NV, Glass AG, Fisher ER, Fisher B. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol. 1999 Nov;17(11):3553-9. link to original article contains verified protocol PubMed
    1. Pooled update: Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. link to original article link to PMC article PubMed
  5. Fountzilas G, Zisiadis A, Dafni U, Konstantaras C, Hatzitheoharis G, Papavramidis S, Bousoulegas A, Basdanis G, Giannoulis E, Dokmetzioglou J, Katsohis C, Nenopoulou E, Karvounis N, Briassoulis E, Aravantinos G, Kosmidis P, Skarlos D, Pavlidis N; Hellenic Cooperative Oncology Group. Fluorouracil and leucovorin with or without interferon alfa-2a as adjuvant treatment, in patients with high-risk colon cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Oncology. 2000 Apr;58(3):227-36. link to original article contains protocol PubMed
  6. Study 157-002: Punt CJ, Nagy A, Douillard JY, Figer A, Skovsgaard T, Monson J, Barone C, Fountzilas G, Riess H, Moylan E, Jones D, Dethling J, Colman J, Coward L, MacGregor S. Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study. Lancet. 2002 Aug 31;360(9334):671-7. link to original article contains verified protocol PubMed
  7. GERCOR C96.1: Andre T, Colin P, Louvet C, Gamelin E, Bouche O, Achille E, Colbert N, Boaziz C, Piedbois P, Tubiana-Mathieu N, Boutan-Laroze A, Flesch M, Buyse M, de Gramont A. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol. 2003 Aug 1;21(15):2896-903. link to original article PubMed
    1. Update: André T, Quinaux E, Louvet C, Colin P, Gamelin E, Bouche O, Achille E, Piedbois P, Tubiana-Mathieu N, Boutan-Laroze A, Flesch M, Lledo G, Raoul Y, Debrix I, Buyse M, de Gramont A. Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1. J Clin Oncol. 2007 Aug 20;25(24):3732-8. link to original article PubMed
  8. MOSAIC: André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004 Jun 3;350(23):2343-51. link to original article contains verified protocol PubMed
    1. Update: André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009 Jul 1;27(19):3109-16. Epub 2009 May 18. link to original article PubMed
    2. Update: André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, Scriva A, Hickish T, Tabernero J, Van Laethem JL, Banzi M, Maartense E, Shmueli E, Carlsson GU, Scheithauer W, Papamichael D, Möehler M, Landolfi S, Demetter P, Colote S, Tournigand C, Louvet C, Duval A, Fléjou JF, de Gramont A. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol. 2015 Dec 10;33(35):4176-87. Epub 2015 Nov 2. link to original article PubMed
  9. X-ACT: Twelves C, Wong A, Nowacki MP, Abt M, Burris HA 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005 Jun 30;352(26):2696-704. link to original article contains verified protocol PubMed
    1. Update: Twelves C, Scheithauer W, McKendrick J, Seitz JF, Van Hazel G, Wong A, Díaz-Rubio E, Gilberg F, Cassidy J. Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy. Ann Oncol. 2012 May;23(5):1190-7. Epub 2011 Sep 6. link to original article PubMed
  10. Intergroup 0089: Haller DG, Catalano PJ, Macdonald JS, O'Rourke MA, Frontiera MS, Jackson DV, Mayer RJ. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 2005 Dec 1;23(34):8671-8. link to original article contains verified protocol PubMed
  11. 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
  12. XELOXA: Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A, Maroun J, Price T, Lim R, Van Cutsem E, Park YS, McKendrick J, Topham C, Soler-Gonzalez G, de Braud F, Hill M, Sirzén F, Haller DG. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007 Jan 1;25(1):102-9. link to original article contains verified protocol PubMed
    1. Update: Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011 Apr 10;29(11):1465-71. Epub 2011 Mar 7. link to original article contains verified protocol PubMed
    2. Update: Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: Final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015 Nov 10;33(32):3733-40. Epub 2015 Aug 31. link to original article PubMed
  13. NSABP C-07: Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, Zapas JL, Goodwin JW, Fehrenbacher L, Ramanathan RK, Conley BA, Flynn PJ, Soori G, Colman LK, Levine EA, Lanier KS, Wolmark N. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007 Jun 1;25(16):2198-204. Epub 2007 Apr 30. link to original article contains protocol PubMed
    1. Update: Yothers G, O'Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, Wolmark N. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011 Oct 1;29(28):3768-74. Epub 2011 Aug 22. link to original article link to PMC article PubMed
  14. CALGB 89803: Saltz LB, Niedzwiecki D, Hollis D, Goldberg RM, Hantel A, Thomas JP, Fields AL, Mayer RJ. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol. 2007 Aug 10;25(23):3456-61. link to original article contains verified protocol PubMed
  15. PETACC-1: Popov I, Carrato A, Sobrero A, Vincent M, Kerr D, Labianca R, Raffaele Bianco A, El-Serafi M, Bedenne L, Paillot B, Mini E, Sanches E, Welch J, Collette L, Praet M, Wils J. Raltitrexed (Tomudex) versus standard leucovorin-modulated bolus 5-fluorouracil: Results from the randomised phase III Pan-European Trial in Adjuvant Colon Cancer 01 (PETACC-1). Eur J Cancer. 2008 Oct;44(15):2204-11. Epub 2008 Aug 15. link to original article PubMed
  16. FFCD 9802: Ychou M, Raoul JL, Douillard JY, Gourgou-Bourgade S, Bugat R, Mineur L, Viret F, Becouarn Y, Bouché O, Gamelin E, Ducreux M, Conroy T, Seitz JF, Bedenne L, Kramar A. A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). Ann Oncol. 2009 Apr;20(4):674-80. Epub 2009 Jan 29. link to original article contains protocol PubMed
  17. Study 157-001: Fields AL, Keller A, Schwartzberg L, Bernard S, Kardinal C, Cohen A, Schulz J, Eisenberg P, Forster J, Wissel P. Adjuvant therapy with the monoclonal antibody edrecolomab plus fluorouracil-based therapy does not improve overall survival of patients with stage III colon cancer. J Clin Oncol. 2009 Apr 20;27(12):1941-7. Epub 2009 Mar 9. link to original article contains verified protocol PubMed
  18. PETACC-3: Van Cutsem E, Labianca R, Bodoky G, Barone C, Aranda E, Nordlinger B, Topham C, Tabernero J, André T, Sobrero AF, Mini E, Greil R, Di Costanzo F, Collette L, Cisar L, Zhang X, Khayat D, Bokemeyer C, Roth AD, Cunningham D. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol. 2009 Jul 1;27(19):3117-25. Epub 2009 May 18. link to original article contains protocol PubMed
  19. Ychou M, Hohenberger W, Thezenas S, Navarro M, Maurel J, Bokemeyer C, Shacham-Shmueli E, Rivera F, Kwok-Keung Choi C, Santoro A. A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer. Ann Oncol. 2009 Dec;20(12):1964-70. Epub 2009 Jun 30. link to original article contains protocol PubMed
  20. Papadimitriou CA, Papakostas P, Karina M, Malettou L, Dimopoulos MA, Pentheroudakis G, Samantas E, Bamias A, Miliaras D, Basdanis G, Xiros N, Klouvas G, Bafaloukos D, Kafiri G, Papaspirou I, Pectasides D, Karanikiotis C, Economopoulos T, Efstratiou I, Korantzis I, Pisanidis N, Makatsoris T, Matsiakou F, Aravantinos G, Kalofonos HP, Fountzilas G; Hellenic Cooperative Oncology Group. A randomized phase III trial of adjuvant chemotherapy with irinotecan, leucovorin and fluorouracil versus leucovorin and fluorouracil for stage II and III colon cancer: a Hellenic Cooperative Oncology Group study. BMC Med. 2011 Jan 31;9:10. link to original article link to PMC article contains protocol PubMed
  21. PETACC-2: Köhne CH, Bedenne L, Carrato A, Bouché O, Popov I, Gaspà L, Valladares M, Rougier P, Gog C, Reichardt P, Wils J, Pignatti F, Biertz F. A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: the Pan-European Trial in Adjuvant Colon Cancer 2 study. Eur J Cancer. 2013 May;49(8):1868-75. Epub 2013 Apr 6. link to original article PubMed

SOX

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SOX: S-1, OXaliplatin

Regimen

Study Evidence Comparator Comparative Efficacy
Sunami et al. 2019 (ACTS-CC 02) Phase III (E-esc) Tegafur, Uracil, Folinic Acid Did not meet primary endpoint of DFS

Preceding treatment

Chemotherapy

21-day cycle for 8 cycles

References

  1. ACTS-CC 02: Sunami E, Kusumoto T, Ota M, SakamotoY, Yoshida K, Tomita N, Maeda A, Teshima J, Okabe M, Tanaka C, Yamauchi J, Itabashi M, Kotake K, Takahashi K, Baba H, Boku N, Aiba K, Ishiguro M, Morita S, Takenaka N, Okude R, Sugihara K. S-1 and oxaliplatin versus tegafur-uracil and leucovorin as postoperative adjuvant chemotherapy in patients with high-risk stage III colon cancer (ACTS-CC 02): a randomized, open-label, multicenter, phase 3, superiority trial. Clinical Colorectal Cancer (2019). Epub Oct 2019. link to original article

Tegafur, Uracil, Folinic acid

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UFT + LV: UFT (Tegafur and uracil) & LeucoVorin (Folinic acid)

Regimen variant #1, 300/75

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hasegawa et al. 2016 2004-2010 Phase III (E-esc) Observation Superior RFS
Sadahiro et al. 2015 (JFMC33-0502) 2005-2007 Phase III (C) UFT + LV weekly x 18 mo Did not meet primary endpoint of DFS
Yoshida et al. 2014 (ACTS-CC) 2008-2009 Phase III (C) S-1 Non-inferior DFS
Shimada et al. 2014 (JCOG0205) Phase III (E-switch-ic) FULV Non-inferior DFS
Miyake et al. 2018 Phase III (C) UFT/PSK Inconclusive whether non-inferior DFS36

Note: Miyake et al. 2018 does not contain treatment details in the abstract.

Preceding treatment

Chemotherapy

35-day cycle for 5 cycles

Regimen variant #2, 300/90

Study Evidence Comparator Comparative Efficacy
Lembersky et al. 2006 (NSABP C-06) Phase III (E-switch-ic) FULV Did not meet primary endpoints of DFS/OS

Preceding treatment

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

Chemotherapy

35-day cycle for 5 cycles

References

  1. NSABP C-06: Lembersky BC, Wieand HS, Petrelli NJ, O'Connell MJ, Colangelo LH, Smith RE, Seay TE, Giguere JK, Marshall ME, Jacobs AD, Colman LK, Soran A, Yothers G, Wolmark N. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 2006 May 1;24(13):2059-64. link to original article contains verified protocol PubMed
  2. ACTS-CC: Yoshida M, Ishiguro M, Ikejiri K, Mochizuki I, Nakamoto Y, Kinugasa Y, Takagane A, Endo T, Shinozaki H, Takii Y, Mochizuki H, Kotake K, Kameoka S, Takahashi K, Watanabe T, Watanabe M, Boku N, Tomita N, Nakatani E, Sugihara K; ACTS-CC study group. S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial). Ann Oncol. 2014 Sep;25(9):1743-9. Epub 2014 Jun 18. link to original article link to PMC article PubMed NCT00660894
  3. JCOG0205: Shimada Y, Hamaguchi T, Mizusawa J, Saito N, Kanemitsu Y, Takiguchi N, Ohue M, Kato T, Takii Y, Sato T, Tomita N, Yamaguchi S, Akaike M, Mishima H, Kubo Y, Nakamura K, Fukuda H, Moriya Y. Randomised phase III trial of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients with stage III colorectal cancer who have undergone Japanese D2/D3 lymph node dissection: final results of JCOG0205. Eur J Cancer. 2014 Sep;50(13):2231-40. Epub 2014 Jun 20. link to original article contains verified protocol PubMed
  4. JFMC33-0502: Sadahiro S, Tsuchiya T, Sasaki K, Kondo K, Katsumata K, Nishimura G, Kakeji Y, Baba H, Sato S, Koda K, Yamaguchi Y, Morita T, Matsuoka J, Usuki H, Hamada C, Kodaira S. Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502. Ann Oncol. 2015 Nov;26(11):2274-80. Epub 2015 Sep 7. link to original article link to PMC article contains protocol PubMed UMIN-CTR C000000245
  5. Hasegawa K, Saiura A, Takayama T, Miyagawa S, Yamamoto J, Ijichi M, Teruya M, Yoshimi F, Kawasaki S, Koyama H, Oba M, Takahashi M, Mizunuma N, Matsuyama Y, Watanabe T, Makuuchi M, Kokudo N. Adjuvant oral uracil-tegafur with leucovorin for colorectal cancer liver metastases: A randomized controlled trial. PLoS One. 2016 Sep 2;11(9):e0162400. eCollection 2016. link to original article link to PMC article contains verified protocol PubMed
  6. Miyake Y, Nishimura J, Kato T, Ikeda M, Tsujie M, Hata T, Takemasa I, Mizushima T, Yamamoto H, Sekimoto M, Nezu R, Doki Y, Mori M; Multi-center Clinical Study Group of Osaka, Colorectal Cancer Treatment Group (MCSGO). Phase III trial comparing UFT + PSK to UFT + LV in stage IIB, III colorectal cancer (MCSGO-CCTG). Surg Today. 2018 Jan;48(1):66-72. Epub 2017 Jun 20. link to original article PubMed

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

FOLFIRI

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Regimen

Study Evidence Comparator Comparative Efficacy
Fiorentini et al. 2012 Phase III (C) DEBIRI Seems to have inferior OS

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given second on day 1 (total dose per cycle: 2000 mg/m2)
  • Folinic acid (Leucovorin) 100 mg/m2 IV over 120 minutes once on day 1, given first, with irinotecan
  • Irinotecan (Camptosar) 180 mg/m2 IV over 120 minutes once on day 1, given first, with leucovorin

14-day cycle for 8 cycles

References

  1. Fiorentini G, Aliberti C, Tilli M, Mulazzani L, Graziano F, Giordani P, Mambrini A, Montagnani F, Alessandroni P, Catalano V, Coschiera P. Intra-arterial infusion of irinotecan-loaded drug-eluting beads (DEBIRI) versus intravenous therapy (FOLFIRI) for hepatic metastases from colorectal cancer: final results of a phase III study. Anticancer Res. 2012 Apr;32(4):1387-95. Erratum in: Anticancer Res. 2013 Nov;33(11):5211. link to original article PubMed

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Nordlinger et al. 2008 (EORTC 40983) 2000-2004 Phase III (E-esc) Observation Superior PFS
Hebbar et al. 2014 (MIROX) 2004-2010 Phase III (C) FOLFOX7-FOLFIRI Did not meet primary endpoint of DFS24

Note: this is the regimen as described by de Gramont et al. 2000; EORTC 40983 refers to this protocol. In MIROX, the treatment could be given perioperatively or postoperatively.

Preceding treatment

Chemotherapy

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

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

References

  1. EORTC 40983: Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie; Australasian Gastro-Intestinal Trials Group; Fédération Francophone de Cancérologie Digestive. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008 Mar 22;371(9617):1007-16. link to original article link to PMC article does not contain protocol PubMed NCT00006479
    1. Update: Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Mauer M, Tanis E, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und–tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie; Australasian Gastro-Intestinal Trials Group; Fédération Francophone de Cancérologie Digestive. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectalcancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1208-15. Epub 2013 Oct 11. link to original article PubMed
  2. MIROX: Hebbar M, Chibaudel B, André T, Mineur L, Smith D, Louvet C, Dutel JL, Ychou M, Legoux JL, Mabro M, Faroux R, Auby D, Brusquant D, Khalil A, Truant S, Hadengue A, Dalban C, Gayet B, Paye F, Pruvot FR, Bonnetain F, Landi B, Flesch M, Carola E, Martin P, Vaillant E, de Gramont A; Group Coopérateur Multidisciplinaire en Oncologie. FOLFOX4 versus sequential dose-dense FOLFOX7 followed by FOLFIRI in patients with resectable metastatic colorectal cancer (MIROX): a pragmatic approach to chemotherapy timing with perioperative or postoperative chemotherapy from an open-label, randomized phase III trial. Ann Oncol. 2015 Feb;26(2):340-7. Epub 2014 Nov 17. Erratum in: Ann Oncol. 2015 May;26(5):1040. Taieb, J [removed]; Brucker, P [removed]. link to original article PubMed NCT00268398

mFOLFOX6 (L-Leucovorin)

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mFOLFOX6: modified L-FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Evidence Comparator Comparative Efficacy
Cashin et al. 2016 (SPS-1) Randomized (C) IP 5-FU & LV Seems to have inferior OS

Chemotherapy

14-day cycle for 12 cycles

References

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

FULV

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FULV: 5-FU & LeucoVorin (Folinic acid)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Portier et al. 2006 (FFCD 9002) 1991-2001 Phase III (E-esc) Observation Might have superior PFS (*)

Reported efficacy is based on the 2008 pooled update.

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

References

  1. FFCD 9002: Portier G, Elias D, Bouche O, Rougier P, Bosset JF, Saric J, Belghiti J, Piedbois P, Guimbaud R, Nordlinger B, Bugat R, Lazorthes F, Bedenne L. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol. 2006 Nov 1;24(31):4976-82. link to original article contains verified protocol PubMed
    1. Pooled update: Mitry E, Fields AL, Bleiberg H, Labianca R, Portier G, Tu D, Nitti D, Torri V, Elias D, O'Callaghan C, Langer B, Martignoni G, Bouché O, Lazorthes F, Van Cutsem E, Bedenne L, Moore MJ, Rougier P. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol. 2008 Oct 20;26(30):4906-11. Epub 2008 Sep 15. link to original article PubMed

Hepatic arterial chemotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Allen-Mersh et al. 1994 Phase III (E-esc) Observation Seems to have superior OS
Kemeny et al. 1999 NR Phase III (E-esc) Observation Seems to have superior OS

Of historic interest; unlikely to be completed.

Preceding treatment

Chemotherapy

Supportive medications

References

  1. Allen-Mersh TG, Earlam S, Fordy C, Abrams K, Houghton J. Quality of life and survival with continuous hepatic-artery floxuridine infusion for colorectal liver metastases. Lancet. 1994 Nov 5;344(8932):1255-60. link to original article PubMed
  2. Kemeny N, Huang Y, Cohen AM, Shi W, Conti JA, Brennan MF, Bertino JR, Turnbull AD, Sullivan D, Stockman J, Blumgart LH, Fong Y. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med. 1999 Dec 30;341(27):2039-48. link to original article PubMed

Intraperitoneal 5-FU

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Regimen

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

Preceding treatment

  • Cytoreductive surgery

Chemotherapy

  • Fluorouracil (5-FU) 550 mg/m2/day IP continuous infusion over 6 days, started on day 1 (total dose per cycle: 3300 mg/m2)
  • Folinic acid (Leucovorin) 30 mg/m2/day IV once on day 1, given 60 minutes after start of 5-FU IP infusion

1-month cycle for 6 cycles

References

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

Intraperitoneal hyperthermic mitomycin

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Regimen

Study Evidence Comparator Comparative Efficacy
Verwaal et al. 2003 Phase III (E-switch-ooc) FULV; modified Laufman regimen Seems to have superior OS

Preceding treatment

  • Cytoreductive surgery

Chemotherapy

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

One treatment

References

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

Advanced or metastatic disease, first-line

Capecitabine monotherapy

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C: Capecitabine

Regimen variant #1, 2000 mg/m2/day

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Kwakman et al. 2017 (SALTO) 2014-2015 Phase III (C) S-1 Did not meet secondary efficacy endpoints (*) Higher incidence of hand-foot syndrome

Note: this trial had a primary toxicity endpoint; this dose was intended for patients at least 70 years old; reported efficacy is based on the 2019 update.

