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	Travis Zack, MD, PhD University of California San Francisco San Francisco, CA, USA LinkedIn

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. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: This page has recently been reorganized, with regimens intended more generically for colorectal cancer being moved to a dedicated page. Now, this page has adjuvant regimens specific to colon cancer. Please see the rectal cancer page for (neo-)adjuvant regimens specific to rectal cancer.

See the RAS wild-type page for biomarker-specific adjuvant regimens.

10 regimens on this page 20 variants on this page

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO

2022: Baxter et al. Adjuvant Therapy for Stage II Colon Cancer: ASCO Guideline Update PubMed
2019: Lieu et al. Duration of oxaliplatin-containing adjuvant therapy for stage III colon cancer: ASCO Clinical Practice Guideline PubMed

ESMO

2021: Yoshino et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis treatment and follow-up of patients with localised colon cancer PubMed
2020: Argilés et al. Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2013: Labianca et al. Early Colon Cancer: ESMO Clinical Practice Guidelines PubMed
- 2009: van Cutsem & Oliveira. Primary colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up PubMed
- 2008: van Cutsem & Oliveira. Colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up PubMed
- 2007: van Cutsem. Colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up PubMed
- 2005: van Cutsem & Kataja. ESMO Minimum Clinical Recommendations for diagnosis, adjuvant treatment and follow-up of colon cancer PubMed
- 2001: ESMO Minimum Clinical Recommendations for diagnosis, adjuvant treatment and follow-up of colon cancer PubMed
2019: Stjepanovic et al. Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

NCCN

NCCN Guidelines - Colon Cancer
2021: Benson et al. Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. PubMed
2017: Benson et al. Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology PubMed
2014: Benson et al. Colon Cancer, Version 3.2014 PubMed
2013: Benson et al. Localized colon cancer, version 3.2013: featured updates to the NCCN Guidelines. PubMed
2011: Benson et al. Colon cancer. PubMed
2009: Engstrom et al. NCCN Clinical Practice Guidelines in Oncology: colon cancer. PubMed
2007: Engstrom et al. Colon cancer. PubMed
2005: Engstrom et al. Colon cancer clinical practice guidelines in oncology. PubMed
2003: Engstrom et al. Colon cancer. Clinical practice guidelines in oncology. PubMed

Perioperative therapy

mFOLFOX6 (L-Leucovorin)

mFOLFOX6: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Morton et al. 2023 (FOxTROT)	2008-05-15 to 2016-12-23	Phase 3 (E-switch-ic)	mFOLFOX6; adjuvant	Seems to have superior rate of residual or recurrent disease within 2 years (primary endpoint) Rate: 16.9% vs 21.5% (RR 0.72, 95% CI 0.54-0.98)

Note: FOxTROT was a 2 x 2 factorial trial, with a sub-randomization to panitumumab, or not, for patients with KRASwt tumors. See paper for details.

Neoadjuvant

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 folinic acid

14-day cycle for 3 cycles, followed by:

Definitive

Local therapy

Surgery

Adjuvant

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 folinic acid

14-day cycle for 9 cycles

References

FOxTROT: Morton D, Seymour M, Magill L, Handley K, Glasbey J, Glimelius B, Palmer A, Seligmann J, Laurberg S, Murakami K, West N, Quirke P, Gray R. Preoperative Chemotherapy for Operable Colon Cancer: Mature Results of an International Randomized Controlled Trial. J Clin Oncol. 2023 Mar 10;41(8):1541-1552. Epub 2023 Jan 19. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00647530

Adjuvant therapy

Capecitabine monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Twelves et al. 2005 (X-ACT)	1998-2001	Phase 3 (E-RT-switch-ic)	FULV	Might have superior OS¹ (secondary endpoint) Median OS: NYR vs NYR (HR 0.86, 95% CI 0.74-1.01) Equivalent DFS (primary endpoint) (HR 0.87, 95% CI 0.75-1.00)
Tomita et al. 2019 (JFMC37-0801)	2008-09 to 2009-12	Phase 3 (C)	Capecitabine x 12 mo	Might have inferior DFS

¹X-ACT was a non-inferiority study. Reported efficacy is based on the 2011 update.

Preceding treatment

Surgery

Chemotherapy

Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

21-day cycle for 8 cycles

References

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 dosing details in manuscript PubMed NCT00009737
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
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 dosing details in manuscript link to PMC article PubMed

CapeOx

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

Example orders

Example orders for CapeOx (XELOX) in colon cancer

Regimen variant #1, 3 months

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yoshino et al. 2019 (ACHIEVE)	2012-08-01 to 2014-06-30	Phase 3 (E-de-esc)	1a. CapeOx x 6 mo 1b. mFOLFOX6 x 6 mo	Seems to have non-inferior DFS¹ (primary endpoint) DFS60: 75.2% vs 74.2% (HR 0.95, 95% CI 0.77-1.18)

¹Reported efficacy is based on the 2022 update.

Preceding treatment

Surgery

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 4 cycles

Regimen variant #2, 6 months

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Schmoll et al. 2007 (XELOXA)	2003-04 to 2004-10	Phase 3 (E-RT-switch-ic)	FULV	Seems to have superior OS¹ (secondary endpoint) OS84: 73% vs 67% (HR 0.83, 95% CI 0.70-0.99) Superior DFS¹ (primary endpoint) DFS84: 63% vs 56% (HR 0.80, 95% CI 0.69-0.93)
Yoshino et al. 2019 (ACHIEVE)	2012-08-01 to 2014-06-30	Phase 3 (C)	1a. CapeOx x 3 mo 1b. mFOLFOX6 x 3 mo	Seems to have non-inferior DFS

¹Reported efficacy for XELOXA is based on the 2015 update.

Preceding treatment

Surgery

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

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 dosing details in manuscript PubMed NCT00069121
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
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 dosing details link to PMC article 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
2. Update: André T, Meyerhardt J, Iveson T, Sobrero A, Yoshino T, Souglakos I, Grothey A, Niedzwiecki D, Saunders M, Labianca R, Yamanaka T, Boukovinas I, Vernerey D, Meyers J, Harkin A, Torri V, Oki E, Georgoulias V, Taieb J, Shields A, Shi Q. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020 Dec;21(12):1620-1629. link to original article link to PMC article PubMed
ACHIEVE: Yoshino T, Yamanaka T, Oki E, Kotaka M, Manaka D, Eto T, Hasegawa J, Takagane A, Nakamura M, Kato T, Munemoto Y, Takeuchi S, Bando H, Taniguchi H, Gamoh M, Shiozawa M, Mizushima T, Saji S, Maehara Y, Ohtsu A, Mori M. Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer: The ACHIEVE Phase 3 Randomized Clinical Trial. JAMA Oncol. 2019 Nov 1;5(11):1574-1581. Erratum in: JAMA Oncol. 2019 Nov 1;5(11):1643. Epub 2019 Sep 12. Erratum in: JAMA Oncol. 2019 Dec 19. link to original article link to PMC article contains dosing details in manuscript PubMed UMIN000008543
1. Update: Yoshino T, Oki E, Misumi T, Kotaka M, Manaka D, Eto T, Hasegawa J, Takagane A, Nakamura M, Kato T, Munemoto Y, Nakamura F, Bando H, Taniguchi H, Sakamoto Y, Shiozawa M, Nishi M, Horiuchi T, Yamagishi H, Sakamoto J, Mizushima T, Ohtsu A, Mori M. Final Analysis of 3 Versus 6 Months of Adjuvant Oxaliplatin and Fluoropyrimidine-Based Therapy in Patients With Stage III Colon Cancer: The Randomized Phase III ACHIEVE Trial. J Clin Oncol. 2022 Oct 10;40(29):3419-3429. Epub 2022 May 5. link to original article PubMed
TOSCA: Petrelli F, Rulli E, Labianca R, Lonardi S, Rosati G, Dotti K, Ronzoni M, Pella N, Pusceddu V, Banzi M, Zampino MG, Yasmina M, Marchetti P, Cantore M, Zaniboni A, Rimassa L, Ciuffreda L, Ferrari D, Zagonel V, Maiello E, Sobrero A; TOSCA Investigators. Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial. Ann Oncol. 2021 Jan;32(1):66-76. Epub 2020 Oct 21. link to original article PubMed NCT00646607
KCSG CO09-07: Kim ST, Kim SY, Lee J, Yun SH, Kim HC, Lee WY, Kim TW, Hong YS, Lim SB, Baek JY, Oh JH, Ahn JB, Shin SJ, Han SW, Kim SG, Kang SY, Sym SJ, Zang DY, Kim YH, Choi IS, Kang JH, Kim MJ, Park YS. Oxaliplatin (3 months v 6 months) With 6 Months of Fluoropyrimidine as Adjuvant Therapy in Patients With Stage II/III Colon Cancer: KCSG CO09-07. J Clin Oncol. 2022 Nov 20;40(33):3868-3877. Epub 2022 Jun 30. link to original article link to PMC article PubMed NCT01092481
CIRCULATE-IDEA: NCT05174169

FLOX

FLOX: Fluorouracil, Leucovorin, OXaliplatin

Example orders

Example orders for FLOX in colon cancer

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kuebler et al. 2007 (NSABP C-07)	2000-2002	Phase 3 (E-esc)	FULV	Superior DFS (primary endpoint) DFS48: 73.2% vs 67% (HR 0.80, 95% CI 0.69-0.93)

Preceding treatment

Surgery

Chemotherapy

Fluorouracil (5-FU) 500 mg/m² IV bolus once per day on days 1, 8, 15, 22, 29, 36, given third, 1 hour after start of leucovorin
Leucovorin (Folinic acid) 500 mg/m² IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, given second
Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once per day on days 1, 15, 29, given first

8-week cycle for 3 cycles

References

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 dosing details in manuscript PubMed NCT00004931
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

FOLFOX4: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
André et al. 2004 (MOSAIC)	1998-2001	Phase 3 (E-RT-esc)	FULV	Seems to have superior OS¹ (secondary endpoint) OS120: 71.7% vs 67.1% (HR 0.85, 95% CI 0.73-0.99) Superior DFS (primary endpoint) DFS36: 78.2% vs 72.9%
de Gramont et al. 2012 (AVANT)	2004-2007	Phase 3 (C)	1. FOLFOX4 & Bevacizumab	Did not meet primary endpoint of DFS
de Gramont et al. 2012 (AVANT)	2004-2007	Phase 3 (C)	2. XELOX & Bevacizumab	Did not meet primary endpoint of DFS
Taieb et al. 2014 (PETACC-8)	2005-2009	Phase 3 (C)	FOLFOX4 & Cetuximab	Did not meet primary endpoint of DFS
Grothey et al. 2018 (IDEA)	2007-2015	Phase 3 (C)	1a. FOLFOX4 x 6 1b. mFOLFOX6 x 3 mo 1c. CapeOx x 3 mo	Inconclusive whether non-inferior DFS36

¹Reported efficacy for MOSAIC is based on the 2015 update.
IDEA is a pooled analysis of six phase 3 RCTs.