Chemotherapy

21-day cycles

Regimen variant #2, 2500 mg/m2/day

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Hoff et al. 2001 1996-1998 Phase III (E-RT-switch-ic) FULV Superior ORR
Van Cutsem et al. 2001 1996-1998 Phase III (E-RT-switch-ic) FULV Equivalent ORR
Koopman et al. 2007 (CAIRO) Phase III (C) See link See link
Tebbutt et al. 2010 (AGITG MAX) Phase III (C) 1. Capecitabine & Bevacizumab Inferior PFS
2. CBM Inferior PFS
Cunningham et al. 2013 (AVEX) Phase III (C) Capecitabine & Bevacizumab Inferior PFS
Kwakman et al. 2017 (SALTO) 2014-2015 Phase III (C) S-1 Did not meet secondary efficacy endpoints (*) Higher incidence of hand-foot syndrome

Note: SALTO had a primary toxicity endpoint; this dose was intended for patients less than 70 years old; reported efficacy is based on the 2019 update.

Chemotherapy

21-day cycles

Subsequent treatment

References

  1. Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001 Apr 15;19(8):2282-92. link to original article contains verified protocol PubMed
    1. Pooled update: Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. link to original article link to PMC article PubMed
  2. Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P; Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001 Nov 1;19(21):4097-106. link to original article contains verified protocol PubMed
    1. Pooled update: Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. link to original article link to PMC article PubMed
  3. CAIRO: Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ; Dutch Colorectal Cancer Group. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article contains verified protocol PubMed
  4. AGITG MAX: Tebbutt NC, Wilson K, Gebski VJ, Cummins MM, Zannino D, van Hazel GA, Robinson B, Broad A, Ganju V, Ackland SP, Forgeson G, Cunningham D, Saunders MP, Stockler MR, Chua Y, Zalcberg JR, Simes RJ, Price TJ. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group randomized phase III MAX study. J Clin Oncol. 2010 Jul 1;28(19):3191-8. Epub 2010 Jun 1. link to original article contains verified protocol PubMed
  5. AVEX: Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, Jonker D, Osborne S, Andre N, Waterkamp D, Saunders MP; AVEX study investigators. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label,randomised phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1077-85. Epub 2013 Sep 10. link to original article PubMed
  6. SALTO: Kwakman JJM, Simkens LHJ, van Rooijen JM, van de Wouw AJ, Ten Tije AJ, Creemers GJM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, van Werkhoven E, Punt CJA; Dutch Colorectal Cancer Group. Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group. Ann Oncol. 2017 Jun 1;28(6):1288-1293. link to original article contains protocol PubMed NCT01918852
    1. Update: Kwakman JJM, van Werkhoven E, Simkens LHJ, van Rooijen JM, van de Wouw YAJ, Tije AJT, Creemers GM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, Punt CJA; Dutch Colorectal Cancer Group. Updated Survival Analysis of the Randomized Phase III Trial of S-1 Versus Capecitabine in the First-Line Treatment of Metastatic Colorectal Cancer by the Dutch Colorectal Cancer Group. Clin Colorectal Cancer. 2019 Jun;18(2):e229-e230. Epub 2019 Jan 29. link to original article PubMed

Capecitabine & Bevacizumab

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CB: Capecitabine & Bevacizumab

Regimen variant #1, 1000/7.5

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

Chemotherapy

Targeted therapy

21-day cycles

Regimen variant #2, 1250/7.5

Study Evidence Comparator Comparative Efficacy
Tebbutt et al. 2010 (AGITG MAX) Phase III (E-esc) Capecitabine Superior PFS

Chemotherapy

Targeted therapy

21-day cycles

References

  1. AGITG MAX: Tebbutt NC, Wilson K, Gebski VJ, Cummins MM, Zannino D, van Hazel GA, Robinson B, Broad A, Ganju V, Ackland SP, Forgeson G, Cunningham D, Saunders MP, Stockler MR, Chua Y, Zalcberg JR, Simes RJ, Price TJ. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group randomized phase III MAX study. J Clin Oncol. 2010 Jul 1;28(19):3191-8. Epub 2010 Jun 1. link to original article PubMed
  2. AVEX: Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, Jonker D, Osborne S, Andre N, Waterkamp D, Saunders MP; AVEX study investigators. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label,randomised phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1077-85. Epub 2013 Sep 10. link to original article contains protocol PubMed
  3. XELAVIRI: Modest DP, Fischer von Weikersthal L, Decker T, Vehling-Kaiser U, Uhlig J, Schenk M, Freiberg-Richter J, Peuser B, Denzlinger C, Peveling Genannt Reddemann C, Graeven U, Schuch G, Schwaner I, Stahler A, Jung A, Kirchner T, Held S, Stintzing S, Giessen-Jung C, Heinemann V; XELAVIRI/AIO KRK0110 Investigators. Sequential Versus Combination Therapy of Metastatic Colorectal Cancer Using Fluoropyrimidines, Irinotecan, and Bevacizumab: A Randomized, Controlled Study-XELAVIRI (AIO KRK0110). J Clin Oncol. 2019 Jan 1;37(1):22-32. Epub 2018 Nov 2. link to original article contains verified protocol PubMed

CapeOx

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CapeOX: Capecitabine & OXaliplatin
XELOX: XELoda & OXaliplatin
COX: Capecitabine & OXaliplatin

Example orders

Regimen variant #1, 850/130

Study Evidence Comparator Comparative Efficacy
Hochster et al. 2008 (TREE-1) Phase III (E-switch-ic) 1. bFOL Did not meet secondary efficacy endpoints
2. mFOLFOX6 Did not meet secondary efficacy endpoints

Note: TREE-1 did not have any primary endpoints.

Chemotherapy

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

21-day cycles

Regimen variant #2, 1000/70

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

Chemotherapy

21-day cycles

Regimen variant #3, 1000/130

Study Evidence Comparator Comparative Efficacy
Díaz-Rubio et al. 2007 Phase III (E-switch-ic) FUOX Did not meet primary endpoint of TTP
Cassidy et al. 2008 (NO16966) Phase III (C) 1. FOLFOX4
2. FOLFOX4 & Bevacizumab 		Non-inferior PFS
3. XELOX & Bevacizumab Not reported
Saltz et al. 2008 (NO16966) Phase III (C) 1. FOLFOX4 & Bevacizumab
2. XELOX & Bevacizumab 		Inferior PFS
3. FOLFOX4 Not reported
Ducreux et al. 2011 Phase III (E-switch-ic) mFOLFOX6 Non-inferior OS
Maughan et al. 2011 (UK MRC COIN) Phase III (C) CapeOx & Cetuximab Did not meet primary endpoint of OS (*)
Hoff et al. 2012 (HORIZON II) Phase III (C) 1. CAPOX & Cediranib
2. FOLFOX4 & Cediranib
3. mFOLFOX6 & Cediranib 		Seems to have inferior PFS
Hong et al. 2012 (SMC 2008-03-012) Phase III (C) SOX Non-inferior PFS

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

Chemotherapy

  • Capecitabine (Xeloda) 1000 mg/m2 PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
    • Note: In Saltz et al. 2008 and SMC 2008-03-012 capecitabine was described as being given 1000 mg/m2 PO twice per day on days 1 to 14
  • Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1

21-day cycles (see note)

Subsequent treatment

References

  1. Porschen R, Arkenau HT, Kubicka S, Greil R, Seufferlein T, Freier W, Kretzschmar A, Graeven U, Grothey A, Hinke A, Schmiegel W, Schmoll HJ; AIO Colorectal Study Group. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol. 2007 Sep 20;25(27):4217-23. Epub 2007 Jun 4. link to original article contains verified protocol PubMed
  2. Díaz-Rubio E, Tabernero J, Gómez-España A, Massutí B, Sastre J, Chaves M, Abad A, Carrato A, Queralt B, Reina JJ, Maurel J, González-Flores E, Aparicio J, Rivera F, Losa F, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol. 2007 Sep 20;25(27):4224-30. Epub 2007 Jun 4. link to original article contains verified protocol PubMed
  3. NO16966: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. link to original article contains verified protocol PubMed
    1. Update: Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. link to original article contains verified protocol PubMed
    2. Update: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64. Epub 2011 Jun 14. link to original article link to PMC article PubMed
  4. TREE: Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. link to original article contains verified protocol PubMed
  5. Ducreux M, Bennouna J, Hebbar M, Ychou M, Lledo G, Conroy T, Adenis A, Faroux R, Rebischung C, Bergougnoux L, Kockler L, Douillard JY; GI Group of the French Anti-Cancer Centers. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer. Int J Cancer. 2011 Feb 1;128(3):682-90. link to original article contains verified protocol PubMed
  6. UK MRC COIN: Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP; MRC COIN Trial Investigators. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011 Jun 18;377(9783):2103-14. Epub 2011 Jun 5. link to original article link to PMC article contains verified protocol PubMed
    1. Update: Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, Kenny SL, Kay E, Hodgkinson E, Pope M, Rogers P, Wasan H, Falk S, Gollins S, Hickish T, Bessell EM, Propper D, Kennedy MJ, Kaplan R, Maughan TS; MRC COIN Trial Investigators. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011 Jul;12(7):642-53. Epub 2011 Jun 5. link to original article link to PMC article PubMed
  7. HORIZON II: Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. link to original article contains verified protocol PubMed
  8. SMC 2008-03-012: Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. link to original article contains protocol PubMed
    1. Update: Kim ST, Hong YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Lee JW, Jo SJ, Park YS. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: updated results from a phase 3 trial. BMC Cancer. 2014 Nov 26;14:883. link to original article link to PMC article PubMed

CapeOx & Bevacizumab

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

Regimen variant #1, 850/130/7.5

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Hochster et al. 2008 (TREE-2) Phase III (E-switch-ic) 1. bFOL & Bevacizumab Did not meet secondary efficacy endpoints Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
2. mFOLFOX6 & Bevacizumab Did not meet secondary efficacy endpoints Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment

Chemotherapy

  • Capecitabine (Xeloda) 850 mg/m2 PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
    • In TREE-2, patients with a CrCl of 30 to 50 mL/min/1.73m2 received 650 mg/m2 PO twice per day
  • Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1

Targeted therapy

21-day cycles

Regimen variant #2, 1000/130/7.5 x 6

Study Years of enrollment Evidence Comparator Comparative Efficacy
Tol et al. 2009 (CAIRO2) Phase III (C) CapeOx, Bevacizumab, Cetuximab Superior PFS
Díaz-Rubio et al. 2012 (MACRO) Non-randomized portion of RCT
Johnsson et al. 2013 (Nordic ACT) 2007-2009 Non-randomized portion of RCT
Simkens et al. 2015 (CAIRO3) 2007-2012 Non-randomized portion of RCT

Chemotherapy

Targeted therapy

21-day cycle for 6 cycles

Subsequent treatment

Regimen variant #3, 1000/130/7.5, indefinite

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cassidy et al. 2008 (NO16966) Phase III (E-esc) 1. FOLFOX4
2. FOLFOX4 & Bevacizumab 		Non-inferior PFS
3. XELOX Not reported
Saltz et al. 2008 (NO16966) Phase III (E-esc) 1. FOLFOX4
2. XELOX 		Superior PFS
3. FOLFOX4 & Bevacizumab Not reported
Yamada et al. 2018 (TRICOLORE) 2012-2014 Phase III (C) IRIS & Bevacizumab Non-inferior PFS
Nakayama 2018 (CCOG-1201) Randomized Phase II (C) CAPIRI & Bevacizumab Did not meet primary endpoint of ORR

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

Chemotherapy

  • Capecitabine (Xeloda) 1000 mg/m2 PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
    • Note: In Saltz et al. 2008--the same study as Cassidy et al. 2008--capecitabine was described as being given 1000 mg/m2 PO twice per day on days 1 to 14
  • Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1, given second

Targeted therapy

21-day cycles

References

  1. NO16966: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. link to original article contains verified protocol PubMed
    1. Update: Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. link to original article contains verified protocol PubMed
    2. Update: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64. Epub 2011 Jun 14. link to original article link to PMC article PubMed
  2. TREE-2: Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. link to original article contains verified protocol PubMed
  3. CAIRO2: Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, Erdkamp FL, Vos AH, van Groeningen CJ, Sinnige HA, Richel DJ, Voest EE, Dijkstra JR, Vink-Börger ME, Antonini NF, Mol L, van Krieken JH, Dalesio O, Punt CJ; Dutch Colorectal Cancer Group. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009 Feb 5;360(6):563-72. Erratum in: N Engl J Med. 2010 Dec 23;363(26):2573. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009 Jul 2;361(1):98-9. Erratum in: N Engl J Med. 2011 Sep 1;365(9):869. link to original article PubMed
  4. MACRO: Díaz-Rubio E, Gómez-España A, Massutí B, Sastre J, Abad A, Valladares M, Rivera F, Safont MJ, Martínez de Prado P, Gallén M, González E, Marcuello E, Benavides M, Fernández-Martos C, Losa F, Escudero P, Arrivi A, Cervantes A, Dueñas R, López-Ladrón A, Lacasta A, Llanos M, Tabernero JM, Antón A, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors. First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study. Oncologist. 2012;17(1):15-25. Epub 2012 Jan 10. link to original article link to PMC article contains verified protocol PubMed
  5. Nordic ACT: Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. link to original article contains verified protocol PubMed NCT00598156
  6. CAIRO3: Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoeven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, Honkoop AH, Mol L, Punt CJ, Koopman M; Dutch Colorectal Cancer Group. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015 May 9;385(9980):1843-52. Epub 2015 Apr 7. link to original article contains verified protocol PubMed NCT00442637
    1. Update: Goey KKH, Elias SG, van Tinteren H, Laclé MM, Willems SM, Offerhaus GJA, de Leng WWJ, Strengman E, Ten Tije AJ, Creemers GM, van der Velden A, de Jongh FE, Erdkamp FLG, Tanis BC, Punt CJA, Koopman M. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann Oncol. 2017 Sep 1;28(9):2128-2134. link to original article PubMed
  7. TRICOLORE: Yamada Y, Denda T, Gamoh M, Iwanaga I, Yuki S, Shimodaira H, Nakamura M, Yamaguchi T, Ohori H, Kobayashi K, Tsuda M, Kobayashi Y, Miyamoto Y, Kotake M, Shimada K, Sato A, Morita S, Takahashi S, Komatsu Y, Ishioka C. S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized, open-label, phase III, noninferiority trial. Ann Oncol. 2018 Mar 1;29(3):624-631. link to original article contains verified protocol link to PMC article PubMed
  8. CCOG-1201: Nakayama G, Mitsuma A, Sunagawa Y, Ishigure K, Yokoyama H, Matsui T, Nakayama H, Nakata K, Ishiyama A, Asada T, Umeda S, Ezaka K, Hattori N, Takami H, Kobayashi D, Tanaka C, Kanda M, Yamada S, Koike M, Fujiwara M, Fujii T, Murotani K, Ando Y, Kodera Y. Randomized phase II trial of CapOX plus bevacizumab and capIRI plus bevacizumab as first-line treatment for Japanese patients with metastatic colorectal cancer (CCOG-1201 study). Oncologist. 2018 Aug;23(8):919-927. Epub 2018 Jul 26. link to original article contains protocol PubMed

CAPIRI

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

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Koopman et al. 2007 (CAIRO) Phase III (E-switch-ic) See link See link
Fuchs et al. 2007 (BICC-C) Phase III (E-switch-ic) 1. FOLFIRI Seems to have inferior PFS
2. mIFL Did not meet primary endpoint of PFS
Köhne et al. 2007 (EORTC 40015) 2003-2005 Phase III (E-switch-ic) FOLFIRI +/- Celecoxib Inconclusive whether non-inferior PFS
Moehler et al. 2009a Phase II

Note: EORTC 40015 was closed prematurely.

Chemotherapy

21-day cycles

Subsequent treatment

  • CAIRO, with progression: CapeOx

References

  1. CAIRO: Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ; Dutch Colorectal Cancer Group. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article contains verified protocol PubMed
  2. BICC-C: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article contains verified protocol PubMed
    1. Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article PubMed
  3. EORTC 40015: Köhne CH, De Greve J, Hartmann JT, Lang I, Vergauwe P, Becker K, Braumann D, Joosens E, Müller L, Janssens J, Bokemeyer C, Reimer P, Link H, Späth-Schwalbe E, Wilke HJ, Bleiberg H, Van Den Brande J, Debois M, Bethe U, Van Cutsem E. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer: EORTC study 40015. Ann Oncol. 2008 May;19(5):920-6. Epub 2007 Dec 6. link to original article contains protocol PubMed
  4. Moehler M, Sprinzl MF, Abdelfattah M, Schimanski CC, Adami B, Godderz W, Majer K, Flieger D, Teufel A, Siebler J, Hoehler T, Galle PR, Kanzler S. Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients. World J Gastroenterol. 2009 Jan 28;15(4):449-56. link to PMC article contains verified protocol link to PMC article PubMed

CAPIRI-Bev

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

Regimen variant #1, 750/150/7.5

Study Years of enrollment Evidence
Johnsson et al. 2013 (Nordic ACT) 2007-2009 Non-randomized portion of RCT

This dose was recommended for patients older than 65 years.

Chemotherapy

Targeted therapy

21-day cycle for 6 cycles

Subsequent treatment

Regimen variant #2, 800/200/7.5

Study Evidence Comparator Comparative Efficacy
Modest et al. 2018 (XELAVIRI) Phase III (E-esc) Cape-Bev Inconclusive whether non-inferior TFS

Chemotherapy

Targeted therapy

21-day cycles

Regimen variant #3, 1000/180/7.5

Study Years of enrollment Evidence
Johnsson et al. 2013 (Nordic ACT) 2007-2009 Non-randomized portion of RCT

Chemotherapy

Targeted therapy

21-day cycle for 6 cycles

Subsequent treatment

Regimen variant #4, 1000/200/7.5

Study Evidence
Moehler et al. 2009a Phase II

Chemotherapy

Targeted therapy

21-day cycles

Regimen variant #5, 1000/240/7.5

Study Evidence Comparator Comparative Efficacy
Pectasides et al. 2012 Phase III (E-switch-ic) FOLFIRI-Bev Did not meet primary endpoint of PFS

Chemotherapy

Targeted therapy

21-day cycle for 6 cycles

References

  1. Moehler M, Sprinzl MF, Abdelfattah M, Schimanski CC, Adami B, Godderz W, Majer K, Flieger D, Teufel A, Siebler J, Hoehler T, Galle PR, Kanzler S. Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients. World J Gastroenterol. 2009 Jan 28;15(4):449-56. link to PMC article contains verified protocol link to PMC article PubMed
  2. Pectasides D, Papaxoinis G, Kalogeras KT, Eleftheraki AG, Xanthakis I, Makatsoris T, Samantas E, Varthalitis I, Papakostas P, Nikitas N, Papandreou CN, Pentheroudakis G, Timotheadou E, Koutras A, Sgouros J, Bafaloukos D, Klouvas G, Economopoulos T, Syrigos KN, Fountzilas G; Hellenic Cooperative Oncology Group. XELIRI-bevacizumab versus FOLFIRI-bevacizumab as first-line treatment in patients with metastatic colorectal cancer: a Hellenic Cooperative Oncology Group phase III trial with collateral biomarker analysis. BMC Cancer. 2012 Jun 29;12:271. link to original article contains verified protocol link to PMC article PubMed
  3. Nordic ACT: Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. link to original article contains verified protocol PubMed NCT00598156
  4. XELAVIRI: Modest DP, Fischer von Weikersthal L, Decker T, Vehling-Kaiser U, Uhlig J, Schenk M, Freiberg-Richter J, Peuser B, Denzlinger C, Peveling Genannt Reddemann C, Graeven U, Schuch G, Schwaner I, Stahler A, Jung A, Kirchner T, Held S, Stintzing S, Giessen-Jung C, Heinemann V; XELAVIRI/AIO KRK0110 Investigators. Sequential Versus Combination Therapy of Metastatic Colorectal Cancer Using Fluoropyrimidines, Irinotecan, and Bevacizumab: A Randomized, Controlled Study-XELAVIRI (AIO KRK0110). J Clin Oncol. 2019 Jan 1;37(1):22-32. Epub 2018 Nov 2. link to original article contains verified protocol PubMed

Fluorouracil monotherapy

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Regimen variant #1, 400 mg/m2 intermittent bolus

Study Years of enrollment Evidence Comparator Comparative Efficacy
Borner et al. 1998 1991-1995 Phase III (C) FULV Seems to have inferior OS

Chemotherapy

1-month cycles

Regimen variant #2, 450 mg/m2 intermittent bolus

Study Evidence Comparator Comparative Efficacy
Molinaro et al. 1989 Phase III (C) Epirubicin Superior ORR

Note: this dose was used for those who had previously been exposed to radiotherapy.