Preceding treatment

Surgery

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)
Leucovorin (Folinic acid) 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

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 dosing details in manuscript PubMed NCT00275210
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
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 dosing details in abstract PubMed NCT00112918
1. Update: André T, Vernerey D, Im SA, Bodoky G, Buzzoni R, Reingold S, Rivera F, McKendrick J, Scheithauer W, Ravit G, Fountzilas G, Yong WP, Isaacs R, Österlund P, Liang JT, Creemers GJ, Rakez M, Van Cutsem E, Cunningham D, Tabernero J, de Gramont A. Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group. Ann Oncol. 2020 Feb;31(2):246-256. Epub 2019 Dec 18. link to original article PubMed
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 NCT00265811
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 dosing details link to PMC article 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
2. Update: André T, Meyerhardt J, Iveson T, Sobrero A, Yoshino T, Souglakos I, Grothey A, Niedzwiecki D, Saunders M, Labianca R, Yamanaka T, Boukovinas I, Vernerey D, Meyers J, Harkin A, Torri V, Oki E, Georgoulias V, Taieb J, Shields A, Shi Q. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020 Dec;21(12):1620-1629. link to original article link to PMC article PubMed
TOSCA: Petrelli F, Rulli E, Labianca R, Lonardi S, Rosati G, Dotti K, Ronzoni M, Pella N, Pusceddu V, Banzi M, Zampino MG, Yasmina M, Marchetti P, Cantore M, Zaniboni A, Rimassa L, Ciuffreda L, Ferrari D, Zagonel V, Maiello E, Sobrero A; TOSCA Investigators. Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial. Ann Oncol. 2021 Jan;32(1):66-76. Epub 2020 Oct 21. link to original article PubMed NCT00646607

mFOLFOX6

mFOLFOX6: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Example orders

Example orders for mFOLFOX 6 in colon cancer

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Allegra et al. 2009 (NSABP C-08)	2004-2006	Phase 3 (C)	mFOLFOX6-B	Did not meet primary endpoint of DFS
Grothey et al. 2018 (IDEA)	2007-2015	Phase 3 (C)	1a. FOLFOX4 x 6 1b. mFOLFOX6 x 3 mo 1c. CapeOx x 3 mo	Inconclusive whether non-inferior DFS36
André et al. 2018 (IDEA France)	2009-2014	Phase 3 (C)	mFOLFOX6 x 3 mo	Seems to have superior DFS
Meyerhardt et al. 2021 (CALGB 80702)	2010-2015	Phase 3 (C)	mFOLFOX6 & Celecoxib	Did not meet primary endpoint of DFS

Note: CALGB 80702 was a 2 x 2 factorial trial, with the other comparison being 3 vs 6 months of mFOLFOX6. This comparison was made as part of the IDEA collaborative and is reported separately.

Preceding treatment

Surgery, within 10 weeks

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)
Leucovorin (Folinic acid) 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

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 dosing details in manuscript link to PMC article PubMed NCT00096278
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. Epub 2010 Oct 12. 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. Epub 2012 Dec 10. link to original article link to PMC article PubMed
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 dosing details link to PMC article 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
2. Update: André T, Meyerhardt J, Iveson T, Sobrero A, Yoshino T, Souglakos I, Grothey A, Niedzwiecki D, Saunders M, Labianca R, Yamanaka T, Boukovinas I, Vernerey D, Meyers J, Harkin A, Torri V, Oki E, Georgoulias V, Taieb J, Shields A, Shi Q. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020 Dec;21(12):1620-1629. link to original article link to PMC article PubMed
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 NCT00958737
TOSCA: Petrelli F, Rulli E, Labianca R, Lonardi S, Rosati G, Dotti K, Ronzoni M, Pella N, Pusceddu V, Banzi M, Zampino MG, Yasmina M, Marchetti P, Cantore M, Zaniboni A, Rimassa L, Ciuffreda L, Ferrari D, Zagonel V, Maiello E, Sobrero A; TOSCA Investigators. Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial. Ann Oncol. 2021 Jan;32(1):66-76. Epub 2020 Oct 21. link to original article PubMed NCT00646607
ACHIEVE-2: Yamazaki K, Yamanaka T, Shiozawa M, Manaka D, Kotaka M, Gamoh M, Shiomi A, Makiyama A, Munemoto Y, Rikiyama T, Fukunaga M, Ueki T, Shitara K, Shinkai H, Tanida N, Oki E, Sunami E, Ohtsu A, Maehara Y, Yoshino T. Oxaliplatin-based adjuvant chemotherapy duration (3 versus 6 months) for high-risk stage II colon cancer: the randomized phase III ACHIEVE-2 trial. Ann Oncol. 2021 Jan;32(1):77-84. Epub 2020 Oct 26. link to original article PubMed UMIN000013036
CALGB 80702: Meyerhardt JA, Shi Q, Fuchs CS, Meyer J, Niedzwiecki D, Zemla T, Kumthekar P, Guthrie KA, Couture F, Kuebler P, Bendell JC, Kumar P, Lewis D, Tan B, Bertagnolli M, Grothey A, Hochster HS, Goldberg RM, Venook A, Blanke C, O'Reilly EM, Shields AF. Effect of Celecoxib vs Placebo Added to Standard Adjuvant Therapy on Disease-Free Survival Among Patients With Stage III Colon Cancer: The CALGB/SWOG 80702 (Alliance) Randomized Clinical Trial. JAMA. 2021 Apr 6;325(13):1277-1286. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01150045
1. Dataset: Project Data Sphere
KCSG CO09-07: Kim ST, Kim SY, Lee J, Yun SH, Kim HC, Lee WY, Kim TW, Hong YS, Lim SB, Baek JY, Oh JH, Ahn JB, Shin SJ, Han SW, Kim SG, Kang SY, Sym SJ, Zang DY, Kim YH, Choi IS, Kang JH, Kim MJ, Park YS. Oxaliplatin (3 months v 6 months) With 6 Months of Fluoropyrimidine as Adjuvant Therapy in Patients With Stage II/III Colon Cancer: KCSG CO09-07. J Clin Oncol. 2022 Nov 20;40(33):3868-3877. Epub 2022 Jun 30. link to original article link to PMC article PubMed NCT01092481

mFOLFOX6 (L-Leucovorin)

mFOLFOX6: modified L-FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Example orders

Example orders for mFOLFOX 6 in colon cancer

Regimen variant #1, 3 months, 200 mg/m² L-LCV

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yoshino et al. 2019 (ACHIEVE)	2012-08-01 to 2014-06-30	Phase 3 (E-de-esc)	1a. CapeOx x 6 mo 1b. mFOLFOX6 x 6 mo	Seems to have non-inferior DFS¹ (primary endpoint) DFS60: 75.2% vs 74.2% (HR 0.95, 95% CI 0.77-1.18)

¹Reported efficacy is based on the 2022 update.

Preceding treatment

Surgery

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) 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 6 cycles

Regimen variant #2, 6 months, 200 mg/m² L-LCV

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yoshino et al. 2019 (ACHIEVE)	2012-08-01 to 2014-06-30	Phase 3 (C)	1a. CapeOx x 3 mo 1b. mFOLFOX6 x 3 mo	Seems to have non-inferior DFS

Preceding treatment

Surgery

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) 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

References

ACHIEVE: Yoshino T, Yamanaka T, Oki E, Kotaka M, Manaka D, Eto T, Hasegawa J, Takagane A, Nakamura M, Kato T, Munemoto Y, Takeuchi S, Bando H, Taniguchi H, Gamoh M, Shiozawa M, Mizushima T, Saji S, Maehara Y, Ohtsu A, Mori M. Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer: The ACHIEVE Phase 3 Randomized Clinical Trial. JAMA Oncol. 2019 Nov 1;5(11):1574-1581. Erratum in: JAMA Oncol. 2019 Nov 1;5(11):1643. Epub 2019 Sep 12. Erratum in: JAMA Oncol. 2019 Dec 19. link to original article link to PMC article contains dosing details in manuscript PubMed UMIN000008543
1. Update: Yoshino T, Oki E, Misumi T, Kotaka M, Manaka D, Eto T, Hasegawa J, Takagane A, Nakamura M, Kato T, Munemoto Y, Nakamura F, Bando H, Taniguchi H, Sakamoto Y, Shiozawa M, Nishi M, Horiuchi T, Yamagishi H, Sakamoto J, Mizushima T, Ohtsu A, Mori M. Final Analysis of 3 Versus 6 Months of Adjuvant Oxaliplatin and Fluoropyrimidine-Based Therapy in Patients With Stage III Colon Cancer: The Randomized Phase III ACHIEVE Trial. J Clin Oncol. 2022 Oct 10;40(29):3419-3429. Epub 2022 May 5. link to original article PubMed

FULV

FULV: 5-FU & LeucoVorin
LV5FU2: LeucoVorin & 5-FU for 2 days

Example orders

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Papadimitriou et al. 2011	1999-2004	Phase 3 (C)	IFL	Did not meet primary endpoint of DFS36

Preceding treatment

Surgery

Chemotherapy

Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36
Leucovorin (Folinic acid) 200 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36

8-week cycle for 4 cycles

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wolmark et al. 1993 (NSABP C-03)	1987-1989	Phase 3 (E-de-esc)	MOF	Superior OS
Wolmark et al. 1999 (NSABP C-04)	1989-07 to 1990-12	Phase 3 (E-switch-ooc)	1. 5-FU & Levamisole	Might have superior OS (co-primary endpoint)
Wolmark et al. 1999 (NSABP C-04)	1989-07 to 1990-12	Phase 3 (E-switch-ooc)	2. FULV & Levamisole	Did not meet co-primary endpoints of DFS/OS
Haller et al. 2005 (Intergroup 0089)	1988-1992	Phase 3 (E-esc)	1. FULV; low-dose	Did not meet primary endpoint of OS
			2. FULV & Levamisole; LDLV	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)	1997-1999	Phase 3 (C)	Tegafur, Uracil, Folinic acid	Did not meet co-primary endpoints of DFS/OS
Saltz et al. 2007 (CALGB 89803)	1999-2001	Phase 3 (C)	IFL	Did not meet co-primary endpoints of DFS/OS
Kuebler et al. 2007 (NSABP C-07)	2000-2002	Phase 3 (C)	FLOX	Inferior DFS
Schmoll et al. 2007 (XELOXA)	2003-04 to 2004-10	Phase 3 (C)	CapeOx	Seems to have inferior OS¹

¹Reported efficacy for XELOXA is based on the 2015 update.
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

Surgery

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
Leucovorin (Folinic acid) 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	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fountzilas et al. 2000	1989-1997	Phase 3 (C)	FULV & IFN alfa-2a	Did not meet primary endpoint of OS

Preceding treatment

Surgery

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
Leucovorin (Folinic acid) 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, 1850/100 ("Mayo Clinic regimen")

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Popov et al. 2008 (PETACC-1)	NR-1999	Phase 3 (C)	Raltitrexed	Inconclusive whether non-inferior RFS/OS

Note: This was the lower bound of 5-FU dosing in PETACC-1.