Chemotherapy

28-day cycles

Regimen variant #3, 500 mg/m2 intermittent bolus

Study Evidence Comparator Comparative Efficacy
Lokich et al. 1989 Phase III (C) PVI 5-FU Inferior ORR
Molinaro et al. 1989 Phase III (C) Epirubicin Superior ORR

Chemotherapy

4- to 5-week cycles

Regimen variant #4, 600 mg/m2/week

Study Years of enrollment Evidence Comparator Comparative Efficacy
Smyth et al. 1995 (F-trial) 1989-1992 Phase III (C) TCNU Did not meet efficacy endpoint

Chemotherapy

7-day cycles

Regimen variant #5, 600 mg/m2/week, 6 out of 8 weeks

Study Evidence Comparator Comparative Efficacy
Richards et al. 1986 Phase III (C) MMF Did not meet efficacy endpoints
Kalofonos et al. 2002 Phase III (C) 1. 5-FU & IFN alfa
2. FULV 		Did not meet primary endpoint of OS

Chemotherapy

8-week cycles

Regimen variant #6, weekly bolus with CI lead-in

Study Evidence Comparator Comparative Efficacy
Hill et al. 1995 Phase III (C) 5-FU & IFN alfa-2b Did not meet efficacy endpoints
Greco et al. 1996 Phase III (C) 5-FU & IFN alfa-2a Did not meet primary endpoint of ORR

Chemotherapy

  • Fluorouracil (5-FU) as follows:
    • Cycle 1: 750 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose: 3750 mg/m2)
    • Cycle 2 onwards: 750 mg/m2 IV once on day 1

7-day cycles

Regimen variant #7, weekly CI

Study Years of enrollment Evidence Comparator Comparative Efficacy
Aranda et al. 1998 1994-1996 Phase III (E-switch-ic) FULV; Mayo Clinic regimen Seems to have superior ORR

Chemotherapy

  • Fluorouracil (5-FU) 1750 mg/m2/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 3500 mg/m2)

7-day cycles

Regimen variant #8, PVI ("Lokich regimen")

Study Evidence Comparator Comparative Efficacy
Lokich et al. 1989 Phase III (E-switch-ic) Bolus 5-FU Superior ORR
Hansen et al. 1996 Phase III (E-switch-ic) Bolus 5-FU Superior TTP
Maughan et al. 2002 Phase III (C) 1. FULV; de Gramont regimen Did not meet primary endpoint of OS
2. Raltitrexed Did not meet primary endpoint of OS

Chemotherapy

Continued indefinitely

Regimen variant #9, load to toxicity

Study Evidence Comparator Comparative Efficacy
Witte et al. 2001 Phase III (C) 5-FU & Levamisole Did not meet primary endpoint of OS

Chemotherapy

  • Fluorouracil (5-FU) as follows:
    • Cycle 1: 480 mg/m2 IV once per day on days 1 to 5, then 240 mg/m2 every other day to toxicity or six additional doses
    • Cycle 2 onwards: 480 mg/m2 IV once per day on days 1 to 5

6-week cycle for 1 cycle, then 5-week cycles

References

  1. Richards F 2nd, Case LD, White DR, Muss HB, Spurr CL, Jackson DV, Cooper MR, Zekan P, Cruz J, Stuart JJ, Capizzi RL, McCulloch JH, McFarland JA, Kincaid WR, Harding RW, Pope E, McMahan R, Wellls HB. Combination chemotherapy (5-fluorouracil, methyl-CCNU, mitomycin C) versus 5-fluorouracil alone for advanced previously untreated colorectal carcinoma: a phase III study of the Piedmont Oncology Association. J Clin Oncol. 1986 Apr;4(4):565-70. link to original article PubMed
  2. Lokich JJ, Ahlgren JD, Gullo JJ, Philips JA, Fryer JG. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol. 1989 Apr;7(4):425-32. link to original article contains verified protocol PubMed
  3. Molinaro P, Lafleur F, Blum RH. A phase III randomized trial of epirubicin versus 5-fluorouracil in metastatic rectal/sigmoid adenocarcinoma. Am J Clin Oncol. 1989 Aug;12(4):332-4. PubMed
  4. Hill M, Norman A, Cunningham D, Findlay M, Nicolson V, Hill A, Iveson A, Evans C, Joffe J, Nicolson M, Hickish T. Royal Marsden phase III trial of fluorouracil with or without interferon alfa-2b in advanced colorectal cancer. J Clin Oncol. 1995 Jun;13(6):1297-302. link to original article contains protocol PubMed
  5. Smyth JF, Hardcastle JD, Denton G, Alderson D, Grace RH, Mansi JL, Yosef HM, Nordle O, Lauri H, Wählby S. Two phase III trials of tauromustine (TCNU) in advanced colorectal cancer. Ann Oncol. 1995 Nov;6(9):948-9. link to original article PubMed
  6. Hansen RM, Ryan L, Anderson T, Krzywda B, Quebbeman E, Benson A 3rd, Haller DG, Tormey DC. Phase III study of bolus versus infusion fluorouracil with or without cisplatin in advanced colorectal cancer. J Natl Cancer Inst. 1996 May 15;88(10):668-74. link to original article PubMed
  7. Greco FA, Figlin R, York M, Einhorn L, Schilsky R, Marshall EM, Buys SS, Froimtchuk MJ, Schuller J, Schuchter L, Buyse M, Ritter L, Man A, Yap AK. Phase III randomized study to compare interferon alfa-2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer. J Clin Oncol. 1996 Oct;14(10):2674-81. link to original article contains protocol PubMed
  8. Aranda E, Díaz-Rubio E, Cervantes A, Antón-Torres A, Carrato A, Massutí T, Tabernero JM, Sastre J, Trés A, Aparicio J, López-Vega JM, Barneto I, García-Conde J; Spanish Cooperative Group for Gastrointestinal Tumor Therapy. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol. 1998 Jul;9(7):727-31. link to original article contains protocol PubMed
  9. Witte RS, Cnaan A, Mansour EG, Barylak E, Harris JE, Schutt AJ. Comparison of 5-fluorouracil alone, 5-fluorouracil with levamisole, and 5-fluorouracil with hepatic irradiation in the treatment of patients with residual, nonmeasurable, intra-abdominal metastasis after undergoing resection for colorectal carcinoma. Cancer. 2001 Mar 1;91(5):1020-8. link to original article contains verified protocol PubMed
  10. Kalofonos HP, Nicolaides C, Samantas E, Mylonakis N, Aravantinos G, Dimopoulos MA, Gennatas C, Kouvatseas G, Giannoulis E, Dervenis C, Basdanis G, Pavlidis N, Androulakis I, Fountzilas G; Hellenic Cooperative Oncology Group. A phase III study of 5-fluorouracil versus 5-fluorouracil plus interferon alpha 2b versus 5-fluorouracil plus leucovorin in patients with advanced colorectal cancer: a Hellenic Cooperative Oncology Group (HeCOG) study. Am J Clin Oncol. 2002 Feb;25(1):23-30. link to original article PubMed
  11. Maughan TS, James RD, Kerr DJ, Ledermann JA, McArdle C, Seymour MT, Cohen D, Hopwood P, Johnston C, Stephens RJ; British MRC Colorectal Cancer Working Party. Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2002 May 4;359(9317):1555-63. link to original article PubMed

Fluorouracil & Levoleucovorin

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Regimen variant #1, 1870/50

Study Years of enrollment Evidence Comparator Comparative Efficacy
Labianca et al. 1997 1991-1994 Phase III (C) FULV; HDLV Did not meet primary endpoint of ORR

Chemotherapy

28-day cycles

Regimen variant #2, 1875/500

Study Evidence Comparator Comparative Efficacy
Colucci et al. 1999 Phase III (C) FULV & IFN alfa-2b Did not meet primary efficacy endpoints

Chemotherapy

21-day cycles

Regimen variant #3, 2800/350 ("modified de Gramont regimen")

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

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

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2), given second
  • Levoleucovorin (Fusilev) 175 mg IV over 2 hours once on day 1, given first

Supportive medications

14-day cycles

References

  1. Labianca R, Cascinu S, Frontini L, Barni S, Fiorentini G, Comella G, Zaniboni A, Gottardi O, Arnoldi E, Oliani C, Duro M, Pavanato G, Martignoni G, Raina A, Piazza E, Dallavalle G, Valsecchi R, Pancera G, Luporini G; Italian Group for the Study of Digestive Tract Cancer. High-versus low-dose levo-leucovorin as a modulator of 5-fluorouracil in advanced colorectal cancer: a 'GISCAD' phase III study. Ann Oncol. 1997 Feb;8(2):169-74. link to original article contains protocol PubMed
  2. Colucci G, Maiello E, Gebbia V, Giuliani F, Serravezza G, Lelli G, Leo S, Filippelli G, Nicolella G, Brandi M; SICOG. 5-fluorouracil and levofolinic acid with or without recombinant interferon-2b in patients with advanced colorectal carcinoma: a randomized multicenter study with stratification for tumor burden and liver involvement by the Southern Italy Oncology Group. Cancer. 1999 Feb 1;85(3):535-45. link to original article contains protocol PubMed
  3. Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12;87(4):393-9. link to original article contains verified protocol link to PMC article PubMed
  4. MRC FOCUS: Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, Smith DB, Shepherd S, Maraveyas A, Ferry DR, Meade AM, Thompson L, Griffiths GO, Parmar MK, Stephens RJ; FOCUS Trial Investigators; National Cancer Research Institute Colorectal Clinical Studies Group. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007 Jul 14;370(9582):143-52. Erratum in: Lancet. 2007 Aug 18;370(9587):566. link to original article PubMed

FOLFIRI

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan
FUFIRI: 5-FU (Fluorouracil), Folinic acid, IRInotecan

Example orders

Regimen variant #1, 400/2000/180, bi-weekly ("Lv5FU2-Iri")

Study Years of enrollment Evidence Comparator Comparative Efficacy
Aranda et al. 2008 1994-1996 Phase III (C) FUIRI Did not meet primary endpoint of ORR (*)
Douillard et al. 2000 1997-1998 Phase III (E-RT-esc) FULV Seems to have superior OS
Souglakos et al. 2006 Phase III (C) FOLFOXIRI Did not meet primary endpoint of OS
Glimelius et al. 2008 2001-2004 Phase III (C) FLIRI Did not meet primary endpoint of PFS
Köhne et al. 2007 (EORTC 40015) 2003-2005 Phase III (C) CAPIRI Inconclusive whether non-inferior PFS
Passardi et al. 2015 (ITACa) 2007-2012 Phase III (C) FOLFIRI & Bevacizumab Did not meet primary endpoint of PFS

Note: EORTC 40015 was closed prematurely. Aranda et al. 2008 is described by the authors as a non-inferiority trial but the statistics used are superiority-based.

Chemotherapy

  • Folinic acid (Leucovorin) 200 mg/m2 IV over 120 minutes once per day on days 1 & 2, given second
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given third (total dose per cycle: 2000 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first

14-day cycles

Regimen variant #2, 400/2800/180

Study Evidence Comparator Comparative Efficacy
Falcone et al. 2007 Phase III (C) FOLFOXIRI Seems to have inferior OS
Fuchs et al. 2007 (BICC-C) Phase III (E-switch-ic) 1. CapeIRI Seems to have superior PFS
2. mIFL Superior PFS
Van Cutsem et al. 2009 (CRYSTAL) Phase III (C) FOLFIRI & Cetuximab Inferior OS (*)
Sanoff et al. 2018 (LCCC 1029) Randomized Phase II (C) FOLFIRI & Regorafenib Might have inferior PFS

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

Chemotherapy

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

14-day cycles

Regimen variant #3, 500/2000/80, 6 out of 7 weeks ("AIO regimen")

Study Evidence Comparator Comparative Efficacy
Köhne et al. 2005 (EORTC 40986) Phase III (E-esc) FULV Superior PFS
Fischer von Weikersthal et al. 2011 Phase III (C) mIROX Did not meet primary endpoint of PFS

Chemotherapy

7-week cycles

Regimen variant #4, 500/2300/80, weekly

Study Years of enrollment Evidence Comparator Comparative Efficacy
Douillard et al. 2000 1997-1998 Phase III (E-RT-esc) FULV Seems to have superior OS
Passardi et al. 2015 (ITACa) 2007-2012 Phase III (C) FOLFIRI & Bevacizumab Did not meet primary endpoint of PFS

Chemotherapy

7-day cycles

References

  1. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-7. link to original article contains verified protocol PubMed
  2. EORTC 40986: Köhne CH, van Cutsem E, Wils J, Bokemeyer C, El-Serafi M, Lutz MP, Lorenz M, Reichardt P, Rückle-Lanz H, Frickhofen N, Fuchs R, Mergenthaler HG, Langenbuch T, Vanhoefer U, Rougier P, Voigtmann R, Müller L, Genicot B, Anak O, Nordlinger B; EORTC Gastrointestinal Group. Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol. 2005 Aug 1;23(22):4856-65. Epub 2005 Jun 6. link to original article contains verified protocol PubMed
  3. Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, Kakolyris S, Tsousis S, Kouroussis Ch, Vamvakas L, Kalykaki A, Samonis G, Mavroudis D, Georgoulias V; Hellenic Oncology Research Group. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-805. link to original article link to PMC article contains verified protocol PubMed
  4. 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
  5. BICC-C: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article contains verified protocol PubMed
    1. Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article PubMed
  6. EORTC 40015: Köhne CH, De Greve J, Hartmann JT, Lang I, Vergauwe P, Becker K, Braumann D, Joosens E, Müller L, Janssens J, Bokemeyer C, Reimer P, Link H, Späth-Schwalbe E, Wilke HJ, Bleiberg H, Van Den Brande J, Debois M, Bethe U, Van Cutsem E. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer: EORTC study 40015. Ann Oncol. 2008 May;19(5):920-6. Epub 2007 Dec 6. link to original article contains protocol PubMed
  7. Glimelius B, Sørbye H, Balteskard L, Byström P, Pfeiffer P, Tveit K, Heikkilä R, Keldsen N, Albertsson M, Starkhammar H, Garmo H, Berglund A. A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer. Ann Oncol. 2008 May;19(5):909-14. Epub 2008 Jan 21. link to original article contains protocol PubMed
  8. Aranda E, Valladares M, Martinez-Villacampa M, Benavides M, Gomez A, Massutti B, Marcuello E, Constenla M, Cámara JC, Carrato A, Dueñas R, Reboredo M, Navarro M, Díaz-Rubio E; TTD. Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study. Ann Oncol. 2009 Feb;20(2):251-7. Epub 2008 Aug 20. link to original article contains verified protocol PubMed
  9. CRYSTAL: Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. link to original article contains verified protocol PubMed
    1. Update: 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
    2. Pooled Update: Bokemeyer C, Van Cutsem E, 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
    3. Biomarker analysis: Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. link to original article PubMed
  10. Fischer von Weikersthal L, Schalhorn A, Stauch M, Quietzsch D, Maubach PA, Lambertz H, Oruzio D, Schlag R, Weigang-Köhler K, Vehling-Kaiser U, Schulze M, Truckenbrodt J, Goebeler M, Mittermüller J, Bosse D, Szukics B, Grundeis M, Zwingers T, Giessen C, Heinemann V. Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer. Eur J Cancer. 2011 Jan;47(2):206-14. link to original article contains protocol PubMed
  11. ITACa: Passardi A, Nanni O, Tassinari D, Turci D, Cavanna L, Fontana A, Ruscelli S, Mucciarini C, Lorusso V, Ragazzini A, Frassineti GL, Amadori D. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015 Jun;26(6):1201-7. Epub 2015 Mar 3. link to original article refers to Douillard et al. 2000 PubMed
  12. LCCC 1029: Sanoff HK, Goldberg RM, Ivanova A, O'Reilly S, Kasbari SS, Kim RD, McDermott R, Moore DT, Zamboni W, Grogan W, Cohn AL, Bekaii-Saab TS, Leonard G, Ryan T, Olowokure OO, Fernando NH, McCaffrey J, El-Rayes BF, Horgan AM, Sherrill GB, Yacoub GH, O'Neil BH. Multicenter, randomized, double-blind phase 2 trial of FOLFIRI with regorafenib or placebo as second-line therapy for metastatic colorectal cancer. Cancer. 2018 Aug 1;124(15):3118-3126. Epub 2018 Jun 15. link to original article contains verified protocol PubMed

FOLFIRI (L-Leucovorin)

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FOLFIRI: L-FOLinic acid, Fluorouracil, IRInotecan

Regimen variant #1, 200/2000/150

Study Evidence Comparator Comparative Efficacy
Colucci et al. 2005 (GOIM 9901) Phase III (C) FOLFOX4 Did not meet primary endpoint of ORR

Note: this variant was intended for patients between 70 to 75 years old.

Chemotherapy

  • Levoleucovorin (Fusilev) 100 mg/m2 IV over 2 hours once per day on days 1 & 2, given second
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given third (total dose per cycle: 2000 mg/m2)
  • Irinotecan (Camptosar) 150 mg/m2 IV over 30 minutes once on day 1, given first

14-day cycles

Regimen variant #2, 200/2000/180

Study Years of enrollment Evidence Comparator Comparative Efficacy
Colucci et al. 2005 (GOIM 9901) Phase III (C) FOLFOX4 Did not meet primary endpoint of ORR
Labianca et al. 2010 2001-2005 Phase III (C) Intermittent FOLFIRI Did not meet primary endpoint of OS

Chemotherapy

  • Levoleucovorin (Fusilev) 100 mg/m2 IV over 2 hours once per day on days 1 & 2, given second
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given third (total dose per cycle: 2000 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 30 minutes once on day 1, given first

14-day cycles

Regimen variant #3, 200/2800/180

Study Evidence Comparator Comparative Efficacy
Van Cutsem et al. 2009 (CRYSTAL) Phase III (C) FOLFIRI & Cetuximab Inferior OS (*)
Carrato et al. 2013 (SUN 1122) Phase III (C) FOLFIRI & Sunitinib Did not meet primary endpoint of PFS

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

Chemotherapy

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

14-day cycles

References

  1. GOIM 9901: Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N, Cartenì G, Agostara B, Pezzella G, Manzione L, Borsellino N, Misino A, Romito S, Durini E, Cordio S, Di Seri M, Lopez M, Maiello E, Montemurro S, Cramarossa A, Lorusso V, Di Bisceglie M, Chiarenza M, Valerio MR, Guida T, Leonardi V, Pisconti S, Rosati G, Carrozza F, Nettis G, Valdesi M, Filippelli G, Fortunato S, Mancarella S, Brunetti C; Gruppo Oncologico Dell'Italia Meridionale. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol. 2005 Aug 1;23(22):4866-75. Epub 2005 Jun 6. link to original article contains verified protocol PubMed
  2. CRYSTAL: Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. link to original article contains verified protocol PubMed
    1. Update: 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
    2. Pooled Update: Bokemeyer C, Van Cutsem E, 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
    3. Biomarker analysis: Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. link to original article PubMed
  3. Labianca R, Sobrero A, Isa L, Cortesi E, Barni S, Nicolella D, Aglietta M, Lonardi S, Corsi D, Turci D, Beretta GD, Fornarini G, Dapretto E, Floriani I, Zaniboni A; Italian Group for the Study of Gastrointestinal Cancer. Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised 'GISCAD' trial. Ann Oncol. 2011 May;22(5):1236-42. Epub 2010 Nov 15. link to original article contains verified protocol PubMed
  4. SUN 1122: Carrato A, Swieboda-Sadlej A, Staszewska-Skurczynska M, Lim R, Roman L, Shparyk Y, Bondarenko I, Jonker DJ, Sun Y, De la Cruz JA, Williams JA, Korytowsky B, Christensen JG, Lin X, Tursi JM, Lechuga MJ, Van Cutsem E. Fluorouracil, leucovorin, and irinotecan plus either sunitinib or placebo in metastatic colorectal cancer: a randomized, phase III trial. J Clin Oncol. 2013 Apr 1;31(10):1341-7. Epub 2013 Jan 28. link to original article contains verified protocol PubMed

FOLFIRI & Bevacizumab

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

Regimen variant #1, indefinite

Study Years of enrollment Evidence Comparator Comparative Efficacy
Fuchs et al. 2007 (BICC-C) Phase III (E-switch-ic) mIFL & Bevacizumab Seems to have superior OS
Yamazaki et al. 2016 (WJOG4407G) 2008-2012 Phase III (E-switch-ic) mFOLFOX6 & Bevacizumab Non-inferior PFS

Chemotherapy

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

Targeted therapy

14-day cycles

Regimen variant #2, lower dose leucovorin

Study Years of enrollment Evidence
Johnsson et al. 2013 (Nordic ACT) 2007-2009 Non-randomized portion of RCT

Chemotherapy

Targeted therapy

14-day cycle for 9 cycles

Subsequent treatment

  • Nordic ACT: Bevacizumab versus Erlotinib & Bevacizumab maintenance

References

  1. BICC-C: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article contains verified protocol PubMed
    1. Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article PubMed
  2. Observational cohort: Bendell JC, Bekaii-Saab TS, Cohn AL, Hurwitz HI, Kozloff M, Tezcan H, Roach N, Mun Y, Fish S, Flick ED, Dalal D, Grothey A. Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-bevacizumab or FOLFIRI-bevacizumab: results from ARIES, a bevacizumab observational cohort study. Oncologist. 2012;17(12):1486-95. link to original article link to PMC article PubMed
  3. Nordic ACT: Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. link to original article contains verified protocol PubMed NCT00598156
  4. WJOG4407G: Yamazaki K, Nagase M, Tamagawa H, Ueda S, Tamura T, Murata K, Eguchi Nakajima T, Baba E, Tsuda M, Moriwaki T, Esaki T, Tsuji Y, Muro K, Taira K, Denda T, Funai S, Shinozaki K, Yamashita H, Sugimoto N, Okuno T, Nishina T, Umeki M, Kurimoto T, Takayama T, Tsuji A, Yoshida M, Hosokawa A, Shibata Y, Suyama K, Okabe M, Suzuki K, Seki N, Kawakami K, Sato M, Fujikawa K, Hirashima T, Shimura T, Taku K, Otsuji T, Tamura F, Shinozaki E, Nakashima K, Hara H, Tsushima T, Ando M, Morita S, Boku N, Hyodo I. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol. 2016 Aug;27(8):1539-46. Epub 2016 May 13. link to original article PubMed UMIN000001396

FOLFIRI & Bevacizumab (L-Leucovorin)

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

Regimen

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

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

Chemotherapy

Targeted therapy

14-day cycle for up to 12 cycles

Subsequent treatment

  • Fluorouracil, leucovorin, bevacizumab maintenance

References

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

FOLFIRINOX

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

Regimen

Study Evidence Comparator Comparative Efficacy
Souglakos et al. 2006 Phase III (E-esc) FOLFIRI Did not meet primary endpoint of OS
Falcone et al. 2007 Phase III (E-esc) FOLFIRI Seems to have superior OS

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

Chemotherapy

14-day cycles

References

  1. Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, Kakolyris S, Tsousis S, Kouroussis Ch, Vamvakas L, Kalykaki A, Samonis G, Mavroudis D, Georgoulias V; Hellenic Oncology Research Group. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-805. link to original article link to PMC article contains verified protocol PubMed
  2. Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6. link to original article contains verified protocol PubMed

FOLFIRINOX & Bevacizumab (L-Leucovorin)

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

Regimen

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

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

Chemotherapy

Targeted therapy

14-day cycle for up to 12 cycles

Subsequent treatment

  • Fluorouracil, leucovorin, bevacizumab maintenance (specific details not provided)

References

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

FOLFOX2

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FOLFOX2: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Evidence Comparator Comparative Efficacy
Giacchetti et al. 2006 Phase III (C) chronoFLO4 Did not meet primary endpoint of OS

Chemotherapy

  • Folinic acid (Leucovorin) 600 mg/m2 IV over 2 hours once per day on days 1 & 2, given first, with oxaliplatin on day 1
  • Fluorouracil (5-FU) 1500 mg/m2 IV continuous infusion over 22 hours once per day, started on days 1 & 2, given second (total dose per cycle: 3000 mg/m2)
  • Oxaliplatin (Eloxatin) 100 mg/m2 IV over 2 hours once on day 1, given first

14-day cycles

References

  1. Giacchetti S, Bjarnason G, Garufi C, Genet D, Iacobelli S, Tampellini M, Smaaland R, Focan C, Coudert B, Humblet Y, Canon JL, Adenis A, Lo Re G, Carvalho C, Schueller J, Anciaux N, Lentz MA, Baron B, Gorlia T, Lévi F; EORTC Chronotherapy Group. Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group. J Clin Oncol. 2006 Aug 1;24(22):3562-9. link to original article contains verified protocol PubMed

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
de Gramont et al. 2000 Phase III (E-esc) FULV Superior PFS
Goldberg et al. 2003 (NCCTG N9741) 1999-2001 Phase III (E-RT-switch-ic) 1. IFL Superior OS
2. IROX Did not meet primary endpoint of TTP
Tournigand et al. 2006 (OPTIMOX1) Phase III (C) FOLFOX7/LV5FU2 Did not meet primary endpoint of DDC
Cassidy et al. 2008 (NO16966) Phase III (C) 1. FOLFOX4 & Bevacizumab Not reported
2. XELOX
3. XELOX & Bevacizumab 		Non-inferior PFS
Saltz et al. 2008 (NO16966) Phase III (C) 1. FOLFOX4 & Bevacizumab
2. XELOX & Bevacizumab 		Inferior PFS
3. XELOX Not reported
Bokemeyer et al. 2008 (OPUS) Randomized Phase II (C) FOLFOX4 & Cetuximab Inferior OS (*)
Douillard et al. 2010 (PRIME) Phase III (C) FOLFOX4 & Panitumumab Seems to have superior PFS (*)
Hecht et al. 2011 Phase III (C) FOLFOX4 & Vatalanib Did not meet primary endpoint of PFS
Hoff et al. 2012 (HORIZON II) Phase III (C) 1. CAPOX & Cediranib
2. FOLFOX4 & Cediranib
3. mFOLFOX6 & Cediranib 		Seems to have inferior PFS
Passardi et al. 2015 (ITACa) 2007-2012 Phase III (C) FOLFOX4 & Bevacizumab Did not meet primary endpoint of PFS

Note: in PRIME, patients with KRAS wild-type tumors receiving this regimen seem to have inferior OS, based on the 2014 update. Conversely, in KRAS mutants, this regimen seems to have superior PFS. Reported efficacy for OPUS is based on the 2012 pooled update and is only for KRAS wild-type tumors.

Chemotherapy

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

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. NCCTG N9741: Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. Epub 2003 Dec 9. link to original article contains verified protocol PubMed
  3. OPTIMOX1: Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, Mineur L, Carola E, Etienne PL, Rivera F, Chirivella I, Perez-Staub N, Louvet C, André T, Tabah-Fisch I, de Gramont A. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006 Jan 20;24(3):394-400. link to original article contains verified protocol PubMed
  4. Retrospective: Goldberg RM, Tabah-Fisch I, Bleiberg H, de Gramont A, Tournigand C, Andre T, Rothenberg ML, Green E, Sargent DJ. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol. 2006 Sep 1;24(25):4085-91. link to original article PubMed content property of HemOnc.org
  5. NO16966: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. link to original article PubMed
    1. Update: Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. link to original article refers to de Gramont et al. 2000 for protocol PubMed
    2. Update: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64. Epub 2011 Jun 14. link to original article link to PMC article PubMed
  6. OPUS: Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29. link to original article contains verified protocol PubMed
    1. Update: Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011 Jul;22(7):1535-46. Epub 2011 Jan 12. link to original article PubMed
    2. Pooled Update: Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article PubMed
  7. PRIME: Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010 Nov 1;28(31):4697-705. Epub 2010 Oct 4. link to original article PubMed
    1. Biomarker analysis: Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013 Sep 12;369(11):1023-34. link to original article PubMed
    2. Update: Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jul;25(7):1346-55. Epub 2014 Apr 8. link to original article PubMed
  8. Hecht JR, Trarbach T, Hainsworth JD, Major P, Jäger E, Wolff RA, Lloyd-Salvant K, Bodoky G, Pendergrass K, Berg W, Chen BL, Jalava T, Meinhardt G, Laurent D, Lebwohl D, Kerr D. Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):1997-2003. Epub 2011 Apr 4. link to original article contains verified protocol PubMed
  9. HORIZON II: Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. link to original article contains verified protocol PubMed
  10. ITACa: Passardi A, Nanni O, Tassinari D, Turci D, Cavanna L, Fontana A, Ruscelli S, Mucciarini C, Lorusso V, Ragazzini A, Frassineti GL, Amadori D. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015 Jun;26(6):1201-7. Epub 2015 Mar 3. link to original article refers to de Gramont et al. 2000 PubMed

FOLFOX4 (L-Leucovorin)

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FOLFOX4: L-FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Evidence Comparator Comparative Efficacy
Colucci et al. 2005 (GOIM 9901) Phase III (C) FOLFIRI Did not meet primary endpoint of ORR
Hecht et al. 2011 Phase III (C) FOLFOX4 & Vatalanib Did not meet primary endpoint of PFS
Correale et al. 2014 (GOLFIG-2) Phase III (C) GOLFIG Inferior PFS

Chemotherapy

  • Levoleucovorin (Fusilev) 100 mg/m2 IV over 2 hours once per day on days 1 & 2, given first, with oxaliplatin on day 1
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given second (total dose per cycle: 2000 mg/m2)
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first, with leucovorin

14-day cycles

References

  1. GOIM 9901: Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N, Cartenì G, Agostara B, Pezzella G, Manzione L, Borsellino N, Misino A, Romito S, Durini E, Cordio S, Di Seri M, Lopez M, Maiello E, Montemurro S, Cramarossa A, Lorusso V, Di Bisceglie M, Chiarenza M, Valerio MR, Guida T, Leonardi V, Pisconti S, Rosati G, Carrozza F, Nettis G, Valdesi M, Filippelli G, Fortunato S, Mancarella S, Brunetti C; Gruppo Oncologico Dell'Italia Meridionale. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol. 2005 Aug 1;23(22):4866-75. Epub 2005 Jun 6. link to original article contains verified protocol PubMed
  2. Hecht JR, Trarbach T, Hainsworth JD, Major P, Jäger E, Wolff RA, Lloyd-Salvant K, Bodoky G, Pendergrass K, Berg W, Chen BL, Jalava T, Meinhardt G, Laurent D, Lebwohl D, Kerr D. Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):1997-2003. Epub 2011 Apr 4. link to original article contains verified protocol PubMed
  3. GOLFIG-2: Correale P, Botta C, Rotundo MS, Guglielmo A, Conca R, Licchetta A, Pastina P, Bestoso E, Ciliberto D, Cusi MG, Fioravanti A, Guidelli GM, Bianco MT, Misso G, Martino E, Caraglia M, Tassone P, Mini E, Mantovani G, Ridolfi R, Pirtoli L, Tagliaferri P. Gemcitabine, oxaliplatin, levofolinate, 5-fluorouracil, granulocyte-macrophage colony-stimulating factor, and interleukin-2 (GOLFIG) versus FOLFOX chemotherapy in metastatic colorectal cancer patients: the GOLFIG-2 multicentric open-label randomized phase III trial. J Immunother. 2014 Jan;37(1):26-35. link to original article PubMed

mFOLFOX6

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

Example orders

Regimen variant #1, LCV 200 mg/m2

Study Evidence Comparator Comparative Efficacy
van Hazel et al. 2016 (SIRFLOX) Phase III (C) mFOLFOX6 plus SIRT Did not meet primary endpoint of PFS (*)
Wasan et al. 2017 (FOXFIRE-Global) Phase III (C) mFOLFOX6 plus SIRT Did not meet primary endpoint of OS

Note: Wasan et al. 2017, which is an update for SIRFLOX and the first publication for FOXFIRE-Global, describes the folinic acid as a flat 200 mg dose; van Hazel et al. 2016 reports 200 mg/m2; the authors were contacted for clarification.

Chemotherapy

14-day cycles

Regimen variant #2, LCV 350 mg/m2

Study Evidence Comparator Comparative Efficacy
Cheeseman et al. 2002 Non-randomized
Hochster et al. 2008 (TREE-1) Phase III (E-switch-ic) 1. bFOL Did not meet secondary efficacy endpoints
2. CapeOx Did not meet secondary efficacy endpoints
Maughan et al. 2011 (UK MRC COIN) Phase III (C) mFOLFOX6 & Cetuximab Did not meet primary endpoint of OS (*)
Wasan et al. 2017 (FOXFIRE) Phase III (C) OxMdG plus SIRT Did not meet primary endpoint of OS

Note: TREE-1 did not have any primary endpoints. Efficacy for UK MRC COIN is as reported for KRAS wild-type patients.

Chemotherapy

14-day cycles

Regimen variant #3, LCV 400 mg/m2

Study Evidence Comparator Comparative Efficacy
Hoff et al. 2012 (HORIZON II) Phase III (C) 1. CAPOX & Cediranib
2. FOLFOX4 & Cediranib
3. mFOLFOX6 & Cediranib 		Seems to have inferior PFS

Chemotherapy

14-day cycles

References

  1. Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12;87(4):393-9. link to original article contains verified protocol link to PMC article PubMed
  2. TREE-1: Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. link to original article contains verified protocol PubMed
  3. UK MRC COIN: Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP; MRC COIN Trial Investigators. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011 Jun 18;377(9783):2103-14. Epub 2011 Jun 5. link to original article link to PMC article contains verified protocol PubMed
    1. Update: Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, Kenny SL, Kay E, Hodgkinson E, Pope M, Rogers P, Wasan H, Falk S, Gollins S, Hickish T, Bessell EM, Propper D, Kennedy MJ, Kaplan R, Maughan TS; MRC COIN Trial Investigators. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011 Jul;12(7):642-53. Epub 2011 Jun 5. link to original article link to PMC article PubMed
  4. HORIZON II: Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. link to original article contains verified protocol PubMed
  5. SIRFLOX: van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M, Perez D, Robinson BA, Strickland AH, Ferguson T, Rodríguez J, Kröning H, Wolf I, Ganju V, Walpole E, Boucher E, Tichler T, Shacham-Shmueli E, Powell A, Eliadis P, Isaacs R, Price D, Moeslein F, Taieb J, Bower G, Gebski V, Van Buskirk M, Cade DN, Thurston K, Gibbs P. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2016 May 20;34(15):1723-31. Epub 2016 Feb 22. link to original article PubMed
    1. Pooled update: Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A, van Hazel G, Sharma RA; FOXFIRE/SIRFLOX/FOXFIRE-Global trial investigators. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. Epub 2017 Aug 3. link to original article contains verified protocol PubMed
  6. FOXFIRE; FOXFIRE-Global: Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A, van Hazel G, Sharma RA; FOXFIRE/SIRFLOX/FOXFIRE-Global trial investigators. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. Epub 2017 Aug 3. link to original article contains verified protocol PubMed

mFOLFOX6 (L-Leucovorin)

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mFOLFOX6: modified FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Evidence Comparator Comparative Efficacy
Maughan et al. 2011 (UK MRC COIN) Phase III (C) mFOLFOX6 & Cetuximab Did not meet primary endpoint of OS (*)
Wasan et al. 2017 (FOXFIRE) Phase III (C) OxMdG plus SIRT Did not meet primary endpoint of OS

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

Chemotherapy

14-day cycles

References

  1. UK MRC COIN: Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP; MRC COIN Trial Investigators. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011 Jun 18;377(9783):2103-14. Epub 2011 Jun 5. link to original article link to PMC article contains verified protocol PubMed
    1. Update: Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, Kenny SL, Kay E, Hodgkinson E, Pope M, Rogers P, Wasan H, Falk S, Gollins S, Hickish T, Bessell EM, Propper D, Kennedy MJ, Kaplan R, Maughan TS; MRC COIN Trial Investigators. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011 Jul;12(7):642-53. Epub 2011 Jun 5. link to original article link to PMC article PubMed
  2. FOXFIRE; FOXFIRE-Global: Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A, van Hazel G, Sharma RA; FOXFIRE/SIRFLOX/FOXFIRE-Global trial investigators. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. Epub 2017 Aug 3. link to original article contains verified protocol PubMed

FOLFOX 7/sLV5FU2

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

Protocol

Study Evidence Comparator Comparative Efficacy
Tournigand et al. 2006 (OPTIMOX1) Phase III (E-switch-ic) FOLFOX4 Did not meet primary endpoint of DDC

Note: this regimen has an unusual alternating schedule; see paper for more details.

Chemotherapy, FOLFOX 7 portion

14-day cycle for up to 6 cycles, then proceed to sLV5FU2:

Chemotherapy, sLV5FU2 portion

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 1500 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 3000 mg/m2)
  • Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, given first

14-day cycle for up to 12 cycles, then resume FOLFOX 7 for 6 additional cycles as described above

References

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

FOLFOX 7/sLV5FU2 (L-Leucovorin)

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FOLFOX 7/sLV5FU2: L-FOLinic acid, Fluorouracil, OXaliplatin alternating with simplified L-LeucoVorin, 5-FU, 2-weekly (every 2 weeks)

Protocol

Study Evidence Comparator Comparative Efficacy
Tournigand et al. 2006 (OPTIMOX1) Phase III (E-switch-ic) FOLFOX4 Did not meet primary endpoint of DDC

Note: this regimen has an unusual alternating schedule; see paper for more details.