Preceding treatment

Surgery

Chemotherapy

Fluorouracil (5-FU) 370 mg/m² IV bolus once per day on days 1 to 5, given second
Leucovorin (Folinic acid) 20 mg/m² IV bolus once per day on days 1 to 5, given first

28-day cycle for 6 cycles

Regimen variant #5, 1850/2500 ("NCI schedule")

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wolmark et al. 1998 (NSABP C-05)	1991-1994	Phase 3 (C)	FULV & Interferon alfa	Did not meet co-primary endpoints of DFS/OS

Preceding treatment

Surgery

Chemotherapy

Fluorouracil (5-FU) 370 mg/m² IV over 60 minutes once per day on days 1 to 5, given second
Leucovorin (Folinic acid) 500 mg/m² IV over 30 minutes once per day on days 1 to 5, given first

28-day cycle for 6 cycles

Regimen variant #6, 2000/400 ("de Gramont regimen"/LV5FU2)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
André et al. 2003 (GERCOR C96.1)	1996-1999	Phase 3 (C)	FULV; monthly	Did not meet primary endpoint of DFS
André et al. 2004 (MOSAIC)	1998-2001	Phase 3 (C)	FOLFOX4	Seems to have inferior OS¹
Ychou et al. 2009 (FFCD 9802)	1998-2002	Phase 3 (C)	IFL	Did not meet primary endpoint of DFS
Van Cutsem et al. 2009 (PETACC-3)	2000-2002	Phase 3 (C)	IFL	Did not meet primary endpoint of DFS

¹Reported efficacy for MOSAIC is based on the 2015 update.

Preceding treatment

Surgery

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)
Leucovorin (Folinic acid) 200 mg/m² IV over 2 hours once per day on days 1 & 2, given first

14-day cycle for 12 cycles

Regimen variant #7, 2000/1000

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Francini et al. 1994	1985-1990	Phase 3 (E-esc)	Observation	Superior OS (secondary endpoint) OS60: 79% vs 65%

Preceding treatment

Surgery, within 3 weeks

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV once per day on days 1 to 5
Leucovorin (Folinic acid) 200 mg/m² IV once per day on days 1 to 5

28-day cycle for 12 cycles

Regimen variant #8, 2125/100 ("Mayo Clinic regimen")

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Twelves et al. 2005 (X-ACT)	1998-2001	Phase 3 (C)	Capecitabine	Might have inferior OS¹
Popov et al. 2008 (PETACC-1)	NR-1999	Phase 3 (C)	Raltitrexed	Inconclusive whether non-inferior RFS/OS
Köhne et al. 2013 (PETACC-2)	1999-2004	Phase 3 (C)	1. FULV; LV5FU2 2. FULV; AIO regimen 3. FULV; TTD regimen	Did not meet primary endpoint of OS60
Schmoll et al. 2007 (XELOXA)	2003-04 to 2004-10	Phase 3 (C)	XELOX	Seems to have inferior OS²

¹X-ACT was a non-inferiority study. Reported efficacy is based on the 2011 update.
²Reported efficacy for XELOXA is based on the 2015 update.
Note: This was the upper bound of 5-FU dosing in PETACC-1.

Preceding treatment

Surgery

Chemotherapy

Fluorouracil (5-FU) 425 mg/m² IV bolus once per day on days 1 to 5, given second
Leucovorin (Folinic acid) 20 mg/m² IV bolus once per day on days 1 to 5, given first

28-day cycle for 6 cycles

Regimen variant #9, 2125/100, with cycle elongation ("Mayo Clinic regimen")

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
O'Connell et al. 1997 (CALGB 8896)	1988-02 to 1989-08	Phase 3 (E-esc)	Observation	Seems to have superior OS
Haller et al. 2005 (Intergroup 0089)	1988-1992	Phase 3 (E-de-esc)	1. FULV; high-dose	Did not meet primary endpoint of OS
			2. FULV & Levamisole; LDLV	Did not meet primary endpoint of OS
			3. 5-FU & Levamisole	Did not meet primary endpoint of OS
Punt et al. 2002 (Study 157-002)	1995-1999	Phase 3 (C)	1. FULV & Edrecolomab	Did not meet primary endpoint of OS
Punt et al. 2002 (Study 157-002)	1995-1999	Phase 3 (C)	2. Edrecolomab	Seems to have superior OS
Fields et al. 2009 (Study 157-001)	1995-1999	Phase 3 (C)	FULV & Edrecolomab	Did not meet primary endpoint of OS

Preceding treatment

Surgery

Chemotherapy

Fluorouracil (5-FU) 425 mg/m² IV bolus once per day on days 1 to 5, given second
Leucovorin (Folinic acid) 20 mg/m² IV bolus once per day on days 1 to 5, given first

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

References

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 dosing details in manuscript 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
Francini G, Petrioli R, Lorenzini L, Mancini S, Armenio S, Tanzini G, Marsili S, Aquino A, Marzocca G, Civitelli S, Mariani L, De Sando D, Bovenga S, Lorenzi M. Folinic acid and 5-fluorouracil as adjuvant chemotherapy in colon cancer. Gastroenterology. 1994 Apr;106(4):899-906. link to original article contains dosing details in manuscript PubMed
CALGB 8896: 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 dosing details in manuscript 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
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
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 dosing details in manuscript PubMed NCT00425152
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
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 dosing details in abstract PubMed
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 dosing details in manuscript PubMed
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
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 dosing details in manuscript PubMed NCT00275210
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
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 dosing details in manuscript PubMed NCT00009737
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
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 dosing details in manuscript PubMed
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 dosing details in manuscript PubMed NCT00378716
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 dosing details in manuscript PubMed NCT00069121
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 dosing details in manuscript 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
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 dosing details in abstract PubMed NCT00004931
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
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 dosing details in manuscript PubMed NCT00003835
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 contains dosing details in manuscript PubMed
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 dosing details in abstract PubMed NCT00005979
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 dosing details in manuscript PubMed
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 dosing details in abstract PubMed NCT00026273
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 dosing details in abstract PubMed ACTRN12610000148077
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; EORTC; FFCD; GETTD. 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 NCT00004150

S-1 monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yoshida et al. 2014 (ACTS-CC)	2008-04 to 2009-06	Phase 3 (E-switch-ic)	UFT + LV	Non-inferior DFS36 (primary endpoint) DFS36: 75.5% vs 72.5% (HR 0.85, 95% CI 0.70-1.03)

Preceding treatment

Surgery

Chemotherapy

Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
- Less than 1.25 m²: 40 mg PO twice per day on days 1 to 28
- BSA between 1.25 m² and 1.50 m²: 50 mg PO twice per day on days 1 to 28
- BSA greater than 1.50 m²: 60 mg PO twice per day on days 1 to 28

42-day cycle for 4 cycles

References

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 contains dosing details in manuscript PubMed NCT00660894

SOX

SOX: S-1, OXaliplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sunami et al. 2019 (ACTS-CC 02)	2010-2014	Phase 3 (E-esc)	Tegafur, Uracil, Folinic Acid	Did not meet primary endpoint of DFS

Preceding treatment

Surgery

Chemotherapy

Tegafur, gimeracil, oteracil (S-1) 40 mg/m² PO twice per day on days 1 to 14
Oxaliplatin (Eloxatin) 100 mg/m² IV once on day 1

21-day cycle for 8 cycles

References

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. Clin Colorectal Cancer. 2020 Mar;19(1):22-31.e6. Epub 2019 Oct 18. link to original article contains dosing details in abstract PubMed JapicCTI-101073
1. Update: Watanabe J, Sasaki S, Kusumoto T, Sakamoto Y, Yoshida K, Tomita N, Maeda A, Teshima J, Yokota M, Tanaka C, Yamauchi J, Uetake H, Itabashi M, Takahashi K, Baba H, Kotake K, Boku N, Aiba K, Morita S, Takenaka N, Sugihara K. S-1 and oxaliplatin versus tegafur-uracil and leucovorin as post-operative adjuvant chemotherapy in patients with high-risk stage III colon cancer: updated 5-year survival of the phase III ACTS-CC 02 trial. ESMO Open. 2021 Apr;6(2):100077. Epub 2021 Mar 11. link to original article link to PMC article PubMed

Tegafur, Uracil, Folinic acid

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

Regimen variant #1, 300/75

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sadahiro et al. 2015 (JFMC33-0502)	2005-2007	Phase 3 (C)	UFT + LV; weekly x 18 mo	Did not meet primary endpoint of DFS
Yoshida et al. 2014 (ACTS-CC)	2008-04 to 2009-06	Phase 3 (C)	S-1	Non-inferior DFS36
Sunami et al. 2019 (ACTS-CC 02)	2010-2014	Phase 3 (C)	SOX	Did not meet primary endpoint of DFS

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

Chemotherapy

Tegafur and uracil (UFT) 100 mg/m² PO every 8 hours on days 1 to 28
Leucovorin (Folinic acid) 25 mg PO every 8 hours on days 1 to 28

35-day cycle for 5 cycles

Regimen variant #2, 300/90

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lembersky et al. 2006 (NSABP C-06)	1997-1999	Phase 3 (E-switch-ic)	FULV	Did not meet co-primary endpoints of DFS/OS

Preceding treatment

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

Chemotherapy

Tegafur and uracil (UFT) 100 mg/m² PO every 8 hours on days 1 to 28
Leucovorin (Folinic acid) 30 mg PO every 8 hours on days 1 to 28
No food for 1 hour before and after each dose of medication.

35-day cycle for 5 cycles

References

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 dosing details in manuscript PubMed NCT00378716
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
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 dosing details in abstract PubMed UMIN C000000245
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. Clin Colorectal Cancer. 2020 Mar;19(1):22-31.e6. Epub 2019 Oct 18. link to original article contains dosing details in manuscript PubMed JapicCTI-101073
1. Update: Watanabe J, Sasaki S, Kusumoto T, Sakamoto Y, Yoshida K, Tomita N, Maeda A, Teshima J, Yokota M, Tanaka C, Yamauchi J, Uetake H, Itabashi M, Takahashi K, Baba H, Kotake K, Boku N, Aiba K, Morita S, Takenaka N, Sugihara K. S-1 and oxaliplatin versus tegafur-uracil and leucovorin as post-operative adjuvant chemotherapy in patients with high-risk stage III colon cancer: updated 5-year survival of the phase III ACTS-CC 02 trial. ESMO Open. 2021 Apr;6(2):100077. Epub 2021 Mar 11. link to original article link to PMC article PubMed

Advanced or metastatic disease

See the colorectal cancer page for colorectal cancer regimens.

@@ Line 1: / Line 1: @@
-{| class="wikitable" style="text-align:center; width:100%;"
+<span id="BackToTop"></span>
-! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Page editor'''
+<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
-! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''
+[[#top|Back to Top]]
-|-
+</div>
-| style="background-color:#F0F0F0; width:15%" |[[File:RyanNguyen.jpg|frameless|upright=0.3|center]]
+{{#lst:Editorial board transclusions|gi}}
-| style="width:35%" |<big>[[User:Ryannguyen|Ryan Nguyen, DO]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br>[https://www.linkedin.com/in/ryan-nguyen-0b12a432/ LinkedIn]
-| style="background-color:#F0F0F0; width:15%" |[[File:nkv.jpg|frameless|upright=0.3|center]]
-| style="width:35%" |<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>University of Illinois at Chicago<br>Chicago, IL</big>
-|-
-|}
 ''Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the [[Colon_cancer_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Colon cancer - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''
-<br><big>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.
+<br><big>'''Note: This page has recently been reorganized, with regimens intended more generically for colorectal cancer being moved to a [[Colorectal_cancer|dedicated page]]. Now, this page has adjuvant regimens specific to colon cancer. Please see the [[Rectal_cancer|'''rectal cancer page''']] for (neo-)adjuvant regimens specific to rectal cancer.</big>
+*See the [[Colon_cancer,_RAS_wild-type|'''RAS wild-type page''']] for biomarker-specific adjuvant regimens.</big>
-*See the [[Rectal_cancer|'''rectal cancer page''']] for regimens specific to rectal cancer.
-*See the [[Colon cancer, BRAF-mutated|'''BRAF-mutated page''']] for biomarker-specific regimens.
-*See the [[Colon cancer, HER2-positive|'''HER2+ page''']] for biomarker-specific regimens.
-*See the [[Colon_cancer,_RAS_wild-type|'''RAS wild-type page''']] for biomarker-specific regimens.</big>
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
@@ Line 23: / Line 13: @@
 |}
 {{TOC limit|limit=3}}
 =Guidelines=
-==[http://www.asco.org/ ASCO]==
+'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
+==[https://www.asco.org/ ASCO]==
+*'''2022:''' Baxter et al. [https://doi.org/10.1200/jco.21.02538 Adjuvant Therapy for Stage II Colon Cancer: ASCO Guideline Update] [https://pubmed.ncbi.nlm.nih.gov/34936379/ PubMed]
+*'''2019:''' Lieu et al. [https://doi.org/10.1200/JCO.19.00281 Duration of oxaliplatin-containing adjuvant therapy for stage III colon cancer: ASCO Clinical Practice Guideline] [https://pubmed.ncbi.nlm.nih.gov/30986117/ PubMed]
+==[https://www.esmo.org/ ESMO]==
+*'''2021:''' Yoshino et al. [https://doi.org/10.1016/j.annonc.2021.08.1752 Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis treatment and follow-up of patients with localised colon cancer] [https://www.ncbi.nlm.nih.gov/pubmed/34411693 PubMed]
+*'''2020:''' Argilés et al. [https://doi.org/10.1016/j.annonc.2020.06.022 Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/32702383 PubMed]
+**'''2013:''' Labianca et al. [https://doi.org/10.1093/annonc/mdt354 Early Colon Cancer: ESMO Clinical Practice Guidelines] [https://www.ncbi.nlm.nih.gov/pubmed/24078664 PubMed]
+**'''2009:''' van Cutsem & Oliveira. [https://doi.org/10.1093/annonc/mdp126 Primary colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454461/ PubMed]
+**'''2008:''' van Cutsem & Oliveira. [https://doi.org/10.1093/annonc/mdn077 Colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456758/ PubMed]
+**'''2007:''' van Cutsem. [https://doi.org/10.1093/annonc/mdm021 Colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/17491030/ PubMed]
+**'''2005:''' van Cutsem & Kataja. [https://doi.org/10.1093/annonc/mdi808 ESMO Minimum Clinical Recommendations for diagnosis, adjuvant treatment and follow-up of colon cancer] [https://pubmed.ncbi.nlm.nih.gov/15888737/ PubMed]
+**'''2001:''' [https://doi.org/10.1023/a:1017492920758 ESMO Minimum Clinical Recommendations for diagnosis, adjuvant treatment and follow-up of colon cancer] [https://pubmed.ncbi.nlm.nih.gov/11583182/ PubMed]
+*'''2019:''' Stjepanovic et al. [https://doi.org/10.1093/annonc/mdz233 Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/31378807 PubMed]
-*'''2019:''' Lieu et al. [https://doi.org/10.1200/JCO.19.00281 Duration of oxaliplatin-containing adjuvant therapy for stage III colon cancer: ASCO Clinical Practice Guideline]
+==NCCN==
+*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428 NCCN Guidelines - Colon Cancer]
+*'''2021:''' Benson et al. [https://doi.org/10.6004/Jnccn.2021.0012 Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/33724754/ PubMed]
+*'''2017:''' Benson et al. [https://doi.org/10.6004/jnccn.2017.0036 Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology] [https://pubmed.ncbi.nlm.nih.gov/28275037/ PubMed]
+*'''2014:''' Benson et al. [https://doi.org/10.6004/jnccn.2014.0099 Colon Cancer, Version 3.2014] [https://pubmed.ncbi.nlm.nih.gov/24994923/ PubMed]
+*'''2013:''' Benson et al. [https://doi.org/10.6004/Jnccn.2013.0069 Localized colon cancer, version 3.2013: featured updates to the NCCN Guidelines.] [https://pubmed.ncbi.nlm.nih.gov/23667203/ PubMed]
+*'''2011:''' Benson et al. [https://doi.org/10.6004/Jnccn.2011.0104 Colon cancer.] [https://pubmed.ncbi.nlm.nih.gov/22056656/ PubMed]
+*'''2009:''' Engstrom et al. [https://doi.org/10.6004/Jnccn.2009.0056 NCCN Clinical Practice Guidelines in Oncology: colon cancer.] [https://pubmed.ncbi.nlm.nih.gov/19755046/ PubMed]
+*'''2007:''' Engstrom et al. Colon cancer. [https://pubmed.ncbi.nlm.nih.gov/17977501/ PubMed]
+*'''2005:''' Engstrom et al. [https://doi.org/10.6004/Jnccn.2005.0024 Colon cancer clinical practice guidelines in oncology.] [https://pubmed.ncbi.nlm.nih.gov/16038639/ PubMed]
+*'''2003:''' Engstrom et al. [https://doi.org/10.6004/Jnccn.2003.0006 Colon cancer. Clinical practice guidelines in oncology.] [https://pubmed.ncbi.nlm.nih.gov/19764149/ PubMed]
-==[http://www.esmo.org/ ESMO]==
+=Perioperative therapy=
-*'''2020:''' Argilés et al. [https://doi.org/10.1016/j.annonc.2020.06.022 Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+==mFOLFOX6 (L-Leucovorin) {{#subobject:8uy6d7|Regimen=1}}==
-*'''2019:''' Stjepanovic et al. [https://doi.org/10.1093/annonc/mdz233 Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-*'''2016:''' Van Cutsem et al. [https://doi.org/10.1093/annonc/mdw235 ESMO consensus guidelines for the management of patients with metastatic colorectal cancer]
+<div class="toccolours" style="background-color:#c8a2c8">
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-===Older===
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
-*'''2013:''' Labianca et al. [https://doi.org/10.1093/annonc/mdt354 Early Colon Cancer: ESMO Clinical Practice Guidelines]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-*'''2013:''' Balmaña et al. [https://doi.org/10.1093/annonc/mdt209 Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-==[http://www.jsccr.jp/en/index.html Japanese Society for Cancer of the Colon and Rectum (JSCCR)]==
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10022855/ Morton et al. 2023 (FOxTROT)]
-*'''2016:''' Watanabe et al. [https://doi.org/10.1007/s10147-017-1101-6 Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5809573/ link to PMC article]
+|2008-05-15 to 2016-12-23
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-==[https://www.nccn.org/ NCCN]==
+|[[#mFOLFOX6_.28L-Leucovorin.29_2|mFOLFOX6]]; adjuvant
+| style="background-color:#91cf60" |Seems to have superior rate of residual or recurrent disease within 2 years (primary endpoint)<br>Rate: 16.9% vs 21.5%<br>(RR 0.72, 95% CI 0.54-0.98)
-*[https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf NCCN Guidelines - Colon Cancer]
+|-
+|}
-==[http://www.siog.org/ SIOG]==
+''Note: FOxTROT was a 2 x 2 factorial trial, with a sub-randomization to panitumumab, or not, for patients with KRASwt tumors. See paper for details.''
+<div class="toccolours" style="background-color:#eeeeee">
-*'''2014:''' Papamichael et al. [https://doi.org/10.1093/annonc/mdu253 Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013]
+===Neoadjuvant {{#subobject:30juz2|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[Levoleucovorin (Fusilev)]] 175 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''
+'''14-day cycle for 3 cycles, followed by:'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Definitive===
+<div class="toccolours" style="background-color:#b3e2cd">
+====Local therapy====
+*[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Adjuvant===
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[Levoleucovorin (Fusilev)]] 175 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''
+'''14-day cycle for 9 cycles'''
+</div></div></div>
+===References===
+#'''FOxTROT:''' Morton D, Seymour M, Magill L, Handley K, Glasbey J, Glimelius B, Palmer A, Seligmann J, Laurberg S, Murakami K, West N, Quirke P, Gray R. Preoperative Chemotherapy for Operable Colon Cancer: Mature Results of an International Randomized Controlled Trial. J Clin Oncol. 2023 Mar 10;41(8):1541-1552. Epub 2023 Jan 19. [https://doi.org/10.1200/JCO.22.00046 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10022855/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/36657089/ PubMed] [https://clinicaltrials.gov/study/NCT00647530 NCT00647530]
 =Adjuvant therapy=
 ==Capecitabine monotherapy {{#subobject:7b50df|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:ed4e3f|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa043116 Twelves et al. 2005 (X-ACT)]
+|[https://doi.org/10.1056/NEJMoa043116 Twelves et al. 2005 (X-ACT)]
 |1998-2001
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
 |[[#FULV|FULV]]
-| style="background-color:#d9ef8b" |Might have superior OS<sup>1</sup> <br>(HR 0.86, 95% CI 0.74-1.01)
+| style="background-color:#d9ef8b" |Might have superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: NYR vs NYR<br>(HR 0.86, 95% CI 0.74-1.01)<br><br>Equivalent DFS (primary endpoint)<br>(HR 0.87, 95% CI 0.75-1.00)
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30172-3/fulltext Kerr et al. 2016 (QUASAR 2)]
-|2005-2010
-| style="background-color:#1a9851" |Phase III (C)
-|Capecitabine & Bevacizumab
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
 |-
-|[https://www.nature.com/articles/s41416-019-0410-0 Tomita et al. 2019 (JFMC37-0801)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6461756/ Tomita et al. 2019 (JFMC37-0801)]
-|2008-2009
+|2008-09 to 2009-12
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#Capecitabine_monotherapy|Capecitabine]] x 12 mo
 | style="background-color:#fee08b" |Might have inferior DFS
-|-
-|[https://www.thelancet.com/journals/langas/article/PIIS2468-1253(17)30297-2/fulltext Hamaguchi et al. 2017 (JCOG0910)]
-|2010-2013
-| style="background-color:#1a9851" |Phase III (C)
-|S-1
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior DFS
 |-
 |}
 ''<sup>1</sup>X-ACT was a non-inferiority study. Reported efficacy is based on the 2011 update.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 '''21-day cycle for 8 cycles'''
+</div></div>
 ===References===
+#'''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. [https://doi.org/10.1056/NEJMoa043116 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15987918/ PubMed] [https://clinicaltrials.gov/study/NCT00009737 NCT00009737]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa043116 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15987918 PubMed]