Chemotherapy, FOLFOX 7 portion

14-day cycle for up to 6 cycles, then proceed to sLV5FU2:

Chemotherapy, sLV5FU2 portion

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 1500 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 3000 mg/m2)
  • Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given first

14-day cycle for up to 12 cycles, then resume FOLFOX 7 for 6 additional cycles as described above

References

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

mFOLFOX7

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mFOLFOX7: modified FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Evidence
Chibaudel et al. 2009 (OPTIMOX2) Non-randomized portion of RCT

Chemotherapy

14-day cycle for 6 cycles

Subsequent treatment

  • sLV5FU2 versus no further treatment

References

  1. OPTIMOX2: Chibaudel B, Maindrault-Goebel F, Lledo G, Mineur L, André T, Bennamoun M, Mabro M, Artru P, Carola E, Flesch M, Dupuis O, Colin P, Larsen AK, Afchain P, Tournigand C, Louvet C, de Gramont A. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol. 2009 Dec 1;27(34):5727-33. Epub 2009 Sep 28. link to original article PubMed

mFOLFOX7 (L-Leucovorin)

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mFOLFOX7: modified L-FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Evidence
Chibaudel et al. 2009 (OPTIMOX2) Non-randomized portion of RCT

Chemotherapy

14-day cycle for 6 cycles

Subsequent treatment

  • sLV5FU2 versus no further treatment

References

  1. OPTIMOX2: Chibaudel B, Maindrault-Goebel F, Lledo G, Mineur L, André T, Bennamoun M, Mabro M, Artru P, Carola E, Flesch M, Dupuis O, Colin P, Larsen AK, Afchain P, Tournigand C, Louvet C, de Gramont A. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol. 2009 Dec 1;27(34):5727-33. Epub 2009 Sep 28. link to original article PubMed

FOLFOX4 & Bevacizumab

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

Regimen

Study Evidence Comparator Comparative Efficacy
Emmanouilides et al. 2007 Phase II
Cassidy et al. 2008 (NO16966) Phase III (E-esc) 1. FOLFOX4
2. XELOX 		Superior PFS
3. XELOX & Bevacizumab Not reported

Chemotherapy

Targeted therapy

  • Bevacizumab (Avastin) 5 mg/kg IV once on day 1, given first
    • Infusion times are 2 hours for cycle 1, 1 hour for cycle 2, then 30 minutes for cycles 3 and later

14-day cycles

References

  1. Emmanouilides C, Sfakiotaki G, Androulakis N, Kalbakis K, Christophylakis C, Kalykaki A, Vamvakas L, Kotsakis A, Agelaki S, Diamandidou E, Touroutoglou N, Chatzidakis A, Georgoulias V, Mavroudis D, Souglakos J. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. BMC Cancer. 2007 May 30;7:91. link to original article link to PMC article PubMed
  2. NO16966: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. link to original article contains verified protocol PubMed
    1. Update: Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. link to original article contains verified protocol PubMed
    2. Update: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64. Epub 2011 Jun 14. link to original article link to PMC article PubMed

mFOLFOX6 & Bevacizumab

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mFOLFOX6 & Bevacizumab: modified FOLinic acid, Fluorouracil, OXaliplatin, Bevacizumab
FOLFOX-B: FOLinic acid, Fluorouracil, OXaliplatin, Bevacizumab

Example orders

Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Hochster et al. 2008 (TREE-2) Phase III (E-switch-ic) 1. bFOL & Bevacizumab Did not meet secondary efficacy endpoints Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
2. CapeOx & Bevacizumab Did not meet secondary efficacy endpoints Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
Hecht et al. 2008 (PACCE) Phase III (C) mFOLFOX6 & Bevacizumab & Panitumumab Superior PFS
Saltz et al. 2011 Phase III (C) FOLF-CB Did not meet primary endpoint of PFS12
Schmoll et al. 2012 (HORIZON III) Phase III (C) mFOLFOX6 & Cediranib Inconclusive whether non-inferior PFS
Yamada et al. 2013 (SOFTCRC) Phase III (C) SOX & Bevacizumab Seems to have non-inferior PFS
Yamazaki et al. 2016 (WJOG4407G) 2008-2012 Phase III (E-switch-ic) FOLFIRI & Bevacizumab Non-inferior PFS

This was the most common oxaliplatin-based reigimen used in PACCE. There is another trial by the name of SOFT in breast cancer.

Chemotherapy

Targeted therapy

14-day cycles

Regimen variant #2, lower dose leucovorin

Study Years of enrollment Evidence
Johnsson et al. 2013 (Nordic ACT) 2007-2009 Non-randomized portion of RCT

Chemotherapy

Targeted therapy

14-day cycle for 9 cycles

Subsequent treatment

  • Nordic ACT: Bevacizumab versus Erlotinib & Bevacizumab maintenance

References

  1. TREE-2: Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. link to original article contains verified protocol PubMed
  2. PACCE: Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, Marshall J, Cohn A, McCollum D, Stella P, Deeter R, Shahin S, Amado RG. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):672-80. Epub 2008 Dec 29. link to original article PubMed
  3. Saltz L, Badarinath S, Dakhil S, Bienvenu B, Harker WG, Birchfield G, Tokaz LK, Barrera D, Conkling PR, O'Rourke MA, Richards DA, Reidy D, Solit D, Vakiani E, Capanu M, Scales A, Zhan F, Boehm KA, Asmar L, Cohn A. Phase III trial of cetuximab, bevacizumab, and 5-fluorouracil/leucovorin vs FOLFOX-bevacizumab in colorectal cancer. Clin Colorectal Cancer. 2012 Jun;11(2):101-11. Epub 2011 Nov 4. link to original article contains verified protocol PubMed
  4. HORIZON III: Schmoll HJ, Cunningham D, Sobrero A, Karapetis CS, Rougier P, Koski SL, Kocakova I, Bondarenko I, Bodoky G, Mainwaring P, Salazar R, Barker P, Mookerjee B, Robertson J, Van Cutsem E. Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III). J Clin Oncol. 2012 Oct 10;30(29):3588-95. Epub 2012 Sep 10. link to original article PubMed
  5. Observational cohort: Bendell JC, Bekaii-Saab TS, Cohn AL, Hurwitz HI, Kozloff M, Tezcan H, Roach N, Mun Y, Fish S, Flick ED, Dalal D, Grothey A. Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-bevacizumab or FOLFIRI-bevacizumab: results from ARIES, a bevacizumab observational cohort study. Oncologist. 2012;17(12):1486-95. Epub 2012 Sep 26. link to original article link to PMC article PubMed
  6. Nordic ACT: Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. link to original article contains verified protocol PubMed NCT00598156
  7. SOFT: Yamada Y, Takahari D, Matsumoto H, Baba H, Nakamura M, Yoshida K, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1278-86. Epub 2013 Nov 11. Erratum in: Lancet Oncol. 2014 Jan;15(1):e4. link to original article PubMed
    1. Update: Baba H, Yamada Y, Takahari D, Matsumoto H, Yoshida K, Nakamura M, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K. S-1 and oxaliplatin (SOX) plus bevacizumab versus mFOLFOX6 plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer: updated overall survival analyses of the open-label, non-inferiority, randomised phase III: SOFT study. ESMO Open. 2017 Mar 9;2(1):e000135. link to original article link to PMC article PubMed
  8. SIRFLOX: van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M, Perez D, Robinson BA, Strickland AH, Ferguson T, Rodríguez J, Kröning H, Wolf I, Ganju V, Walpole E, Boucher E, Tichler T, Shacham-Shmueli E, Powell A, Eliadis P, Isaacs R, Price D, Moeslein F, Taieb J, Bower G, Gebski V, Van Buskirk M, Cade DN, Thurston K, Gibbs P. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2016 May 20;34(15):1723-31. Epub 2016 Feb 22. link to original article PubMed
  9. WJOG4407G: Yamazaki K, Nagase M, Tamagawa H, Ueda S, Tamura T, Murata K, Eguchi Nakajima T, Baba E, Tsuda M, Moriwaki T, Esaki T, Tsuji Y, Muro K, Taira K, Denda T, Funai S, Shinozaki K, Yamashita H, Sugimoto N, Okuno T, Nishina T, Umeki M, Kurimoto T, Takayama T, Tsuji A, Yoshida M, Hosokawa A, Shibata Y, Suyama K, Okabe M, Suzuki K, Seki N, Kawakami K, Sato M, Fujikawa K, Hirashima T, Shimura T, Taku K, Otsuji T, Tamura F, Shinozaki E, Nakashima K, Hara H, Tsushima T, Ando M, Morita S, Boku N, Hyodo I. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol. 2016 Aug;27(8):1539-46. Epub 2016 May 13. link to original article PubMed UMIN000001396

mFOLFOX6 & Bevacizumab (L-Leucovorin)

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mFOLFOX6 & Bevacizumab: modified L-FOLinic acid, Fluorouracil, OXaliplatin, Bevacizumab
FOLFOX-B: FOLinic acid, Fluorouracil, OXaliplatin, Bevacizumab

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Yamada et al. 2018 (TRICOLORE) 2012-2014 Phase III (C) IRIS & Bevacizumab Non-inferior PFS

Chemotherapy

Targeted therapy

14-day cycles

References

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

FUIRI

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FUIRI: 5-FU & IRInotecan

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Aranda et al. 2008 1994-1996 Phase III (E-de-esc) FOLFIRI Did not meet primary endpoint of ORR (*)

Note: Aranda et al. 2008 is described by the authors as a non-inferiority trial but the statistics used are superiority-based.

Chemotherapy

7-day cycles

References

  1. Aranda E, Valladares M, Martinez-Villacampa M, Benavides M, Gomez A, Massutti B, Marcuello E, Constenla M, Cámara JC, Carrato A, Dueñas R, Reboredo M, Navarro M, Díaz-Rubio E; TTD. Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study. Ann Oncol. 2009 Feb;20(2):251-7. Epub 2008 Aug 20. link to original article contains verified protocol PubMed

FULV

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FULV: 5-FU & LeucoVorin (Folinic acid)
LV5FU2: LeucoVorin and 5-FU, two days out of the month
sLV5FU2: simplified LeucoVorin and 5-FU, two days out of the month

Example orders

Regimen variant #1, 400/80 ("modified Laufman regimen")

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

Chemotherapy

7-day cycle for up to 26 cycles (6 months)

Regimen variant #2, 450/200

Study Evidence Comparator Comparative Efficacy
Kosmidis et al. 1996 Phase III (C) FULV & IFN alfa-2b Superior OS

Chemotherapy

7-day cycles

Regimen variant #3, 500/20

Study Evidence Comparator Comparative Efficacy
Jäger et al. 1996 Phase III (C) FULV; high-dose Did not meet primary endpoint of ORR

Chemotherapy

7-day cycles

Regimen variant #4, 500/200, 6 out of 8 weeks

Study Years of enrollment Evidence Comparator Comparative Efficacy
Blanke et al. 2002 1995-1999 Phase III (C) FULV & Trimetrexate Did not meet primary endpoint of PFS

Chemotherapy

8-week cycles

Regimen variant #5, 600/500 ("Roswell Park regimen")

Study Evidence Comparator Comparative Efficacy
Petrelli et al. 1987 Phase III (E-esc) 1. 5-FU
2. 5-FU & MTX 		Superior ORR
Petrelli et al. 1989 Phase III (E-esc) 1. 5-FU
2. FULV; LDLV 		Might have superior OS
Buroker et al. 1994 Phase III (E-esc) FULV; Mayo Clinic regimen Did not meet primary endpoint of OS50%
Jones et al. 1995 Phase III (C) MFL Did not meet primary endpoint of ORR
Kabbinavar et al. 2003 (AVF0780) Randomized Phase II (C) FULV & Bevacizumab Might have inferior OS

Note: the original regimen described by Petrelli et al. 1987 & 1989 used a 5-FU dose of 600 mg/m2.

Chemotherapy

  • Fluorouracil (5-FU) 500 to 600 mg/m2 IV bolus once per day on days 1, 8, 15, 22, 29, 36, given second, 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 first

8-week cycles

Regimen variant #6, 1500/400

Study Evidence Comparator Comparative Efficacy
Gamelin et al. 2008 Phase III (C) FULV; PK-guided Might have inferior OS

Chemotherapy

7-day cycles

Regimen variant #7, 1850/1000

Study Evidence Comparator Comparative Efficacy
Man et al. 1995 (Corfu-A) Phase III (E-switch-ooc) 5-FU & IFN alfa-2a Did not meet primary endpoint of ORR
Goldberg et al. 1997 Phase III (E-esc) 1. FULV; low-dose LV
2. FULV; oral LV 		Did not meet primary endpoint of OS

Chemotherapy

28-day cycle for 2 cycles, then 35-day cycles

Regimen variant #8, 2000/100

Study Years of enrollment Evidence Comparator Comparative Efficacy
Borner et al. 1998 1991-1995 Phase III (E-esc) 5-FU Seems to have superior OS

Chemotherapy

1-month cycles

Regimen variant #9, 2000/400 (LV5FU2 aka "de Gramont regimen")

Study Years of enrollment Evidence Comparator Comparative Efficacy
de Gramont et al. 1997 (FFCD 9101) Phase III (E-esc) FULV; Mayo Clinic regimen Superior PFS
Douillard et al. 2000 1997-1998 Phase III (C) 1. IFL
2. FOLFIRI 		Seems to have inferior OS
de Gramont et al. 2000 Phase III (C) FOLFOX4 Inferior PFS
Maughan et al. 2002 Phase III (C) 1. Lokich regimen Did not meet primary endpoint of OS
2. Raltitrexed Did not meet primary endpoint of OS
Kerr et al. 2003 Phase III (C) FULV; IHA LV5FU2 Did not meet primary endpoint of OS
Maughan et al. 2003 Phase III (C) FULV; intermittent LV5FU2 Did not meet primary endpoint of OS
Ducreux et al. 2006 (FFCD 9601) Phase III (C) 1. FULV; ldLV5FU2
2. 5-FU 		Did not meet primary endpoint of PFS
2. Raltitrexed Seems to have superior PFS
Cunningham et al. 2008 2000-NR Phase IIIb (C) FOLFOX4 Did not meet primary endpoint of OS
Aparicio et al. 2015 (FFCD 2001-02) 2003-2010 Phase III (C) 1. FOLFIRI; "classic"
2. FOLFIRI; "simplified" 		Did not meet primary endpoint of PFS
3. FULV; sLV5FU2 Did not meet primary endpoint of PFS

Note: Maughan et al. 2003 randomized patients to 12 weeks of treatment with re-treatment upon progression, versus continuous treatment. There was no difference in outcome between the two arms. FFCD 2001-02 enrolled elderly (75 or older) patients.

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given second (total dose per cycle: 2000 mg/m2)
  • Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, given first

14-day cycles (see note)

Regimen variant #10, 2000/500

Study Years of enrollment Evidence Comparator Comparative Efficacy
Scheithauer et al. 1997 1991-1994 Phase III (C) FULV (L-leucovorin) Did not meet primary endpoint of OS12

Chemotherapy

28-day cycle for up to 6 cycles

Regimen variant #11, 2000/1000

Study Years of enrollment Evidence Comparator Comparative Efficacy
Labianca et al. 1991 1987-1989 Phase III (E-esc) 5-FU Seems to have superior ORR

Chemotherapy

28-day cycles

Regimen variant #12, 2125/100 ("Mayo Clinic regimen")

Study Years of enrollment Evidence Comparator Comparative Efficacy
O'Connell 1989 NR Phase III (E-RT-esc) 5-FU Seems to have superior OS
FULV; HDLV Did not meet primary efficacy endpoint
Poon et al. 1989 1984-1987 Phase III (E-RT-esc) 5-FU Seems to have superior OS
Buroker et al. 1994 Phase III (E-de-esc) FULV; Roswell Park regimen Did not meet primary endpoint of OS50%
de Gramont et al. 1997 (FFCD 9101) Phase III (C) FULV; LV5FU2 Inferior PFS
Aranda et al. 1998 1994-1996 Phase III (C) 5-FU; high-dose Seems to have inferior ORR
Saltz et al. 2000 1996-1998 Phase III (C) 1. IFL Seems to have inferior OS
2. Irinotecan Did not meet primary endpoint of PFS
Hoff et al. 2001 1996-1998 Phase III (C) Capecitabine Inferior ORR
Van Cutsem et al. 2001 1996-1998 Phase III (C) Capecitabine Equivalent ORR
Schilsky et al. 2002 (FUMA3008) Phase III (C) Eniluracil & 5-FU Inconclusive whether non-inferior OS
Douillard et al. 2002 Phase III (C) UFT & Leucovorin Seems to have equivalent OS
Carmichael et al. 2002 Phase III (C) UFT & Leucovorin Did not meet primary endpoint of TTP
Köhne et al. 2003 (EORTC 40952) Phase III (C) 1. FU24h
2. FU24h + LV 		Did not meet primary endpoint of OS
Chong et al. 2005 1998-2001 Phase III (C) FULV & 3H1 Did not meet primary endpoint of OS
Hospers et al. 2006 1999-2002 Phase III (C) FOLFOX6 Seems to have inferior PFS

Note: not all manuscripts explicitly describe the timing described here; O'Connell 1989 is the clearest.

Chemotherapy

28-day cycle for 3 cycles, then 35-day cycle for 3 cycles (see note)

Regimen variant #13, 2560/175 (reduced-dose sLV5FU2)

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Seymour et al. 2011 (MRC FOCUS2) Phase III (C) 1. Capecitabine
2. CapeOx
3. OxFU 		Might have inferior PFS (see note) Similar QoL (see note)

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

Chemotherapy

14-day cycles

Regimen variant #14, 2600/500

Study Years of enrollment Evidence Comparator Comparative Efficacy
Douillard et al. 2000 1997-1998 Phase III (C) 1. IFL
2. FOLFIRI 		Seems to have inferior OS

Chemotherapy

7-day cycles

Regimen variant #15, 2800/350 ("modified de Gramont regimen")

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

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

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2), given second
  • Folinic acid (Leucovorin) 350 mg IV over 2 hours once on day 1, given first

Supportive medications

14-day cycles

Regimen variant #16, 2800/400 (sLV5FU2)

Study Evidence Comparator Comparative Efficacy
Ducreux et al. 2011 (FFCD 2000-05) Phase III (C) See link See link

Chemotherapy

14-day cycles

Subsequent treatment

Regimen variant #17, other

Study Evidence Comparator Comparative Efficacy
Heys et al. 1995 Phase III (C) FULV & rIL2 Might have inferior OS
Hausmaninger et al. 1999 Phase III (C) FULV & IFN alfa-2c Did not meet primary endpoint of ORR
Giacchetti et al. 2000 Phase III (C) Chronomodulated FOLFOX Seems to have inferior PFS

See papers for details.