+##'''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. [https://doi.org/10.1093/annonc/mdr366 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21896539/ PubMed]
-##'''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. [https://doi.org/10.1093/annonc/mdr366 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21896539 PubMed]
+#'''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. [https://doi.org/10.1038/s41416-019-0410-0 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6461756/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30833647/ PubMed]
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30172-3/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/27660192 PubMed] ISRCTN45133151
-#'''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. [https://www.thelancet.com/journals/langas/article/PIIS2468-1253(17)30297-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29079411 PubMed] UMIN000003272
-#'''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. [https://www.nature.com/articles/s41416-019-0410-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30833647 PubMed]
 ==CapeOx {{#subobject:cf9acc|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 CapeOx: '''<u>Cape</u>'''citabine & '''<u>Ox</u>'''aliplatin
 <br>CAPOX: '''<u>CAP</u>'''ecitabine & '''<u>OX</u>'''aliplatin
 <br>XELOX: '''<u>XEL</u>'''oda (Capecitabine) & '''<u>OX</u>'''aliplatin
 ===Example orders===
 *[[Example orders for CapeOx (XELOX) in colon cancer]]
+<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 3 months {{#subobject:205ad6|Variant=1}}===
+===Regimen variant #1, 3 months {{#subobject:jgui19a|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext Iveson et al. 2018 (SCOT)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743062/ Yoshino et al. 2019 (ACHIEVE)]
-|2008-2013
+|2012-08-01 to 2014-06-30
-| style="background-color:#1a9851" |Phase III (E-de-esc)
+| style="background-color:#1a9851" |Phase 3 (E-de-esc)
-|[[#CapeOx|CapeOx]] x 6 mo
+|1a. [[#CapeOx|CapeOx]] x 6 mo<br>1b. [[#mFOLFOX6|mFOLFOX6]] x 6 mo
-| style="background-color:#eeee01" |Seems to have non-inferior DFS
+| style="background-color:#eeee01" |Seems to have non-inferior DFS<sup>1</sup> (primary endpoint)<br>DFS60: 75.2% vs 74.2%<br>(HR 0.95, 95% CI 0.77-1.18)
 |-
 |}
+''<sup>1</sup>Reported efficacy is based on the 2022 update.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> 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/m<sup>2</sup> IV over 2 hours once on day 1
 '''21-day cycle for 4 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2, 6 months {{#subobject:1ef938|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 156: / Line 170: @@
 |-
 |[https://doi.org/10.1200/jco.2006.08.1075 Schmoll et al. 2007 (XELOXA)]
-|2003-2004
+|2003-04 to 2004-10
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
 |[[#FULV|FULV]]
-| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup> <br>(HR 0.83, 95% CI 0.70-0.99)
+| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup> (secondary endpoint)<br>OS84: 73% vs 67%<br>(HR 0.83, 95% CI 0.70-0.99)<br><br>Superior DFS<sup>1</sup> (primary endpoint)<br>DFS84: 63% vs 56%<br>(HR 0.80, 95% CI 0.69-0.93)
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445286/ Pectasides et al. 2015]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743062/ Yoshino et al. 2019 (ACHIEVE)]
-|2005-2008
+|2012-08-01 to 2014-06-30
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#mFOLFOX6|mFOLFOX6]]
+|1a. [[#CapeOx|CapeOx]] x 3 mo<br>1b. [[#mFOLFOX6|mFOLFOX6]] x 3 mo
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237801/ Snoeren et al. 2017 (HEPATICA)]
-|NR
-| style="background-color:#1a9851" |Phase III (C)
-|CapeOx & Bevacizumab
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext Iveson et al. 2018 (SCOT)]
-|2008-2013
-| style="background-color:#1a9851" |Phase III (C)
-|[[#CapeOx|CapeOx]] x 3 mo
 | style="background-color:#eeee01" |Seems to have non-inferior DFS
 |-
 |}
-''<sup>1</sup>Reported efficacy for XELOXA is based on the 2015 update.''<br>
+''<sup>1</sup>Reported efficacy for XELOXA is based on the 2015 update.''
-''Note: HEPATICA enrolled patients with resected colorectal liver metastases.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> 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/m<sup>2</sup> IV over 2 hours once on day 1
 '''21-day cycle for 8 cycles'''
+</div></div>
 ===References===
+#'''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. [https://doi.org/10.1200/jco.2006.08.1075 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17194911/ PubMed] [https://clinicaltrials.gov/study/NCT00069121 NCT00069121]
-#'''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. [https://doi.org/10.1200/jco.2006.08.1075 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17194911 PubMed] NCT00069121
+##'''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. [https://doi.org/10.1200/jco.2010.33.6297 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21383294/ PubMed]
-##'''Update:''' Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011 Apr 10;29(11):1465-71. Epub 2011 Mar 7. [https://doi.org/10.1200/jco.2010.33.6297 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21383294 PubMed]
+##'''Update:''' Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: Final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015 Nov 10;33(32):3733-40. Epub 2015 Aug 31. [https://doi.org/10.1200/jco.2015.60.9107 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26324362/ PubMed]
-##'''Update:''' Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: Final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015 Nov 10;33(32):3733-40. Epub 2015 Aug 31. [https://doi.org/10.1200/jco.2015.60.9107 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26324362 PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1713709 link to original article] '''does not contain dosing details''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6426127/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29590544/ PubMed] [https://clinicaltrials.gov/study/NCT01308086 NCT01308086]
-#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. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1406-7 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445286/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25956750 PubMed]
+##'''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. [https://doi.org/10.1093/annonc/mdz193 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31228203/ PubMed]
-#'''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. [https://www.clinicalkey.com/#!/content/playContent/1-s2.0-S1476558616301701 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237801/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28088688 PubMed]
+##'''Update:''' André T, Meyerhardt J, Iveson T, Sobrero A, Yoshino T, Souglakos I, Grothey A, Niedzwiecki D, Saunders M, Labianca R, Yamanaka T, Boukovinas I, Vernerey D, Meyers J, Harkin A, Torri V, Oki E, Georgoulias V, Taieb J, Shields A, Shi Q. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020 Dec;21(12):1620-1629. [https://doi.org/10.1016/S1470-2045(20)30527-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7786835/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33271092/ PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1713709 link to original article] '''does not contain protocol''' [https://pubmed.ncbi.nlm.nih.gov/29590544 PubMed] NCT01308086
+#'''ACHIEVE:''' Yoshino T, Yamanaka T, Oki E, Kotaka M, Manaka D, Eto T, Hasegawa J, Takagane A, Nakamura M, Kato T, Munemoto Y, Takeuchi S, Bando H, Taniguchi H, Gamoh M, Shiozawa M, Mizushima T, Saji S, Maehara Y, Ohtsu A, Mori M. Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer: The ACHIEVE Phase 3 Randomized Clinical Trial. JAMA Oncol. 2019 Nov 1;5(11):1574-1581. Erratum in: JAMA Oncol. 2019 Nov 1;5(11):1643. Epub 2019 Sep 12. Erratum in: JAMA Oncol. 2019 Dec 19. [https://doi.org/10.1001/jamaoncol.2019.2572 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743062/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31513248/ PubMed] UMIN000008543
-##'''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. [https://doi.org/10.1093/annonc/mdz193 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31228203 PubMed]
+##'''Update:''' Yoshino T, Oki E, Misumi T, Kotaka M, Manaka D, Eto T, Hasegawa J, Takagane A, Nakamura M, Kato T, Munemoto Y, Nakamura F, Bando H, Taniguchi H, Sakamoto Y, Shiozawa M, Nishi M, Horiuchi T, Yamagishi H, Sakamoto J, Mizushima T, Ohtsu A, Mori M. Final Analysis of 3 Versus 6 Months of Adjuvant Oxaliplatin and Fluoropyrimidine-Based Therapy in Patients With Stage III Colon Cancer: The Randomized Phase III ACHIEVE Trial. J Clin Oncol. 2022 Oct 10;40(29):3419-3429. Epub 2022 May 5. [https://doi.org/10.1200/jco.21.02628 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35512259/ PubMed]
-##'''Update:''' André T, Meyerhardt J, Iveson T, Sobrero A, Yoshino T, Souglakos I, Grothey A, Niedzwiecki D, Saunders M, Labianca R, Yamanaka T, Boukovinas I, Vernerey D, Meyers J, Harkin A, Torri V, Oki E, Georgoulias V, Taieb J, Shields A, Shi Q. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020 Dec;21(12):1620-1629. [https://doi.org/10.1016/S1470-2045(20)30527-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33271092 PubMed]
+#'''TOSCA:''' Petrelli F, Rulli E, Labianca R, Lonardi S, Rosati G, Dotti K, Ronzoni M, Pella N, Pusceddu V, Banzi M, Zampino MG, Yasmina M, Marchetti P, Cantore M, Zaniboni A, Rimassa L, Ciuffreda L, Ferrari D, Zagonel V, Maiello E, Sobrero A; TOSCA Investigators. Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial. Ann Oncol. 2021 Jan;32(1):66-76. Epub 2020 Oct 21. [https://doi.org/10.1016/j.annonc.2020.10.477 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33098997/ PubMed] [https://clinicaltrials.gov/study/NCT00646607 NCT00646607]
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29611518 PubMed] ISRCTN59757862
+#'''KCSG CO09-07:''' Kim ST, Kim SY, Lee J, Yun SH, Kim HC, Lee WY, Kim TW, Hong YS, Lim SB, Baek JY, Oh JH, Ahn JB, Shin SJ, Han SW, Kim SG, Kang SY, Sym SJ, Zang DY, Kim YH, Choi IS, Kang JH, Kim MJ, Park YS. Oxaliplatin (3 months v 6 months) With 6 Months of Fluoropyrimidine as Adjuvant Therapy in Patients With Stage II/III Colon Cancer: KCSG CO09-07. J Clin Oncol. 2022 Nov 20;40(33):3868-3877. Epub 2022 Jun 30. [https://doi.org/10.1200/jco.21.02962 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9671755/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35772045/ PubMed] [https://clinicaltrials.gov/study/NCT01092481 NCT01092481]
+#'''CIRCULATE-IDEA:''' [https://clinicaltrials.gov/study/NCT05174169 NCT05174169]
 ==FLOX {{#subobject:617cc1|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 FLOX: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>OX</u>'''aliplatin
 ===Example orders===
 *[[Example orders for FLOX in colon cancer]]
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:c80e20|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 227: / Line 223: @@
 |[https://doi.org/10.1200/jco.2006.08.2974 Kuebler et al. 2007 (NSABP C-07)]
 |2000-2002
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
 |[[#FULV|FULV]]
-| style="background-color:#1a9850" |Superior DFS
+| style="background-color:#1a9850" |Superior DFS (primary endpoint)<br>DFS48: 73.2% vs 67%<br>(HR 0.80, 95% CI 0.69-0.93)
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, 29, 36, '''given third, 1 hour after start of leucovorin'''
-*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, '''given second'''
+*[[Leucovorin (Folinic acid)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, '''given second'''
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29, '''given first'''
 '''8-week cycle for 3 cycles'''
+</div></div>
 ===References===
+#'''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. [https://doi.org/10.1200/jco.2006.08.2974 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17470851/ PubMed] [https://clinicaltrials.gov/study/NCT00004931 NCT00004931]
-#'''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. [https://doi.org/10.1200/jco.2006.08.2974 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17470851 PubMed] NCT00004931
+##'''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. [https://doi.org/10.1200/JCO.2011.36.4539 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188282/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21859995/ PubMed]
-##'''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. [https://doi.org/10.1200/JCO.2011.36.4539 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188282/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21859995 PubMed]
 ==FOLFOX4 {{#subobject:f61339|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+FOLFOX4: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-|-
+<div class="toccolours" style="background-color:#eeeeee">
-|[[#top|back to top]]
-|}
-FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
 ===Regimen {{#subobject:671bbe|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa032709 André et al. 2004 (MOSAIC)]
+|[https://doi.org/10.1056/NEJMoa032709 André et al. 2004 (MOSAIC)]
 |1998-2001
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 |[[#FULV|FULV]]
-| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup> <br>(HR 0.85, 95% CI 0.73-0.99)
+| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup> (secondary endpoint)<br>OS120: 71.7% vs 67.1%<br>(HR 0.85, 95% CI 0.73-0.99)<br><br>Superior DFS (primary endpoint)<br>DFS36: 78.2% vs 72.9%
 |-
-| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70509-0/fulltext de Gramont et al. 2012 (AVANT)]
+| rowspan="2" |[https://doi.org/10.1016/S1470-2045(12)70509-0 de Gramont et al. 2012 (AVANT)]
 |rowspan=2|2004-2007
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
-|1. FOLFOX4 & Bevacizumab
+|1. [[#FOLFOX4_.26_Bevacizumab_999|FOLFOX4 & Bevacizumab]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|2. XELOX & Bevacizumab
+|2. [[#CapeOx_.26_Bevacizumab_999|XELOX & Bevacizumab]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70227-X/fulltext Taieb et al. 2014 (PETACC-8)]
+|[https://doi.org/10.1016/S1470-2045(14)70227-X Taieb et al. 2014 (PETACC-8)]
 |2005-2009
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|FOLFOX4 & Cetuximab
+|[[#FOLFOX4_.26_Cetuximab_999|FOLFOX4 & Cetuximab]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1713709 Grothey et al. 2018 (IDEA)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6426127/ Grothey et al. 2018 (IDEA)]
 |2007-2015
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#FOLFOX4|FOLFOX4]] x 6
+|1a. [[#FOLFOX4|FOLFOX4]] x 6<br>1b. [[#mFOLFOX6|mFOLFOX6]] x 3 mo<br>1c. [[#CapeOx|CapeOx]] x 3 mo
 | style="background-color:#ffffbf" |Inconclusive whether non-inferior DFS36
 |-
 |}
-''<sup>1</sup>Reported efficacy for MOSAIC is based on the 2009 update.''<br>
+''<sup>1</sup>Reported efficacy for MOSAIC is based on the 2015 update.''<br>
-''IDEA is a pooled analysis of six phase III RCTs.''
+''IDEA is a pooled analysis of six phase 3 RCTs.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with leucovorin'''
 '''14-day cycle for 12 cycles'''
+</div></div>
 ===References===
+#'''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. [https://doi.org/10.1056/NEJMoa032709 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15175436/ PubMed] [https://clinicaltrials.gov/study/NCT00275210 NCT00275210]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa032709 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15175436 PubMed] NCT00275210
+##'''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. [https://doi.org/10.1200/JCO.2008.20.6771 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19451431/ PubMed]
-##'''Update:''' André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009 Jul 1;27(19):3109-16. Epub 2009 May 18. [https://doi.org/10.1200/JCO.2008.20.6771 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19451431 PubMed]
+##'''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. [https://doi.org/10.1200/JCO.2015.63.4238 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26527776/ PubMed]
-##'''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. [https://doi.org/10.1200/JCO.2015.63.4238 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26527776 PubMed]
+#'''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. [https://doi.org/10.1016/S1470-2045(12)70509-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/23168362/ PubMed] [https://clinicaltrials.gov/study/NCT00112918 NCT00112918]
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70509-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23168362 PubMed] NCT00112918
+##'''Update:''' André T, Vernerey D, Im SA, Bodoky G, Buzzoni R, Reingold S, Rivera F, McKendrick J, Scheithauer W, Ravit G, Fountzilas G, Yong WP, Isaacs R, Österlund P, Liang JT, Creemers GJ, Rakez M, Van Cutsem E, Cunningham D, Tabernero J, de Gramont A. Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group. Ann Oncol. 2020 Feb;31(2):246-256. Epub 2019 Dec 18. [https://doi.org/10.1016/j.annonc.2019.12.006 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31959341/ PubMed]
-##'''Update:''' André T, Vernerey D, Im SA, Bodoky G, Buzzoni R, Reingold S, Rivera F, McKendrick J, Scheithauer W, Ravit G, Fountzilas G, Yong WP, Isaacs R, Österlund P, Liang JT, Creemers GJ, Rakez M, Van Cutsem E, Cunningham D, Tabernero J, de Gramont A. Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group. Ann Oncol. 2020 Feb;31(2):246-256. Epub 2019 Dec 18. [https://doi.org/10.1016/j.annonc.2019.12.006 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31959341 PubMed]
+#'''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. [https://doi.org/10.1016/S1470-2045(14)70227-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/24928083/ PubMed] [https://clinicaltrials.gov/study/NCT00265811 NCT00265811]
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70227-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/24928083 PubMed] EudraCT 2005-003463-23
+#'''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. [https://doi.org/10.1056/NEJMoa1713709 link to original article] '''does not contain dosing details''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6426127/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29590544/ PubMed] [https://clinicaltrials.gov/study/NCT01308086 NCT01308086]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1713709 link to original article] '''does not contain protocol''' [https://pubmed.ncbi.nlm.nih.gov/29590544 PubMed] NCT01308086
+##'''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. [https://doi.org/10.1093/annonc/mdz193 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31228203/ PubMed]
-##'''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. [https://doi.org/10.1093/annonc/mdz193 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31228203 PubMed]
+##'''Update:''' André T, Meyerhardt J, Iveson T, Sobrero A, Yoshino T, Souglakos I, Grothey A, Niedzwiecki D, Saunders M, Labianca R, Yamanaka T, Boukovinas I, Vernerey D, Meyers J, Harkin A, Torri V, Oki E, Georgoulias V, Taieb J, Shields A, Shi Q. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020 Dec;21(12):1620-1629. [https://doi.org/10.1016/S1470-2045(20)30527-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7786835/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33271092/ PubMed]
-##'''Update:''' André T, Meyerhardt J, Iveson T, Sobrero A, Yoshino T, Souglakos I, Grothey A, Niedzwiecki D, Saunders M, Labianca R, Yamanaka T, Boukovinas I, Vernerey D, Meyers J, Harkin A, Torri V, Oki E, Georgoulias V, Taieb J, Shields A, Shi Q. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020 Dec;21(12):1620-1629. [https://doi.org/10.1016/S1470-2045(20)30527-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33271092 PubMed]
+#'''TOSCA:''' Petrelli F, Rulli E, Labianca R, Lonardi S, Rosati G, Dotti K, Ronzoni M, Pella N, Pusceddu V, Banzi M, Zampino MG, Yasmina M, Marchetti P, Cantore M, Zaniboni A, Rimassa L, Ciuffreda L, Ferrari D, Zagonel V, Maiello E, Sobrero A; TOSCA Investigators. Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial. Ann Oncol. 2021 Jan;32(1):66-76. Epub 2020 Oct 21. [https://doi.org/10.1016/j.annonc.2020.10.477 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33098997/ PubMed] [https://clinicaltrials.gov/study/NCT00646607 NCT00646607]
 ==mFOLFOX6 {{#subobject:32d6c5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
 ===Example orders===
 *[[Example orders for mFOLFOX 6 in colon cancer]]
+<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 3 months {{#subobject:205ad6|Variant=1}}===
+===Regimen {{#subobject:30juz2|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext Iveson et al. 2018 (SCOT)]
-|2008-2013
-| style="background-color:#1a9851" |Phase III (E-de-esc)
-|[[#mFOLFOX6|mFOLFOX6]] x 6 mo
-| style="background-color:#eeee01" |Seems to have non-inferior DFS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 350 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> 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/m<sup>2</sup>) {{#subobject:30b6e7|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445286/ Pectasides et al. 2015]
-|2005-2008
-| style="background-color:#1a9851" |Phase III (C)
-|[[#CapeOx|CAPOX]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]], within 10 weeks
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> 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/m<sup>2</sup>) {{#subobject:308ic7|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext Iveson et al. 2018 (SCOT)]
-|2008-2013
-| style="background-color:#1a9851" |Phase III (C)
-|[[#mFOLFOX6|mFOLFOX6]] x 3 mo
-| style="background-color:#eeee01" |Seems to have non-inferior DFS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]], within 10 weeks
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 350 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> 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/m<sup>2</sup>) {{#subobject:30juz2|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 418: / Line 321: @@
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717026/ Allegra et al. 2009 (NSABP C-08)]
 |2004-2006
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[Colon_cancer_-_historical#mFOLFOX6-B|mFOLFOX6-B]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1713709 Grothey et al. 2018 (IDEA)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6426127/ Grothey et al. 2018 (IDEA)]
 |2007-2015
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#mFOLFOX6|mFOLFOX6]] x 3 mo
+|1a. [[#FOLFOX4|FOLFOX4]] x 6<br>1b. [[#mFOLFOX6|mFOLFOX6]] x 3 mo<br>1c. [[#CapeOx|CapeOx]] x 3 mo
 | style="background-color:#ffffbf" |Inconclusive whether non-inferior DFS36
 |-
 |[https://doi.org/10.1200/JCO.2017.76.0355 André et al. 2018 (IDEA France)]
 |2009-2014
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#mFOLFOX6|mFOLFOX6]] x 3 mo
+|[[#mFOLFOX6_2|mFOLFOX6]] x 3 mo
 | style="background-color:#91cf60" |Seems to have superior DFS
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8025124/ Meyerhardt et al. 2021 (CALGB 80702)]
+|2010-2015
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#mFOLFOX6_.26_Celecoxib_999|mFOLFOX6 & Celecoxib]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