Chemotherapy

References

  1. Petrelli N, Herrera L, Rustum Y, Burke P, Creaven P, Stulc J, Emrich LJ, Mittelman A. A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol. 1987 Oct;5(10):1559-65. link to original article contains verified protocol PubMed
  2. O'Connell MJ; North Central Cancer Treatment Group. A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer: a Mayo Clinic/North Central Cancer Treatment Group study. Cancer. 1989 Mar 15;63(6 Suppl):1026-30. link to original article PubMed
  3. Poon MA, O'Connell MJ, Moertel CG, Wieand HS, Cullinan SA, Everson LK, Krook JE, Mailliard JA, Laurie JA, Tschetter LK, Wiesenfeld M. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol. 1989 Oct;7(10):1407-18. link to original article PubMed
    1. Update: Poon MA, O'Connell MJ, Wieand HS, Krook JE, Gerstner JB, Tschetter LK, Levitt R, Kardinal CG, Mailliard JA. Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol. 1991 Nov;9(11):1967-72. link to original article PubMed
  4. Petrelli N, Douglass HO Jr, Herrera L, Russell D, Stablein DM, Bruckner HW, Mayer RJ, Schinella R, Green MD, Muggia FM, Megibow A, Greenwald ES, Bukowski RM, Harris J, Levin B, Gaynor E, Loutfi A, Kaiser MH, Barkin JS, Benedetto P, Woolley PV, Nauta R, Weaver DW, Leichman LP; Gastrointestinal Tumor Study Group. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. J Clin Oncol. 1989 Oct;7(10):1419-26. Erratum in: J Clin Oncol 1990 Jan;8(1):185. link to original article contains protocol PubMed
  5. Labianca R, Pancera G, Aitini E, Barni S, Beretta A, Beretta GD, Cesana B, Comella G, Cozzaglio L, Cristoni M, Spagnolli P, Frontini L, Gottardi O, Martignoni G, Scapaticci R, Smerieri F, Vinci M, Zadro A, Zaniboni A, Luporini G; GISCAD. Folinic acid + 5-fluorouracil (5-FU) versus equidose 5-FU in advanced colorectal cancer: phase III study of 'GISCAD' (Italian Group for the Study of Digestive Tract Cancer). Ann Oncol. 1991 Oct;2(9):673-9. link to original article contains protocol PubMed
  6. Buroker TR, O'Connell MJ, Wieand HS, Krook JE, Gerstner JB, Mailliard JA, Schaefer PL, Levitt R, Kardinal CG, Gesme DH Jr. Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol. 1994 Jan;12(1):14-20. link to original article contains protocol PubMed
  7. Corfu-A: Man A, Levi J, Weinerman B, Kjaer M, Yap AKL; Corfu-A Study Group. Phase III randomized study of two fluorouracil combinations with either interferon alfa-2a or leucovorin for advanced colorectal cancer. J Clin Oncol. 1995 Apr;13(4):921-8. link to original article contains protocol PubMed
  8. Jones DV Jr, Winn RJ, Brown BW, Levy LB, Pugh RP, Wade JL 3rd, Gross HM, Pendergrass KB, Levin B, Abbruzzese JL. Randomized phase III study of 5-fluorouracil plus high dose folinic acid versus 5-fluorouracil plus folinic acid plus methyl-lomustine for patients with advanced colorectal cancer. Cancer. 1995 Nov 15;76(10):1709-14. link to original article PubMed
  9. Heys SD, Eremin O, Ruggeri EM, Pein F, Rainer H, Oskam R, de Peuter RA, Palmer PA, Franks CR. A phase III study of recombinant interleukin-2, 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in patients with unresectable or metastatic colorectal carcinoma. Eur J Cancer. 1995;31A(1):19-25. link to original article PubMed
  10. Jäger E, Heike M, Bernhard H, Klein O, Bernhard G, Lautz D, Michaelis J, Meyer zum Büschenfelde KH, Knuth Al; Study Group for Palliative Treatment of Metastatic Colorectal Cancer. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. J Clin Oncol. 1996 Aug;14(8):2274-9. link to original article contains verified protocol PubMed
  11. Kosmidis PA, Tsavaris N, Skarlos D, Theocharis D, Samantas E, Pavlidis N, Briassoulis E, Fountzilas G; Hellenic Cooperative Oncology Group. Fluorouracil and leucovorin with or without interferon alfa-2b in advanced colorectal cancer: analysis of a prospective randomized phase III trial. J Clin Oncol. 1996 Oct;14(10):2682-7. link to original article contains protocol PubMed
  12. FFCD 9101: de Gramont A, Bosset JF, Milan C, Rougier P, Bouché O, Etienne PL, Morvan F, Louvet C, Guillot T, François E, Bedenne L. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol. 1997 Feb;15(2):808-15. link to original article contains verified protocol PubMed
  13. Scheithauer W, Kornek G, Marczell A, Salem G, Karner J, Kovats E, Burger D, Greiner R, Pidlich J, Schneeweiss B, Raderer M, Rosen H, Depisch D. Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study. J Clin Oncol. 1997 Mar;15(3):908-14. link to original article contains protocol PubMed
  14. Goldberg RM, Hatfield AK, Kahn M, Sargent DJ, Knost JA, O'Connell MJ, Krook JE, Maillard JA, Wiesenfeld M, Schaefer PL, Tirona MT, Moertel CG; North Central Cancer Treatment Group. Prospectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. J Clin Oncol. 1997 Nov;15(11):3320-9. link to original article contains protocol PubMed
  15. Borner MM, Castiglione M, Bacchi M, Weber W, Herrmann R, Fey MF, Pagani O, Leyvraz S, Morant R, Pestalozzi B, Hanselmann S, Goldhirsch A; Swiss Group for Clinical Cancer Research. The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: results of a phase III trial. Ann Oncol. 1998 May;9(5):535-41. link to original article contains protocol PubMed
  16. Aranda E, Díaz-Rubio E, Cervantes A, Antón-Torres A, Carrato A, Massutí T, Tabernero JM, Sastre J, Trés A, Aparicio J, López-Vega JM, Barneto I, García-Conde J; TTD. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol. 1998 Jul;9(7):727-31. link to original article contains protocol PubMed
  17. Hausmaninger H, Moser R, Samonigg H, Mlineritsch B, Schmidt H, Pecherstorfer M, Fridrik M, Kopf C, Nitsche D, Kaider A, Ludwig H. Biochemical modulation of 5-fluorouracil by leucovorin with or without interferon-alpha-2c in patients with advanced colorectal cancer: final results of a randomised phase III study. Eur J Cancer. 1999 Mar;35(3):380-5. link to original article PubMed
  18. Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet P, Llory JF, Letourneau Y, Coudert B, Bertheaut-Cvitkovic F, Larregain-Fournier D, Le Rol A, Walter S, Adam R, Misset JL, Lévi F. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2000 Jan;18(1):136-47. link to original article PubMed
  19. 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
  20. 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
  21. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. link to original article contains verified protocol PubMed
  22. Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001 Apr 15;19(8):2282-92. link to original article contains verified protocol PubMed
    1. Pooled update: Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. link to original article link to PMC article PubMed
  23. Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P; Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001 Nov 1;19(21):4097-106. link to original article contains verified protocol PubMed
    1. Pooled update: Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. link to original article link to PMC article PubMed
  24. Blanke CD, Shultz J, Cox J, Modiano M, Isaacs R, Kasimis B, Schilsky R, Fleagle J, Moore M, Kemeny N, Carlin D, Hammershaimb L, Haller D. A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer. Ann Oncol. 2002 Jan;13(1):87-91. link to original article contains protocol PubMed
  25. FUMA3008: Schilsky RL, Levin J, West WH, Wong A, Colwell B, Thirlwell MP, Ansari RH, Bell WN, White RL, Yates BB, McGuirt PV, Pazdur R. Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. J Clin Oncol. 2002 Mar 15;20(6):1519-26. link to original article contains protocol PubMed
  26. Maughan TS, James RD, Kerr DJ, Ledermann JA, McArdle C, Seymour MT, Cohen D, Hopwood P, Johnston C, Stephens RJ; British MRC Colorectal Cancer Working Party. Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2002 May 4;359(9317):1555-63. link to original article PubMed
  27. Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12;87(4):393-9. link to original article contains verified protocol link to PMC article PubMed
  28. Douillard JY, Hoff PM, Skillings JR, Eisenberg P, Davidson N, Harper P, Vincent MD, Lembersky BC, Thompson S, Maniero A, Benner SE. Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2002 Sep 1;20(17):3605-16. link to original article contains protocol PubMed
  29. Carmichael J, Popiela T, Radstone D, Falk S, Borner M, Oza A, Skovsgaard T, Munier S, Martin C. Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2002 Sep 1;20(17):3617-27. link to original article contains protocol PubMed
  30. AVF0780: Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, Griffing S, Bergsland E. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003 Jan 1;21(1):60-5. link to original article contains verified protocol PubMed
  31. Kerr DJ, McArdle CS, Ledermann J, Taylor I, Sherlock DJ, Schlag PM, Buckels J, Mayer D, Cain D, Stephens RJ; Medical Research Council's colorectal cancer study group; EORTC colorectal cancer study group. Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. Lancet. 2003 Feb 1;361(9355):368-73. link to original article contains protocol PubMed
  32. Maughan TS, James RD, Kerr DJ, Ledermann JA, Seymour MT, Topham C, McArdle C, Cain D, Stephens RJ; Medical Research Council Colorectal Cancer Group. Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial. Lancet. 2003 Feb 8;361(9356):457-64. link to original article PubMed
  33. EORTC 40952: Köhne CH, Wils J, Lorenz M, Schöffski P, Voigtmann R, Bokemeyer C, Lutz M, Kleeberg C, Ridwelski K, Souchon R, El-Serafi M, Weiss U, Burkhard O, Rückle H, Lichnitser M, Langenbuch T, Scheithauer W, Baron B, Couvreur ML, Schmoll HJ; European Organization of Research and Treatment of Cancer Gastrointestinal Group. Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952. J Clin Oncol. 2003 Oct 15;21(20):3721-8. Epub 2003 Sep 8. link to original article contains protocol PubMed
  34. Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003 Oct 15;21(20):3737-43. link to original article PubMed
  35. Chong G, Bhatnagar A, Cunningham D, Cosgriff TM, Harper PG, Steward W, Bridgewater J, Moore M, Cassidy J, Coleman R, Coxon F, Redfern CH, Jones JJ, Hawkins R, Northfelt D, Sreedharan S, Valone F, Carmichael J. Phase III trial of 5-fluorouracil and leucovorin plus either 3H1 anti-idiotype monoclonal antibody or placebo in patients with advanced colorectal cancer. Ann Oncol. 2006 Mar;17(3):437-42. Epub 2005 Nov 25. link to original article contains verified protocol PubMed
  36. Hospers GA, Schaapveld M, Nortier JW, Wils J, van Bochove A, de Jong RS, Creemers GJ, Erjavec Z, de Gooyer DJ, Slee PH, Gerrits CJ, Smit JM, Mulder NH. Randomised Phase III study of biweekly 24-h infusion of high-dose 5FU with folinic acid and oxaliplatin versus monthly plus 5-FU/folinic acid in first-line treatment of advanced colorectal cancer. Ann Oncol. 2006 Mar;17(3):443-9. link to original article contains protocol PubMed
  37. FFCD 9601: Ducreux M, Bouche O, Pignon JP, Mousseau M, Raoul JL, Cassan P, Leduc B, Berger C, Dunant A, Fournet J, Bedenne L; FFCD. Randomised trial comparing three different schedules of infusional 5FU and raltitrexed alone as first-line therapy in metastatic colorectal cancer: final results of the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 trial. Oncology. 2006;70(3):222-30. Epub 2006 Jun 30. link to original article PubMed
  38. MRC FOCUS: Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, Smith DB, Shepherd S, Maraveyas A, Ferry DR, Meade AM, Thompson L, Griffiths GO, Parmar MK, Stephens RJ; FOCUS Trial Investigators; National Cancer Research Institute Colorectal Clinical Studies Group. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007 Jul 14;370(9582):143-52. Erratum in: Lancet. 2007 Aug 18;370(9587):566. link to original article PubMed
  39. Gamelin E, Delva R, Jacob J, Merrouche Y, Raoul JL, Pezet D, Dorval E, Piot G, Morel A, Boisdron-Celle M. Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer. J Clin Oncol. 2008 May 1;26(13):2099-105. Erratum in: J Clin Oncol. 2013 Oct 1;31(28):3612. link to original article contains verified protocol PubMed
  40. Cunningham D, Sirohi B, Pluzanska A, Utracka-Hutka B, Zaluski J, Glynne-Jones R, Koralewski P, Bridgewater J, Mainwaring P, Wasan H, Wang JY, Szczylik C, Clingan P, Chan RT, Tabah-Fisch I, Cassidy J. Two different first-line 5-fluorouracil regimens with or without oxaliplatin in patients with metastatic colorectal cancer. Ann Oncol. 2009 Feb;20(2):244-50. Epub 2008 Oct 14. link to original article contains protocol PubMed
  41. MRC FOCUS2: Seymour MT, Thompson LC, Wasan HS, Middleton G, Brewster AE, Shepherd SF, O'Mahony MS, Maughan TS, Parmar M, Langley RE; FOCUS2 Investigators; National Cancer Research Institute Colorectal Cancer Clinical Studies Group. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. Lancet. 2011 May 21;377(9779):1749-59. Epub 2011 May 11. link to original article link to PMC article contains verified protocol PubMed
  42. FFCD 2000-05: Ducreux M, Malka D, Mendiboure J, Etienne PL, Texereau P, Auby D, Rougier P, Gasmi M, Castaing M, Abbas M, Michel P, Gargot D, Azzedine A, Lombard-Bohas C, Geoffroy P, Denis B, Pignon JP, Bedenne L, Bouché O; Fédération Francophone de Cancérologie Digestive. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol. 2011 Oct;12(11):1032-44. Epub 2011 Sep 6. link to original article contains protocol PubMed
  43. FFCD 2001-02: Aparicio T, Lavau-Denes S, Phelip JM, Maillard E, Jouve JL, Gargot D, Gasmi M, Locher C, Adhoute X, Michel P, Khemissa F, Lecomte T, Provençal J, Breysacher G, Legoux JL, Lepère C, Charneau J, Cretin J, Chone L, Azzedine A, Bouché O, Sobhani I, Bedenne L, Mitry E; FFCD. Randomized phase III trial in elderly patients comparing LV5FU2 with or without irinotecan for first-line treatment of metastatic colorectal cancer (FFCD 2001-02). Ann Oncol. 2016 Jan;27(1):121-7. Epub 2015 Oct 20. link to original article contains verified protocol in supplement PubMed

FUOX

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FUOX: 5-FU & OXaliplatin

Regimen

Study Evidence Comparator Comparative Efficacy
Díaz-Rubio et al. 2007 Phase III (C) CapeOx Did not meet primary endpoint of TTP

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

14-day cycle for 18 cycles

References

  1. Díaz-Rubio E, Tabernero J, Gómez-España A, Massutí B, Sastre J, Chaves M, Abad A, Carrato A, Queralt B, Reina JJ, Maurel J, González-Flores E, Aparicio J, Rivera F, Losa F, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol. 2007 Sep 20;25(27):4224-30. Epub 2007 Jun 4. link to original article contains verified protocol PubMed

IFL

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

Regimen variant #1, q3wk

Study Evidence Comparator Comparative Efficacy
Stathopoulos et al. 2010 Phase III (C) IFL & Bevacizumab Did not meet primary endpoint of OS36

Chemotherapy

21-day cycles

Regimen variant #2, 4 out of 6 weeks

Study Years of enrollment Evidence Comparator Comparative Efficacy
Saltz et al. 2000 1996-1998 Phase III (E-RT-esc) 1. FULV Seems to have superior OS
2. Irinotecan Might have superior OS
Goldberg et al. 2003 (NCCTG N9741) 1999-2001 Phase III (C) 1. FOLFOX4 Inferior OS
2. IROX Seems to have inferior OS
Hurwitz et al. 2004 (AVF2107g) 2000-2002 Phase III (C) 1. FULV & Bevacizumab Not reported
2. IFL & Bevacizumab Inferior OS
Fuchs et al. 2007 (BICC-C) Phase III (E-switch-ic) 1. CapeIRI Did not meet primary endpoint of PFS
2. FOLFIRI Inferior PFS
Guan et al. 2011 (ARTISTCRC) Phase III (C) mIFL & Bevacizumab Seems to have inferior OS

Note: 5-FU in ARTIST was given over 6 to 8 hours. ARTIST should not be confused for the trial with the same name in gastric cancer.

Chemotherapy

42-day cycles

References

  1. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. link to original article contains verified protocol PubMed
  2. NCCTG N9741: Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. Epub 2003 Dec 9. link to original article contains verified protocol PubMed
  3. AVF2107g: 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
    1. Update: Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, Hambleton J, Novotny WF, Kabbinavar F. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol. 2005 May 20;23(15):3502-8. link to original article PubMed
  4. BICC-C: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article contains verified protocol PubMed
    1. Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article PubMed
  5. Stathopoulos GP, Batziou C, Trafalis D, Koutantos J, Batzios S, Stathopoulos J, Legakis J, Armakolas A. Treatment of colorectal cancer with and without bevacizumab: a phase III study. Oncology. 2010;78(5-6):376-81. Epub 2010 Aug 27. link to original article contains verified protocol PubMed
  6. ARTIST: Guan ZZ, Xu JM, Luo RC, Feng FY, Wang LW, Shen L, Yu SY, Ba Y, Liang J, Wang D, Qin SK, Wang JJ, He J, Qi C, Xu RH. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer. 2011 Oct;30(10):682-9. link to PMC article contains verified protocol PubMed

IFL & Bevacizumab

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

Regimen variant #1, IFL

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hurwitz et al. 2004 (AVF2107g) 2000-2002 Phase III (E-RT-esc) 1. FL & Bevacizumab Not reported
2. IFL Superior OS
Fuchs et al. 2007 (BICC-C) Phase III (E-switch-ic) FOLFIRI+Bev Seems to have inferior OS

Chemotherapy

Targeted therapy

21-day cycles

Regimen variant #2, mIFL

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

Note: this trial should not be confused for the trial with the same name in gastric cancer.

Chemotherapy

Targeted therapy

42-day cycles

References

  1. AVF2107g: Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. link to original article PubMed
  2. BICC-C: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article contains verified protocol PubMed
    1. Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article PubMed
  3. ARTIST: Guan ZZ, Xu JM, Luo RC, Feng FY, Wang LW, Shen L, Yu SY, Ba Y, Liang J, Wang D, Qin SK, Wang JJ, He J, Qi C, Xu RH. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer. 2011 Oct;30(10):682-9. link to PMC article contains verified protocol PubMed

Irinotecan monotherapy

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Example orders

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Saltz et al. 2000 1996-1998 Phase III (E-de-esc) 1. FULV Did not meet primary endpoint of PFS
2. IFL Might have inferior OS

Chemotherapy

42-day cycles

References

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

IRIS & Bevacizumab

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IRIS & Bevacizumab: IRInotecan, S-1, Bevacizumab

Regimen variant #1, q3wk

Study Years of enrollment Evidence Comparator Comparative Efficacy
Yamada et al. 2018 (TRICOLORE) 2012-2014 Phase III (E-switch-ic) 1. CapeOx & Bevacizumab
2. mFOLFOX6 & Bevacizumab 		Non-inferior PFS

Chemotherapy

Targeted therapy

21-day cycles

Regimen variant #2, q4wk

Study Years of enrollment Evidence Comparator Comparative Efficacy
Yamada et al. 2018 (TRICOLORE) 2012-2014 Phase III (E-switch-ic) 1. CapeOx & Bevacizumab
2. mFOLFOX6 & Bevacizumab 		Non-inferior PFS

Chemotherapy

Targeted therapy

28-day cycles

References

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

IROX

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IROX: IRinotecan & OXaliplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Goldberg et al. 2003 (NCCTG N9741) 1999-2001 Phase III (E-RT-switch-ic) 1. FOLFOX4 Did not meet primary endpoint of TTP
2. IFL Seems to have superior OS

Chemotherapy

21-day cycles

References

  1. NCCTG N9741: Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. Epub 2003 Dec 9. link to original article contains verified protocol PubMed

Nordic FLOX

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FLOX: Fluorouracil, Leucovorin, OXaliplatin

Example orders

Regimen

Study Evidence Comparator Comparative Efficacy
Sørbye et al. 2004 Phase II
Tveit et al. 2012 (NORDIC-VII) Phase III (C) Nordic FLOX & Cetuximab Did not meet primary endpoint of PFS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

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

References

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

OXAFAFU

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OXAFAFU: OXAliplatin, Folinic Acid (Leucovorin), 5-FU (Fluorouracil)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Comella et al. 2005 2001-2003 Phase III (E-switch-ic) IRIFAFU Seems to have superior OS

Chemotherapy

14-day cycles

References

  1. Comella P, Massidda B, Filippelli G, Palmeri S, Natale D, Farris A, De Vita F, Buzzi F, Tafuto S, Maiorino L, Mancarella S, Leo S, Lorusso V, De Lucia L, Roselli M; SICOG. Oxaliplatin plus high-dose folinic acid and 5-fluorouracil IV bolus (OXAFAFU) versus irinotecan plus high-dose folinic acid and 5-fluorouracil IV bolus (IRIFAFU) in patients with metastatic colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase III trial. Ann Oncol. 2005 Jun;16(6):878-86. Epub 2005 Apr 18. link to original article contains protocol PubMed

S-1 monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Kwakman et al. 2017 (SALTO) 2014-2015 Phase III (E-switch-ic) Capecitabine Did not meet secondary efficacy endpoints (*) Lower incidence of hand-foot syndrome

Note: this trial had a primary toxicity endpoint; reported efficacy is based on the 2019 update.