 |}
+''Note: CALGB 80702 was a 2 x 2 factorial trial, with the other comparison being 3 vs 6 months of mFOLFOX6. This comparison was made as part of the IDEA collaborative and is reported separately.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]], within 10 weeks
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''
 '''14-day cycle for 12 cycles'''
+</div></div>
 ===References===
 <!-- Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL. -->
+#'''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. [https://doi.org/10.1200/jco.2009.21.9220 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717026/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19414665/ PubMed] [https://clinicaltrials.gov/study/NCT00096278 NCT00096278]
+## '''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. Epub 2010 Oct 12. [https://doi.org/10.1200/JCO.2010.30.0855 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055856/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20940184/ PubMed]
+## '''Update:''' Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Lopa SH, Wolmark N. Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J Clin Oncol. 2013 Jan 20;31(3):359-64. Epub 2012 Dec 10. [https://doi.org/10.1200/JCO.2012.44.4711 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732014/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23233715/ PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1713709 link to original article] '''does not contain dosing details''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6426127/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29590544/ PubMed] [https://clinicaltrials.gov/study/NCT01308086 NCT01308086]
+##'''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. [https://doi.org/10.1093/annonc/mdz193 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31228203/ PubMed]
+##'''Update:''' André T, Meyerhardt J, Iveson T, Sobrero A, Yoshino T, Souglakos I, Grothey A, Niedzwiecki D, Saunders M, Labianca R, Yamanaka T, Boukovinas I, Vernerey D, Meyers J, Harkin A, Torri V, Oki E, Georgoulias V, Taieb J, Shields A, Shi Q. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020 Dec;21(12):1620-1629. [https://doi.org/10.1016/S1470-2045(20)30527-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7786835/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33271092/ PubMed]
+#'''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. [https://doi.org/10.1200/JCO.2017.76.0355 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29620995/ PubMed] [https://clinicaltrials.gov/study/NCT00958737 NCT00958737]
+#'''TOSCA:''' Petrelli F, Rulli E, Labianca R, Lonardi S, Rosati G, Dotti K, Ronzoni M, Pella N, Pusceddu V, Banzi M, Zampino MG, Yasmina M, Marchetti P, Cantore M, Zaniboni A, Rimassa L, Ciuffreda L, Ferrari D, Zagonel V, Maiello E, Sobrero A; TOSCA Investigators. Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial. Ann Oncol. 2021 Jan;32(1):66-76. Epub 2020 Oct 21. [https://doi.org/10.1016/j.annonc.2020.10.477 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33098997/ PubMed] [https://clinicaltrials.gov/study/NCT00646607 NCT00646607]
+#'''ACHIEVE-2:''' Yamazaki K, Yamanaka T, Shiozawa M, Manaka D, Kotaka M, Gamoh M, Shiomi A, Makiyama A, Munemoto Y, Rikiyama T, Fukunaga M, Ueki T, Shitara K, Shinkai H, Tanida N, Oki E, Sunami E, Ohtsu A, Maehara Y, Yoshino T. Oxaliplatin-based adjuvant chemotherapy duration (3 versus 6 months) for high-risk stage II colon cancer: the randomized phase III ACHIEVE-2 trial. Ann Oncol. 2021 Jan;32(1):77-84. Epub 2020 Oct 26. [https://doi.org/10.1016/j.annonc.2020.10.480 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33121997/ PubMed] UMIN000013036
+#'''CALGB 80702:''' Meyerhardt JA, Shi Q, Fuchs CS, Meyer J, Niedzwiecki D, Zemla T, Kumthekar P, Guthrie KA, Couture F, Kuebler P, Bendell JC, Kumar P, Lewis D, Tan B, Bertagnolli M, Grothey A, Hochster HS, Goldberg RM, Venook A, Blanke C, O'Reilly EM, Shields AF. Effect of Celecoxib vs Placebo Added to Standard Adjuvant Therapy on Disease-Free Survival Among Patients With Stage III Colon Cancer: The CALGB/SWOG 80702 (Alliance) Randomized Clinical Trial. JAMA. 2021 Apr 6;325(13):1277-1286. [https://doi.org/10.1001/jama.2021.2454 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8025124/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33821899/ PubMed] [https://clinicaltrials.gov/study/NCT01150045 NCT01150045]
+##'''Dataset:''' [https://data.projectdatasphere.org/projectdatasphere/html/content/489 Project Data Sphere]
+#'''KCSG CO09-07:''' Kim ST, Kim SY, Lee J, Yun SH, Kim HC, Lee WY, Kim TW, Hong YS, Lim SB, Baek JY, Oh JH, Ahn JB, Shin SJ, Han SW, Kim SG, Kang SY, Sym SJ, Zang DY, Kim YH, Choi IS, Kang JH, Kim MJ, Park YS. Oxaliplatin (3 months v 6 months) With 6 Months of Fluoropyrimidine as Adjuvant Therapy in Patients With Stage II/III Colon Cancer: KCSG CO09-07. J Clin Oncol. 2022 Nov 20;40(33):3868-3877. Epub 2022 Jun 30. [https://doi.org/10.1200/jco.21.02962 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9671755/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35772045/ PubMed] [https://clinicaltrials.gov/study/NCT01092481 NCT01092481]
-#'''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. [https://doi.org/10.1200/jco.2009.21.9220 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717026/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19414665 PubMed] NCT00096278
+==mFOLFOX6 (L-Leucovorin) {{#subobject:32d6d7|Regimen=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. [https://doi.org/10.1200/JCO.2010.30.0855 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055856/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20940184 PubMed]
+mFOLFOX6: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-##'''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. [https://doi.org/10.1200/JCO.2012.44.4711 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732014/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23233715 PubMed]
-#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. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1406-7 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445286/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25956750 PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1713709 link to original article] '''does not contain protocol''' [https://pubmed.ncbi.nlm.nih.gov/29590544 PubMed] NCT01308086
-##'''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. [https://doi.org/10.1093/annonc/mdz193 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31228203 PubMed]
-##'''Update:''' André T, Meyerhardt J, Iveson T, Sobrero A, Yoshino T, Souglakos I, Grothey A, Niedzwiecki D, Saunders M, Labianca R, Yamanaka T, Boukovinas I, Vernerey D, Meyers J, Harkin A, Torri V, Oki E, Georgoulias V, Taieb J, Shields A, Shi Q. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020 Dec;21(12):1620-1629. [https://doi.org/10.1016/S1470-2045(20)30527-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33271092 PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2017.76.0355 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29620995 PubMed] NCT00958737
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29611518 PubMed] ISRCTN59757862
-==mFOLFOX6 (L-Leucovorin) {{#subobject:32d6c5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
 ===Example orders===
 *[[Example orders for mFOLFOX 6 in colon cancer]]
+<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 3 months, 175 mg/m<sup>2</sup> L-LCV {{#subobject:205ad6|Variant=1}}===
+===Regimen variant #1, 3 months, 200 mg/m<sup>2</sup> L-LCV {{#subobject:38ig9a|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext Iveson et al. 2018 (SCOT)]
-|2008-2013
-| style="background-color:#1a9851" |Phase III (E-de-esc)
-|[[#mFOLFOX6|mFOLFOX6]] x 6 mo
-| style="background-color:#eeee01" |Seems to have non-inferior DFS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Levoleucovorin (Fusilev)]] 175 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with L-folinic acid'''
-'''14-day cycle for 6 cycles'''
-===Regimen variant #2, 3 months, 200 mg/m<sup>2</sup> L-LCV {{#subobject:38ig9a|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 506: / Line 385: @@
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743062/ Yoshino et al. 2019 (ACHIEVE)]
-|2012-2014
+|2012-08-01 to 2014-06-30
-| style="background-color:#1a9851" |Phase III (E-de-esc)
+| style="background-color:#1a9851" |Phase 3 (E-de-esc)
-|[[#mFOLFOX6|mFOLFOX6]] x 6 mo
+|1a. [[#CapeOx|CapeOx]] x 6 mo<br>1b. [[#mFOLFOX6|mFOLFOX6]] x 6 mo
-| style="background-color:#eeee01" |Seems to have non-inferior DFS
+| style="background-color:#eeee01" |Seems to have non-inferior DFS<sup>1</sup> (primary endpoint)<br>DFS60: 75.2% vs 74.2%<br>(HR 0.95, 95% CI 0.77-1.18)
 |-
 |}
+''<sup>1</sup>Reported efficacy is based on the 2022 update.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
 *[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''
 '''14-day cycle for 6 cycles'''
+</div></div><br>
-===Regimen variant #3, 6 months, 175 mg/m<sup>2</sup> L-LCV {{#subobject:372bh7|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+===Regimen variant #2, 6 months, 200 mg/m<sup>2</sup> L-LCV {{#subobject:38guh7|Variant=1}}===
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext Iveson et al. 2018 (SCOT)]
-|2008-2013
-| style="background-color:#1a9851" |Phase III (C)
-|[[#mFOLFOX6|mFOLFOX6]] x 3 mo
-| style="background-color:#eeee01" |Seems to have non-inferior DFS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]], within 10 weeks
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Levoleucovorin (Fusilev)]] 175 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''
-'''14-day cycle for 12 cycles'''
-===Regimen variant #4, 6 months, 200 mg/m<sup>2</sup> L-LCV {{#subobject:38guh7|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 560: / Line 413: @@
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743062/ Yoshino et al. 2019 (ACHIEVE)]
-|2012-2014
+|2012-08-01 to 2014-06-30
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#mFOLFOX6|mFOLFOX6]] x 3 mo
+|1a. [[#CapeOx|CapeOx]] x 3 mo<br>1b. [[#mFOLFOX6|mFOLFOX6]] x 3 mo
 | style="background-color:#eeee01" |Seems to have non-inferior DFS
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
 *[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''
 '''14-day cycle for 12 cycles'''
+</div></div>
 ===References===
+#'''ACHIEVE:''' Yoshino T, Yamanaka T, Oki E, Kotaka M, Manaka D, Eto T, Hasegawa J, Takagane A, Nakamura M, Kato T, Munemoto Y, Takeuchi S, Bando H, Taniguchi H, Gamoh M, Shiozawa M, Mizushima T, Saji S, Maehara Y, Ohtsu A, Mori M. Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer: The ACHIEVE Phase 3 Randomized Clinical Trial. JAMA Oncol. 2019 Nov 1;5(11):1574-1581. Erratum in: JAMA Oncol. 2019 Nov 1;5(11):1643. Epub 2019 Sep 12. Erratum in: JAMA Oncol. 2019 Dec 19. [https://doi.org/10.1001/jamaoncol.2019.2572 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743062/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31513248/ PubMed] UMIN000008543
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29611518 PubMed] ISRCTN59757862
+##'''Update:''' Yoshino T, Oki E, Misumi T, Kotaka M, Manaka D, Eto T, Hasegawa J, Takagane A, Nakamura M, Kato T, Munemoto Y, Nakamura F, Bando H, Taniguchi H, Sakamoto Y, Shiozawa M, Nishi M, Horiuchi T, Yamagishi H, Sakamoto J, Mizushima T, Ohtsu A, Mori M. Final Analysis of 3 Versus 6 Months of Adjuvant Oxaliplatin and Fluoropyrimidine-Based Therapy in Patients With Stage III Colon Cancer: The Randomized Phase III ACHIEVE Trial. J Clin Oncol. 2022 Oct 10;40(29):3419-3429. Epub 2022 May 5. [https://doi.org/10.1200/jco.21.02628 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35512259/ PubMed]