Chemotherapy

21-day cycles

References

  1. SALTO: Kwakman JJM, Simkens LHJ, van Rooijen JM, van de Wouw AJ, Ten Tije AJ, Creemers GJM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, van Werkhoven E, Punt CJA; Dutch Colorectal Cancer Group. Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group. Ann Oncol. 2017 Jun 1;28(6):1288-1293. link to original article contains protocol PubMed NCT01918852
    1. Update: Kwakman JJM, van Werkhoven E, Simkens LHJ, van Rooijen JM, van de Wouw YAJ, Tije AJT, Creemers GM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, Punt CJA; Dutch Colorectal Cancer Group. Updated Survival Analysis of the Randomized Phase III Trial of S-1 Versus Capecitabine in the First-Line Treatment of Metastatic Colorectal Cancer by the Dutch Colorectal Cancer Group. Clin Colorectal Cancer. 2019 Jun;18(2):e229-e230. Epub 2019 Jan 29. link to original article PubMed

SOX

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SOX: S-1 & OXaliplatin

Regimen

Study Evidence Comparator Comparative Efficacy
Hong et al. 2012 (SMC 2008-03-012) Phase III (E-switch-ic) CapeOX Non-inferior PFS

Chemotherapy

21-day cycle for up to 9 cycles

Subsequent treatment

References

  1. SMC 2008-03-012: Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. link to original article contains protocol PubMed
    1. Update: Kim ST, Hong YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Lee JW, Jo SJ, Park YS. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: updated results from a phase 3 trial. BMC Cancer. 2014 Nov 26;14:883. link to original article link to PMC article PubMed

SOX & Bevacizumab

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SOX & Bevacizumab: S-1, OXaliplatin, Bevacizumab

Regimen

Study Evidence Comparator Comparative Efficacy
Yamada et al. 2013 (SOFTCRC) Phase III (C) mFOLFOX6 & Bevacizumab Seems to have non-inferior PFS

Note: S-1 is given starting on the evening of day 1, completing after breakfast on day 15.

Chemotherapy

  • Tegafur, gimeracil, oteracil (S-1) as follows:
    • BSA less than 1.25 m2: 40 mg PO twice per day on days 1 to 14 (see note)
    • BSA between 1.25 and 1.5 m2: 50 mg PO twice per day on days 1 to 14 (see note)
    • BSA 1.5 m2 or more: 60 mg PO twice per day on days 1 to 14 (see note)
  • Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1, given second

Targeted therapy

21-day cycles

References

  1. SOFT: Yamada Y, Takahari D, Matsumoto H, Baba H, Nakamura M, Yoshida K, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1278-86. Epub 2013 Nov 11. Erratum in: Lancet Oncol. 2014 Jan;15(1):e4. link to original article PubMed
    1. Update: Baba H, Yamada Y, Takahari D, Matsumoto H, Yoshida K, Nakamura M, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K. S-1 and oxaliplatin (SOX) plus bevacizumab versus mFOLFOX6 plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer: updated overall survival analyses of the open-label, non-inferiority, randomised phase III: SOFT study. ESMO Open. 2017 Mar 9;2(1):e000135. link to original article link to PMC article contains verified protocol PubMed

Maintenance after first-line therapy

Bevacizumab monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Johnsson et al. 2013 (Nordic ACT) 2007-2009 Phase III (C) Erlotinib & Bevacizumab Did not meet primary endpoint of PFS
Koeberle et al. 2015 (SAKK 41/06) 2007-2012 Phase III (E-esc) No further treatment Inconclusive whether non-inferior TTP
Hegewisch-Becker et al. 2015 (AIO KRK 0207) Phase III (E-esc) 1. No further treatment Not reported
2. Fluoropyrimidine & Bevacizumab Non-inferior TTF
Tournigand et al. 2015 (OPTIMOX3) Phase III (C) Erlotinib & Bevacizumab Might have inferior PFS
Aparicio et al. 2018 (PRODIGE 9) 2010-2013 Phase III (E-esc) No further treatment Did not meet primary endpoint of TCD

Preceding treatment

Targeted therapy

21-day cycles

References

  1. Nordic ACT: Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. link to original article contains verified protocol PubMed NCT00598156
  2. SAKK 41/06: Koeberle D, Betticher DC, von Moos R, Dietrich D, Brauchli P, Baertschi D, Matter K, Winterhalder R, Borner M, Anchisi S, Moosmann P, Kollar A, Saletti P, Roth A, Frueh M, Kueng M, Popescu RA, Schacher S, Hess V, Herrmann R. Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06). Ann Oncol. 2015 Apr;26(4):709-14. Epub 2015 Jan 20. link to original article contains verified protocol PubMed NCT00544700
  3. AIO KRK 0207: Hegewisch-Becker S, Graeven U, Lerchenmüller CA, Killing B, Depenbusch R, Steffens CC, Al-Batran SE, Lange T, Dietrich G, Stoehlmacher J, Tannapfel A, Reinacher-Schick A, Quidde J, Trarbach T, Hinke A, Schmoll HJ, Arnold D. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1355-69. Epub 2015 Sep 8. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. link to original article PubMed
  4. OPTIMOX3: Tournigand C, Chibaudel B, Samson B, Scheithauer W, Vernerey D, Mésange P, Lledo G, Viret F, Ramée JF, Tubiana-Mathieu N, Dauba J, Dupuis O, Rinaldi Y, Mabro M, Aucoin N, Latreille J, Bonnetain F, Louvet C, Larsen AK, André T, de Gramont A. Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1493-1505. Epub 2015 Oct 22. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. link to original article contains protocol PubMed
  5. PRODIGE 9: Aparicio T, Ghiringhelli F, Boige V, Le Malicot K, Taieb J, Bouché O, Phelip JM, François E, Borel C, Faroux R, Dahan L, Jacquot S, Genet D, Khemissa F, Suc E, Desseigne F, Texereau P, Lepage C, Bennouna J; PRODIGE 9 Investigators. Bevacizumab maintenance versus no maintenance during chemotherapy-free intervals in metastatic colorectal cancer: a randomized phase III trial (PRODIGE 9). J Clin Oncol. 2018 Mar 1;36(7):674-681. Epub 2018 Jan 18. link to original article PubMed

Capecitabine monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hong et al. 2012 (SMC 2008-03-012) Non-randomized portion of RCT
Luo et al. 2016 2010-2013 Phase III (E-esc) Observation Superior PFS

Preceding treatment

Chemotherapy

21-day cycles

References

  1. SMC 2008-03-012: Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. link to original article contains protocol PubMed
  2. Luo HY, Li YH, Wang W, Wang ZQ, Yuan X, Ma D, Wang FH, Zhang DS, Lin DR, Lin YC, Jia J, Hu XH, Peng JW, Xu RH. Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety. Ann Oncol. 2016 Jun;27(6):1074-81. Epub 2016 Mar 2. link to original article contains verified protocol PubMed NCT02027363

Capecitabine & Bevacizumab

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CAP-B: CAPecitabine & Bevacizumab

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Yalcin et al. 2013 (Stop and Go) Phase III (E-de-esc) Continued XELOX-B Superior PFS
Simkens et al. 2015 (CAIRO3) 2007-2012 Phase III (E-esc) Observation Superior PFS-2

Preceding treatment

Chemotherapy

Targeted therapy

21-day cycles

References

  1. Stop and Go: Yalcin S, Uslu R, Dane F, Yilmaz U, Zengin N, Buyukunal E, Buyukberber S, Camci C, Sencan O, Kilickap S, Ozdener F, Cevik D; Turkish Oncology Group. Bevacizumab + capecitabine as maintenance therapy after initial bevacizumab + XELOX treatment in previously untreated patients with metastatic colorectal cancer: phase III 'Stop and Go' study results--a Turkish Oncology Group trial. Oncology. 2013;85(6):328-35. Epub 2013 Nov 12. link to original article PubMed
  2. CAIRO3: Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoeven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, Honkoop AH, Mol L, Punt CJ, Koopman M; Dutch Colorectal Cancer Group. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015 May 9;385(9980):1843-52. Epub 2015 Apr 7. link to original article contains verified protocol PubMed NCT00442637
    1. Update: Goey KKH, Elias SG, van Tinteren H, Laclé MM, Willems SM, Offerhaus GJA, de Leng WWJ, Strengman E, Ten Tije AJ, Creemers GM, van der Velden A, de Jongh FE, Erdkamp FLG, Tanis BC, Punt CJA, Koopman M. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann Oncol. 2017 Sep 1;28(9):2128-2134. link to original article PubMed

S-1 monotherapy

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Regimen

Study Evidence
Hong et al. 2012 (SMC 2008-03-012) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

21-day cycles

References

  1. SMC 2008-03-012: Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. link to original article contains protocol PubMed

Advanced or metastatic disease, second-line therapy

CapeOx

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CapeOx: Capecitabine & Oxaliplatin
XELOX: XELoda & OXaliplatin

Example orders

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Koopman et al. 2007 (CAIRO) Phase III (E-switch-ic) See link See link
Rothenberg et al. 2008 2003-2005 Phase III (E-switch-ic) FOLFOX4 Non-inferior PFS

Preceding treatment

  • CAIRO: CAPIRI, with progression

Chemotherapy

21-day cycles

References

  1. CAIRO: Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ; Dutch Colorectal Cancer Group. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article contains verified protocol PubMed
  2. Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, Gollins S, Siu LL, Laguerre S, Cunningham D. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008 Oct;19(10):1720-6. Epub 2008 Jun 10. link to original article contains verified protocol PubMed

CapeOx & Erlotinib

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CapeOx & Erlotinib: Capecitabine, OXaliplatin, Erlotinib

Regimen

Study Years of enrollment Evidence
Meyerhardt et al. 2006 2003-2004 Phase II

Chemotherapy

Targeted therapy

21-day cycles

References

  1. Meyerhardt JA, Zhu AX, Enzinger PC, Ryan DP, Clark JW, Kulke MH, Earle CC, Vincitore M, Michelini A, Sheehan S, Fuchs CS. Phase II study of capecitabine, oxaliplatin, and erlotinib in previously treated patients with metastastic colorectal cancer. J Clin Oncol. 2006 Apr 20;24(12):1892-7. link to original article PubMed

CAPIRI

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

Regimen variant #1, "standard"

Study Evidence Comparator Comparative Efficacy
Lim et al. 2015 (SMC 2009-11-017) Phase III (C) XELIRI & Simvastatin Did not meet primary endpoint of PFS

Chemotherapy

21-day cycles

Regimen variant #2, "modified"

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

Chemotherapy

21-day cycles

References

  1. SMC 2009-11-017: Lim SH, Kim TW, Hong YS, Han SW, Lee KH, Kang HJ, Hwang IG, Lee JY, Kim HS, Kim ST, Lee J, Park JO, Park SH, Park YS, Lim HY, Jung SH, Kang WK. A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer. Br J Cancer. 2015 Nov 17;113(10):1421-6. Epub 2015 Oct 27. link to original article contains verified protocol link to PMC article PubMed
  2. AXEPT: Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. link to original article contains verified protocol PubMed

CAPIRI-Bev

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

Regimen

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

Chemotherapy

Targeted therapy

21-day cycles

References

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

Fluorouracil monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rougier et al. 1998 (V302) 1995-1997 Phase III (C) Irinotecan Seems to have inferior OS

Note: this was one of three control regimens; see paper for details.

Chemotherapy

Continued indefinitely

References

  1. V302: Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Awad L, Herait P, Jacques C. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1407-12. Erratum in: Lancet 1998 Nov 14;352(9140):1634. link to original article contains verified protocol PubMed

FOLFIRI

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Example orders

Regimen variant #1, lower-dose leucovorin

Study Evidence Comparator Comparative Efficacy
Lim et al. 2015 (SMC 2009-11-017) Phase III (C) FOLFIRI & Simvastatin Did not meet primary endpoint of PFS

Chemotherapy

14-day cycles

Regimen variant #2, higher-dose leucovorin

Study Years of enrollment Evidence Comparator Comparative Efficacy
Tournigand et al. 2003 Phase III (E-switch-ic) mFOLFOX6 Did not meet primary endpoint of PFS15
Peeters et al. 2010 (20050181) Phase III (C) FOLFIRI & Panitumumab Seems to have inferior PFS (*)
Van Cutsem et al. 2012 (VELOUR) 2007-2010 Phase III (C) FOLFIRI & Ziv-aflibercept Inferior OS
Masi et al. 2015 (BEBYP) 2008-2012 Phase III (C) FOLFIRI & Bevacizumab Seems to have inferior OS
Tabernero et al. 2015 (RAISE) 2010-2013 Phase III (C) FOLFIRI & Ramucirumab Seems to have inferior OS
Xu et al. 2018 (AXEPT) Phase III (C) CAPIRI Non-inferior OS

Note: BEBYP does not provide dosing details; this is the most commonly used variant of FOLFIRI. Reported efficacy for 20050181 is for wild-type KRAS, only, and is based on the 2014 update.

Chemotherapy

  • Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1, given first, with irinotecan
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours, given second (total dose per cycle: 2800 mg/m2)
    • In Tournigand et al. 2003, if no toxicity greater than grade 1 in cycles 1 & 2, increased to: 400 mg/m2 IV bolus once on day 1, then 3000 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 3400 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first, with leucovorin

14-day cycles

Subsequent treatment

  • Tournigand et al. 2003, upon progression: mFOLFOX6

References

  1. Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15;22(2):229-37. Epub 2003 Dec 2. link to original article contains verified protocol PubMed
  2. 20050181: 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
    1. Update: 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, Tian Y, Sidhu R. Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jan;25(1):107-16. Erratum in: Ann Oncol. 2014 Mar;25(3):757. link to original article PubMed
  3. FFCD 2000-05: Ducreux M, Malka D, Mendiboure J, Etienne PL, Texereau P, Auby D, Rougier P, Gasmi M, Castaing M, Abbas M, Michel P, Gargot D, Azzedine A, Lombard-Bohas C, Geoffroy P, Denis B, Pignon JP, Bedenne L, Bouché O; Fédération Francophone de Cancérologie Digestive. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol. 2011 Oct;12(11):1032-44. Epub 2011 Sep 6. link to original article contains protocol PubMed
  4. VELOUR: Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012 Oct 1;30(28):3499-506. Epub 2012 Sep 4. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Tabernero J, Van Cutsem E, Lakomý R, Prausová J, Ruff P, van Hazel GA, Moiseyenko VM, Ferry DR, McKendrick JJ, Soussan-Lazard K, Chevalier S, Allegra CJ. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014 Jan;50(2):320-31. link to original article PubMed
    2. Subgroup analysis: Ruff P, Van Cutsem E, Lakomy R, Prausova J, van Hazel GA, Moiseyenko VM, Soussan-Lazard K, Dochy E, Magherini E, Macarulla T, Papamichael D. Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: An age-based analysis from the randomized placebo-controlled phase III VELOUR trial. J Geriatr Oncol. 2018 Jan;9(1):32-39. Epub 2017 Aug 12. link to original article PubMed
  5. BEBYP: Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-30. Epub 2015 Jan 18. link to original article does not contain protocol PubMed
  6. RAISE: Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F; RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 May;16(5):499-508. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Obermannová R, Van Cutsem E, Yoshino T, Bodoky G, Prausová J, Garcia-Carbonero R, Ciuleanu T, Garcia Alfonso P, Portnoy D, Cohn A, Yamazaki K, Clingan P, Lonardi S, Kim TW, Yang L, Nasroulah F, Tabernero J. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016 Nov;27(11):2082-2090. Epub 2016 Aug 29. link to original article link to PMC article PubMed
  7. SMC 2009-11-017: Lim SH, Kim TW, Hong YS, Han SW, Lee KH, Kang HJ, Hwang IG, Lee JY, Kim HS, Kim ST, Lee J, Park JO, Park SH, Park YS, Lim HY, Jung SH, Kang WK. A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer. Br J Cancer. 2015 Nov 17;113(10):1421-6. Epub 2015 Oct 27. link to original article contains verified protocol link to PMC article PubMed
  8. AXEPT: Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. link to original article contains verified protocol PubMed

FOLFIRI (L-Leucovorin)

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FOLFIRI: L-FOLinic acid, Fluorouracil, IRInotecan

Regimen

Study Evidence Comparator Comparative Efficacy
Tournigand et al. 2003 Phase III (E-switch-ic) mFOLFOX6 Did not meet primary endpoint of PFS15
Xu et al. 2018 (AXEPT) Phase III (C) CAPIRI Non-inferior OS

Chemotherapy

  • Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given first, with irinotecan
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 2800 mg/m2)
    • In Tournigand et al. 2003, if no toxicity greater than grade 1 in cycles 1 & 2, increased to: 400 mg/m2 IV bolus once on day 1, then 3000 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 3400 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1, given first, with levoleucovorin

14-day cycles

Subsequent treatment

  • Tournigand et al. 2003, upon progression: mFOLFOX6

References

  1. Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15;22(2):229-37. Epub 2003 Dec 2. link to original article contains verified protocol PubMed
  2. AXEPT: Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. link to original article contains verified protocol PubMed

FOLFIRI & Bevacizumab

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

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bennouna et al. 2012 (ML18147) 2006-2010 Phase III (E-RT-esc) FOLFIRI Superior OS
Masi et al. 2015 (BEBYP) 2008-2012 Phase III (E-esc) FOLFIRI Seems to have superior OS
Xu et al. 2018 (AXEPT) Phase III (C) mXELIRI & Bevacizumab Non-inferior OS

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

Chemotherapy

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

Targeted therapy

14-day cycles

References

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

FOLFIRI & Bevacizumab (L-Leucovorin)

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

Regimen variant #1, 200/2800/150/5

Study Years of enrollment Evidence Comparator Comparative Efficacy
Iwamoto et al. 2015 (EAGLE) 2009-2012 Phase III (C) FOLFIRI & Bevacizumab; lower-dose bevacizumab (10 mg/kg) Did not meet primary endpoint of PFS

Chemotherapy

  • Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given second, with irinotecan
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours, given third (total dose per cycle: 2800 mg/m2)
  • Irinotecan (Camptosar) 150 mg/m2 IV over 90 minutes once on day 1, given second, with levoleucovorin

Targeted therapy

14-day cycles

Regimen variant #2, 200/2800/180/5

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

Chemotherapy

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

Targeted therapy

14-day cycles

References

  1. EAGLE: Iwamoto S, Takahashi T, Tamagawa H, Nakamura M, Munemoto Y, Kato T, Hata T, Denda T, Morita Y, Inukai M, Kunieda K, Nagata N, Kurachi K, Ina K, Ooshiro M, Shimoyama T, Baba H, Oba K, Sakamoto J, Mishima H. FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study. Ann Oncol. 2015 Jul;26(7):1427-33. Epub 2015 Apr 23. link to original article link to PMC article contains verified protocol PubMed UMIN000002557
  2. AXEPT: Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. link to original article contains verified protocol PubMed

FOLFIRI & Ramucirumab

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

Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Tabernero et al. 2015 (RAISE) 2010-2013 Phase III (E-RT-esc) FOLFIRI Seems to have superior OS

Chemotherapy

14-day cycles

References

  1. RAISE: Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F; RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 May;16(5):499-508. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Obermannová R, Van Cutsem E, Yoshino T, Bodoky G, Prausová J, Garcia-Carbonero R, Ciuleanu T, Garcia Alfonso P, Portnoy D, Cohn A, Yamazaki K, Clingan P, Lonardi S, Kim TW, Yang L, Nasroulah F, Tabernero J. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016 Nov;27(11):2082-2090. Epub 2016 Aug 29. link to original article link to PMC article PubMed

FOLFIRI & Ziv-aflibercept

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

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Van Cutsem et al. 2012 (VELOUR) 2007-2010 Phase III (E-RT-esc) FOLFIRI Superior OS
Li et al. 2018 (AFLAME) Phase III (E-esc) FOLFIRI Superior PFS

Chemotherapy

Targeted therapy

Supportive medications

14-day cycles

References

  1. VELOUR: Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012 Oct 1;30(28):3499-506. Epub 2012 Sep 4. link to original article PubMed
    1. Subgroup analysis: Tabernero J, Van Cutsem E, Lakomý R, Prausová J, Ruff P, van Hazel GA, Moiseyenko VM, Ferry DR, McKendrick JJ, Soussan-Lazard K, Chevalier S, Allegra CJ. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014 Jan;50(2):320-31. link to original article contains verified protocol PubMed
    2. Subgroup analysis: Ruff P, Van Cutsem E, Lakomy R, Prausova J, van Hazel GA, Moiseyenko VM, Soussan-Lazard K, Dochy E, Magherini E, Macarulla T, Papamichael D. Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: An age-based analysis from the randomized placebo-controlled phase III VELOUR trial. J Geriatr Oncol. 2018 Jan;9(1):32-39. Epub 2017 Aug 12. link to original article PubMed
  2. AFLAME: Li J, Xu R, Qin S, Liu T, Pan H, Xu J, Bi F, Lim R, Zhang S, Ba Y, Bai Y, Fan N, Tsuji A, Yeh KH, Ma B, Wei V, Shi D, Magherini E, Shen L. Aflibercept plus FOLFIRI in Asian patients with pretreated metastatic colorectal cancer: a randomized Phase III study. Future Oncol. 2018 Aug;14(20):2031-2044. Epub 2018 Aug 17. Erratum in: Future Oncol. 2019 Feb;15(4):451. link to original article contains verified protocol PubMed

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rothenberg et al. 2003 2000-2001 Phase III (E-RT-esc) 1. LV5FU2
2. Oxaliplatin 		Superior TTP
Rothenberg et al. 2008 2003-2005 Phase III (E-switch-ic) XELOX Non-inferior PFS

Chemotherapy

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

14-day cycles

References

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

mFOLFOX6

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mFOLFOX6: modified FOLinic acid, Fluorouracil, OXaliplatin

Example orders

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Masi et al. 2015 (BEBYP) 2008-2012 Phase III (C) mFOLFOX6 & Bevacizumab Seems to have inferior OS

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

Chemotherapy

14-day cycles

References

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

mFOLFOX6 & Bevacizumab

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

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Masi et al. 2015 (BEBYP) 2008-2012 Phase III (E-esc) mFOLFOX6 Seems to have superior OS

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

Chemotherapy

Targeted therapy

14-day cycles

References

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

Irinotecan monotherapy

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Example orders

Regimen variant #1, 100 mg/m2, 4 weeks out of 6

Study Years of enrollment Evidence
Rothenberg et al. 1999 1994 Phase II (RT)

Note: this was a mid-protocol dose amendment for excess toxicity.

Chemotherapy

42-day cycles

Regimen variant #2, 125 mg/m2, 4 weeks out of 6

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rothenberg et al. 1996 NR Phase II (RT)
Pitot et al. 1997 1993-1994 Phase II (RT)
Fuchs et al. 2003 Phase III (E-switch-ic) Irinotecan; every 3 weeks Did not meet primary endpoint of OS12

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

Chemotherapy

42-day cycles

Regimen variant #3, 250 mg/m2 q3wk

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

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

Chemotherapy

21-day cycles

Regimen variant #4, 300 mg/m2 q3wk

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rougier et al. 1998 (V302) 1995-1997 Phase III (E-RT-switch-ic) CI 5-FU Seems to have superior OS
Fuchs et al. 2003 Phase III (E-switch-ic) Irinotecan; 4 weeks out of 6 Did not meet primary endpoint of OS12
Sobrero et al. 2008 (EPIC) Phase III (C) Irinotecan & Cetuximab Did not meet primary endpoint of OS
Kim et al. 2009 (N9841) Phase III (C) FOLFOX4 Non-inferior OS

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

Chemotherapy

21-day cycles

Regimen variant #5, 350 mg/m2 q3wk

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rougier et al. 1997 1992-1993 Phase II (RT)
Rougier et al. 1998 (V302) 1995-1997 Phase III (E-RT-switch-ic) CI 5-FU Seems to have superior OS
Fuchs et al. 2003 Phase III (E-switch-ic) Irinotecan; 4 weeks out of 6 Did not meet primary endpoint of OS12
Lal et al. 2004 Phase III (C) Irinotecan x 8 Did not meet primary endpoint of FFS
Koopman et al. 2007 (CAIRO) Phase III (C) See link See link
Sobrero et al. 2008 (EPIC) Phase III (C) Irinotecan & Cetuximab Did not meet primary endpoint of OS
Haller et al. 2008 Phase III (C) IROX Inferior OS
Kim et al. 2009 (N9841) Phase III (C) FOLFOX4 Non-inferior OS

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

Preceding treatment

Chemotherapy

Supportive medications

21-day cycles

Subsequent treatment

  • CAIRO, with progression: CapeOx

References

  1. Rothenberg ML, Eckardt JR, Kuhn JG, Burris HA 3rd, Nelson J, Hilsenbeck SG, Rodriguez GI, Thurman AM, Smith LS, Eckhardt SG, Weiss GR, Elfring GL, Rinaldi DA, Schaaf LJ, Von Hoff DD. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol. 1996 Apr;14(4):1128-35. link to original article contains protocol PubMed
  2. Rougier P, Bugat R, Douillard JY, Culine S, Suc E, Brunet P, Becouarn Y, Ychou M, Marty M, Extra JM, Bonneterre J, Adenis A, Seitz JF, Ganem G, Namer M, Conroy T, Negrier S, Merrouche Y, Burki F, Mousseau M, Herait P, Mahjoubi M. Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol. 1997 Jan;15(1):251-60. link to original article PubMed
  3. Pitot HC, Wender DB, O'Connell MJ, Schroeder G, Goldberg RM, Rubin J, Mailliard JA, Knost JA, Ghosh C, Kirschling RJ, Levitt R, Windschitl HE. Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol. 1997 Aug;15(8):2910-9. link to original article contains protocol PubMed
  4. Rothenberg ML, Cox JV, DeVore RF, Hainsworth JD, Pazdur R, Rivkin SE, Macdonald JS, Geyer CE Jr, Sandbach J, Wolf DL, Mohrland JS, Elfring GL, Miller LL, Von Hoff DD. A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer. 1999 Feb 15;85(4):786-95. link to original article contains protocol PubMed
  5. V302: Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Awad L, Herait P, Jacques C. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1407-12. Erratum in: Lancet 1998 Nov 14;352(9140):1634. link to original article contains protocol PubMed
  6. 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
  7. Lal R, Dickson J, Cunningham D, Chau I, Norman AR, Ross PJ, Topham C, Middleton G, Hill M, Oates J. A randomized trial comparing defined-duration with continuous irinotecan until disease progression in fluoropyrimidine and thymidylate synthase inhibitor-resistant advanced colorectal cancer. J Clin Oncol. 2004 Aug 1;22(15):3023-31. link to original article contains protocol PubMed
  8. CAIRO: Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ; Dutch Colorectal Cancer Group. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article contains verified protocol PubMed
  9. EPIC: Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kröning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008 May 10;26(14):2311-9. Epub 2008 Apr 7. link to original article contains verified protocol PubMed
  10. 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
  11. N9841: Kim GP, Sargent DJ, Mahoney MR, Rowland KM Jr, Philip PA, Mitchell E, Mathews AP, Fitch TR, Goldberg RM, Alberts SR, Pitot HC. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol. 2009 Jun 10;27(17):2848-54. Epub 2009 Apr 20. link to original article link to PMC article contains verified protocol PubMed

IRIS

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IRIS: IRInotecan & S-1

Regimen

Study Evidence Comparator Comparative Efficacy
Muro et al. 2010 (FIRIS) Phase III (E-switch-ic) FOLFIRI Non-inferior OS (*)

Note: reported efficacy is based on the 2014 update.

Chemotherapy

  • Irinotecan (Camptosar) 125 mg/m2 IV once per day on days 1 & 15
  • Tegafur, gimeracil, oteracil (S-1) as follows:
    • BSA less than 1.25 m2: 40 mg PO twice per day on days 1 to 14
    • BSA between 1.25 and 1.5 m2: 50 mg PO twice per day on days 1 to 14
    • BSA at least 1.5 m2: 60 mg PO twice per day on days 1 to 14

28-day cycles

References

  1. FIRIS: Muro K, Boku N, Shimada Y, Tsuji A, Sameshima S, Baba H, Satoh T, Denda T, Ina K, Nishina T, Yamaguchi K, Takiuchi H, Esaki T, Tokunaga S, Kuwano H, Komatsu Y, Watanabe M, Hyodo I, Morita S, Sugihara K. Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study). Lancet Oncol. 2010 Sep;11(9):853-60. Epub 2010 Aug 12. link to original article contains verified protocol PubMed
    1. Update: Yasui H, Muro K, Shimada Y, Tsuji A, Sameshima S, Baba H, Satoh T, Denda T, Ina K, Nishina T, Yamaguchi K, Esaki T, Tokunaga S, Kuwano H, Boku N, Komatsu Y, Watanabe M, Hyodo I, Morita S, Sugihara K. A phase 3 non-inferiority study of 5-FU/l-leucovorin/irinotecan (FOLFIRI) versus irinotecan/S-1 (IRIS) as second-line chemotherapy for metastatic colorectal cancer: updated results of the FIRIS study. J Cancer Res Clin Oncol. 2015 Jan;141(1):153-60. Epub 2014 Aug 9. link to original article PubMed

IROX

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IROX: IRinotecan & OXaliplatin

Regimen

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

Chemotherapy

21-day cycles

References

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

Advanced or metastatic disease, third-line therapy

CapeOx

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CapeOX: Capecitabine, OXaliplatin

Example orders

Regimen

Study Evidence Comparator Comparative Efficacy
Koopman et al. 2007 (CAIRO) Phase III (C) See link See link

Preceding treatment

Chemotherapy

21-day cycles

References

  1. CAIRO: Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ; Dutch Colorectal Cancer Group. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article contains verified protocol PubMed

FOLFIRI

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Example orders

Regimen

Study Evidence
André et al. 1999 Non-randomized

Chemotherapy

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

14-day cycles

References

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

Regorafenib monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Eng et al. 2019 (IMblaze370) Phase III (C) 1. Atezolizumab
2. Atezolizumab & Cobimetinib 		Did not meet primary endpoint of OS

Targeted therapy

28-day cycles

References

  1. IMblaze370: Eng C, Kim TW, Bendell J, Argilés G, Tebbutt NC, Di Bartolomeo M, Falcone A, Fakih M, Kozloff M, Segal NH, Sobrero A, Yan Y, Chang I, Uyei A, Roberts L, Ciardiello F; IMblaze370 Investigators. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2019 Jun;20(6):849-861. Epub 2019 Apr 16. Erratum in: Lancet Oncol. 2019 Jun;20(6):e293. link to original article contains protocol PubMed

Advanced or metastatic disease, subsequent lines of therapy

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

Fluorouracil monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Hendlisz et al. 2010 Phase III (C) 5-FU & Radioembolization Seems to have inferior TTP

Chemotherapy

  • Fluorouracil (5-FU) 300 mg/m2/day IV continuous infusion over 14 days, started on day 1 (total dose per cycle: 4200 mg/m2)

21-day cycles

References

  1. Hendlisz A, Van den Eynde M, Peeters M, Maleux G, Lambert B, Vannoote J, De Keukeleire K, Verslype C, Defreyne L, Van Cutsem E, Delatte P, Delaunoit T, Personeni N, Paesmans M, Van Laethem JL, Flamen P. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol. 2010 Aug 10;28(23):3687-94. Epub 2010 Jun 21. link to original article contains protocol PubMed

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Giantonio et al. 2007 (ECOG E3200) 2001-2003 Phase III (C) 1. FOLFOX4 & Bevacizumab Inferior OS
2. Bevacizumab Not reported
Kim et al. 2009 (N9841) Phase III (E-esc) Irinotecan Non-inferior OS
Van Cutsem et al. 2011 (CONFIRM 2) Phase III (C) FOLFOX4 & Vatalanib Did not meet primary endpoint of OS

Note: patients in N9841 had not previously received irinotecan or oxaliplatin; patients in CONFIRM 2 had not previously received oxaliplatin.

Chemotherapy

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

14-day cycles

References

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

FOLFOX4 (L-Leucovorin)

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FOLFOX4: L-FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Evidence Comparator Comparative Efficacy
Van Cutsem et al. 2011 (CONFIRM 2) Phase III (C) FOLFOX4 & Vatalanib Did not meet primary endpoint of OS

Note: these patients had not previously received oxaliplatin.

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given second (total dose per cycle: 2000 mg/m2)
  • Levoleucovorin (Fusilev) 100 mg/m2 IV over 2 hours once per day on days 1 & 2, given first, with oxaliplatin on day 1
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first

14-day cycles

References

  1. CONFIRM 2: Van Cutsem E, Bajetta E, Valle J, Köhne CH, Hecht JR, Moore M, Germond C, Berg W, Chen BL, Jalava T, Lebwohl D, Meinhardt G, Laurent D, Lin E. Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):2004-10. Epub 2011 Apr 4. link to original article contains verified protocol PubMed

FOLFOX4 & Bevacizumab

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

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Giantonio et al. 2007 (ECOG E3200) 2001-2003 Phase III (E-RT-esc) 1. FOLFOX4 Superior OS
2. Bevacizumab Not reported

Chemotherapy

Targeted therapy

14-day cycles

References

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

FULV & Bevacizumab

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FULV & Bevacizumab: 5-FU, LeucoVorin (Folinic acid), Bevacizumab

Regimen variant #1, Roswell Park backbone

Study Years of enrollment Evidence
Chen et al. 2006 (TRC-301) 2003 Phase II (RT)

Note: this is based on the Roswell Park regimen backbone.

Chemotherapy

Targeted therapy

56-day cycles

Regimen variant #2, de Gramont backbone

Study Years of enrollment Evidence
Chen et al. 2006 (TRC-301) 2003 Phase II (RT)

Note: this is based on the de Gramont regimen backbone.

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, (total dose per cycle: 2000 mg/m2)
  • Folinic acid (Leucovorin) 400 mg/m2 IV once per day on days 1 & 2

Targeted therapy

14-day cycles

References

  1. TRC-301: Chen HX, Mooney M, Boron M, Vena D, Mosby K, Grochow L, Jaffe C, Rubinstein L, Zwiebel J, Kaplan RS. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. J Clin Oncol. 2006 Jul 20;24(21):3354-60. link to original article contains verified protocol PubMed

Ipilimumab & Nivolumab

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Regimen

Study Years of enrollment Evidence
Overman et al. 2018 (CheckMate 142) 2015-2016 Phase II (RT)

Immunotherapy

21-day cycle for 4 cycles, then 14-day cycles

References

  1. CheckMate 142: Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, Morse MA, Van Cutsem E, McDermott R, Hill A, Sawyer MB, Hendlisz A, Neyns B, Svrcek M, Moss RA, Ledeine JM, Cao ZA, Kamble S, Kopetz S, André T. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol. 2018 Mar 10;36(8):773-779. Epub 2018 Jan 20. link to original article contains protocol PubMed

Irinotecan monotherapy

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Example orders

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cunningham et al. 1998 (V301) 1995-NR Phase III (E-RT-esc) Supportive care Superior OS

Chemotherapy

Supportive medications

21-day cycles

References

  1. V301: 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

Nivolumab monotherapy

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Regimen

Study Years of enrollment Evidence
Overman et al. 2017 (CheckMate 142) 2014-2016 Phase II (RT)

Biomarker eligibility criteria

  • dMMR or MSI-H colorectal cancer.

Immunotherapy

14-day cycles

References

  1. CheckMate 142: Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, Desai J, Hill A, Axelson M, Moss RA, Goldberg MV, Cao ZA, Ledeine JM, Maglinte GA, Kopetz S, André T. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017 Sep;18(9):1182-1191. Epub 2017 Jul 19. Erratum in: Lancet Oncol. 2017 Sep;18(9):e510. link to original article link to PMC article contains protocol PubMed

Pembrolizumab monotherapy

Pembrolizumab (Keytruda) for unresectable or metastatic colon cancer

Regorafenib monotherapy

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Regimen variant #1, Standard Dosing

Study Years of enrollment Evidence Comparator Comparative Efficacy
Grothey et al. 2012 (CORRECT) 2010-2011 Phase III (E-RT-esc) Placebo Superior OS
Li et al. 2015 (CONCUR) 2012-2013 Phase III (E-esc) Placebo Superior OS

Targeted therapy

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

28-day cycles

Regimen variant #2, Dose-escalation

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Bekaii-Saab et al. 2019 (ReDOS) Randomized Phase II (E-esc) Regorafenib; standard dosing Seems to have superior OS Superior rate of patients proceeding to cycle 3

Targeted therapy

    • Regorafenib (Stivarga) as follows:
    • Cycle 1: 80 mg PO once per day on days 1 to 7, then 120 mg PO once per day on days 8 to 15, then 160 mg PO once per day on days 16 to 21
    • Cycle 2 onwards: 160 mg PO once per day on days 1 to 21

Supportive medications

  • Patients received 0.05% Clobetasol cream twice daily applied to palms and soles starting cycle 1 day 1 or applied when when hand-foot skin reaction developed (no difference in adverse events was found between the two clobetasol strategy groups)

28-day cycles

References

  1. CORRECT: Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. Epub 2012 Nov 22. link to original article contains verified protocol PubMed
    1. Dataset: Project Data Sphere
  2. CONCUR: Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L, Yeh KH, Bi F, Cheng Y, Le AT, Lin JK, Liu T, Ma D, Kappeler C, Kalmus J, Kim TW; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):619-29. Epub 2015 May 13. link to original article PubMed NCT01584830
  3. ReDOS: Bekaii-Saab TS, Ou FS, Ahn DH, Boland PM, Ciombor KK, Heying EN, Dockter TJ, Jacobs NL, Pasche BC, Cleary JM, Meyers JP, Desnoyers RJ, McCune JS, Pedersen K, Barzi A, Chiorean EG, Sloan J, Lacouture ME, Lenz HJ, Grothey A. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019 Aug;20(8):1070-1082. Epub 2019 Jun 28. link to original article contains protocol PubMed

Trifluridine and tipiracil monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Yoshino et al. 2012 2009-2010 Randomized Phase II (E-esc) Placebo Superior OS
Mayer et al. 2015 (RECOURSE) 2012-2013 Phase III (E-RT-esc) Placebo Superior OS
Xu et al. 2017 (TERRA) 2013-2015 Phase III (E-esc) Placebo Seems to have superior OS

Chemotherapy

28-day cycles

References

  1. Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, Tsuji A, Yamaguchi K, Muro K, Sugimoto N, Tsuji Y, Moriwaki T, Esaki T, Hamada C, Tanase T, Ohtsu A. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2012 Oct;13(10):993-1001. Epub 2012 Aug 28. link to original article contains verified protocol PubMed
  2. RECOURSE: Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14;372(20):1909-19. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Van Cutsem E, Mayer RJ, Laurent S, Winkler R, Grávalos C, Benavides M, Longo-Munoz F, Portales F, Ciardiello F, Siena S, Yamaguchi K, Muro K, Denda T, Tsuji Y, Makris L, Loehrer P, Lenz HJ, Ohtsu A; RECOURSE Study Group. The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer. Eur J Cancer. 2018 Feb;90:63-72. Epub 2017 Dec 21. link to original article PubMed
  3. TERRA: Xu J, Kim TW, Shen L, Sriuranpong V, Pan H, Xu R, Guo W, Han SW, Liu T, Park YS, Shi C, Bai Y, Bi F, Ahn JB, Qin S, Li Q, Wu C, Ma D, Lin D, Li J. Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: The TERRA study. J Clin Oncol. 2018 Feb 1;36(4):350-358. Epub 2017 Dec 7. link to original article contains verified protocol PubMed NCT01955837


Trifluridine and tipiracil & Bevacizumab

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Pfeiffer et al. 2020 2017-2018 Randomized Phase II Trifluridine and tipiracil monotherapy Superior PFS

Chemotherapy

Targeted therapy

28-day cycles

References

  1. Pfeiffer P, Yilmaz M, Möller S, Zitnjak D, Krogh M, Petersen LN, Poulsen LO, Winther SB, Thomsen KG, Ovortrup C. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21(3):412-420. link to original article PubMed
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