-#'''ACHIEVE:''' Yoshino T, Yamanaka T, Oki E, Kotaka M, Manaka D, Eto T, Hasegawa J, Takagane A, Nakamura M, Kato T, Munemoto Y, Takeuchi S, Bando H, Taniguchi H, Gamoh M, Shiozawa M, Mizushima T, Saji S, Maehara Y, Ohtsu A, Mori M. Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer: The ACHIEVE Phase 3 Randomized Clinical Trial. JAMA Oncol. 2019 Nov 1;5(11):1574-1581. Erratum in: JAMA Oncol. 2019 Nov 1;5(11):1643. Erratum in: JAMA Oncol. 2019 Dec 19. [https://doi.org/10.1001/jamaoncol.2019.2572 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743062/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/31513248 PubMed] UMIN000008543
 ==FULV {{#subobject:a93a|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+FULV: 5-'''<u>FU</u>''' & '''<u>L</u>'''euco'''<u>V</u>'''orin
-|-
+<br>LV5FU2: '''<u>L</u>'''euco'''<u>V</u>'''orin & '''<u>5-FU</u>''' for '''<u>2</u>''' days
-|[[#top|back to top]]
-|}
-FULV: 5-'''<u>FU</u>''' & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid)
-<br>LV5FU2: '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid) & '''<u>5-FU</u>''' for '''<u>2</u>''' days
 ===Example orders===
+*[[Example orders for 5-FU & low-dose Leucovorin (Mayo Clinic regimen - LDLV) in colon cancer]]
-*[[Example orders for 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV) in colon cancer]]
+*[[Example orders for 5-FU & high-dose Leucovorin (Roswell Park regimen - HDLV) in colon cancer]]
-*[[Example orders for 5-FU & high-dose Leucovorin (Roswell Park regimen/HDLV) in colon cancer]]
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #1, 500/200, 6 out of 8 weeks {{#subobject:2c3f1b|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 605: / Line 450: @@
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038965/ Papadimitriou et al. 2011]
 |1999-2004
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|IFL
+|[[#IFL_999|IFL]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
 '''8-week cycle for 4 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2, 500/500, 6 out of 8 weeks {{#subobject:489be0|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 630: / Line 475: @@
 |-
 |[https://doi.org/10.1200/JCO.1993.11.10.1879 Wolmark et al. 1993 (NSABP C-03)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-258-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
+|-
+|} -->
 |1987-1989
-| style="background-color:#1a9851" |Phase III (E-de-esc)
+| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 |[[Colon_cancer_-_historical#MOF|MOF]]
 | style="background-color:#1a9850" |Superior OS
 |-
 | rowspan="2" |[https://doi.org/10.1200/JCO.1999.17.11.3553 Wolmark et al. 1999 (NSABP C-04)]
-|rowspan=2|1989-1990
+|rowspan=2|1989-07 to 1990-12
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ooc)
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 |1. [[Colon_cancer_-_historical#Fluorouracil_.26_Levamisole|5-FU & Levamisole]]
-| style="background-color:#d9ef8b" |Might have superior OS
+| style="background-color:#d9ef8b" |Might have superior OS (co-primary endpoint)
 |-
-|2. FULV & Levamisole
+|2. [[Colon_cancer_-_historical#FULV_.26_Levamisole|FULV & Levamisole]]
-| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS/OS
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of DFS/OS
 |-
 | rowspan="3" |[https://doi.org/10.1200/jco.2004.00.5686 Haller et al. 2005 (Intergroup 0089)]
 |rowspan=3|1988-1992
-| rowspan="3" style="background-color:#1a9851" |Phase III (E-esc)
+| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-esc)
 |1. [[#FULV|FULV]]; low-dose
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|2. LDLV & Levamisole
+|2. [[Colon_cancer_-_historical#FULV_.26_Levamisole|FULV & Levamisole]]; LDLV
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|3. 5-FU & Levamisole
+|3. [[Colon_cancer_-_historical#Fluorouracil_.26_Levamisole|5-FU & Levamisole]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |[https://doi.org/10.1200/jco.2005.04.7498 Lembersky et al. 2006 (NSABP C-06)]
 |1997-1999
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#Tegafur.2C_Uracil.2C_Folinic_acid|Tegafur, Uracil, Folinic acid]]
-| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS/OS
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of DFS/OS
 |-
 |[https://doi.org/10.1200/JCO.2007.11.2144 Saltz et al. 2007 (CALGB 89803)]
 |1999-2001
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|IFL
+|[[#IFL_999|IFL]]
-| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS/OS
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of DFS/OS
 |-
 |[https://doi.org/10.1200/jco.2006.08.2974 Kuebler et al. 2007 (NSABP C-07)]
 |2000-2002
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#FLOX|FLOX]]
 | style="background-color:#d73027" |Inferior DFS
 |-
 |[https://doi.org/10.1200/jco.2006.08.1075 Schmoll et al. 2007 (XELOXA)]
-|2003-2004
+|2003-04 to 2004-10
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#CapeOx|CapeOx]]
 | style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
@@ Line 683: / Line 532: @@
 ''<sup>1</sup>Reported efficacy for XELOXA is based on the 2015 update.''<br>
 ''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/m<sup>2</sup>.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> 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/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, '''given first'''
+*[[Leucovorin (Folinic acid)]] 500 mg/m<sup>2</sup> 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'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #3, 600/500, 6 out of 8 weeks ("Roswell Park regimen") {{#subobject:50ybe0|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.karger.com/Article/Abstract/12105 Fountzilas et al. 2000]
+|[https://doi.org/10.1159/000012105 Fountzilas et al. 2000]
 |1989-1997
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|FULV & IFN alfa-2a
+|[[#FULV_.26_Interferon_alfa-2a_999|FULV & IFN alfa-2a]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> 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/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, '''given first'''
+*[[Leucovorin (Folinic acid)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, '''given first'''
 '''8-week cycle for 4 cycles'''
+</div></div><br>
-===Regimen variant #4, 1850/2500 ("NCI schedule") {{#subobject:7cc2b9|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, 1850/100 ("Mayo Clinic regimen") {{#subobject:4bnc36|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/j.ejca.2008.07.002 Popov et al. 2008 (PETACC-1)]
+|NR-1999
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Raltitrexed_monotherapy_999|Raltitrexed]]
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior RFS/OS
+|-
+|}
+''Note: This was the lower bound of 5-FU dosing in PETACC-1.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''
+*[[Leucovorin (Folinic acid)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''
+'''28-day cycle for 6 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #5, 1850/2500 ("NCI schedule") {{#subobject:7cc2b9|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://academic.oup.com/jnci/article/90/23/1810/2520545 Wolmark et al. 1998 (NSABP C-05)]
+|[https://doi.org/10.1093/jnci/90.23.1810 Wolmark et al. 1998 (NSABP C-05)]
 |1991-1994
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|FULV & Interferon alfa
+|[[#FULV_.26_Interferon_alfa_999|FULV & Interferon alfa]]
-| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS/OS
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of DFS/OS
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, '''given second'''
-*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first'''
+*[[Leucovorin (Folinic acid)]] 500 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first'''
 '''28-day cycle for 6 cycles'''
+</div></div><br>
-===Regimen variant #5, 2000/400 ("de Gramont regimen"/LV5FU2) {{#subobject:685f89|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #6, 2000/400 ("de Gramont regimen"/LV5FU2) {{#subobject:685f89|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 756: / Line 633: @@
 |[https://doi.org/10.1200/JCO.2003.10.065 André et al. 2003 (GERCOR C96.1)]
 |1996-1999
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#FULV|FULV]]; monthly
 | style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa032709 André et al. 2004 (MOSAIC)]
+|[https://doi.org/10.1056/NEJMoa032709 André et al. 2004 (MOSAIC)]
 |1998-2001
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#FOLFOX4|FOLFOX4]]
 | style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
@@ Line 768: / Line 645: @@
 |[https://doi.org/10.1093/annonc/mdn680 Ychou et al. 2009 (FFCD 9802)]
 |1998-2002
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|IFL
+|[[#IFL_999|IFL]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
 |[https://doi.org/10.1200/JCO.2008.21.6663 Van Cutsem et al. 2009 (PETACC-3)]
 |2000-2002
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|IFL
+|[[#IFL_999|IFL]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
 |}
-''<sup>1</sup>Reported efficacy for MOSAIC is based on the 2009 update.''
+''<sup>1</sup>Reported efficacy for MOSAIC is based on the 2015 update.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first'''
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first'''
 '''14-day cycle for 12 cycles'''
+</div></div><br>
-===Regimen variant #6, 2125/100 ("Mayo Clinic regimen") {{#subobject:4bd336|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #7, 2000/1000 {{#subobject:6igjc9|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/0016-5085(94)90748-x Francini et al. 1994]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-259-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
+|-
+|} -->
+|1985-1990
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Colon_cancer_-_null_regimens#Observation_2|Observation]]
+| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>OS60: 79% vs 65%
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#Colorectal_cancer_surgery|Surgery]], within 3 weeks
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 5
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5
+'''28-day cycle for 12 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #8, 2125/100 ("Mayo Clinic regimen") {{#subobject:4bd336|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-||[https://www.nejm.org/doi/full/10.1056/NEJMoa043116 Twelves et al. 2005 (X-ACT)]
+||[https://doi.org/10.1056/NEJMoa043116 Twelves et al. 2005 (X-ACT)]
 |1998-2001
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#Capecitabine_monotherapy|Capecitabine]]
 | style="background-color:#fee08b" |Might have inferior OS<sup>1</sup>
 |-
-|[https://www.ejcancer.com/article/S0959-8049(08)00535-2/fulltext Popov et al. 2008 (PETACC-1)]
+|[https://doi.org/10.1016/j.ejca.2008.07.002 Popov et al. 2008 (PETACC-1)]
 |NR-1999
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|Raltitrexed
+|[[#Raltitrexed_monotherapy_999|Raltitrexed]]
 | style="background-color:#ffffbf" |Inconclusive whether non-inferior RFS/OS
 |-
-|[https://www.ejcancer.com/article/S0959-8049(13)00094-4/fulltext Köhne et al. 2013 (PETACC-2)]
+|[https://doi.org/10.1016/j.ejca.2013.01.030 Köhne et al. 2013 (PETACC-2)]
 |1999-2004
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|1. LV5FU2<br> 2. AIO regimen<br> 3. TTD regimen
+|1. [[#FULV|FULV]]; LV5FU2<br>2. [[#FULV|FULV]]; AIO regimen<br> 3. [[#FULV|FULV]]; TTD regimen
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS60
 |-
 |[https://doi.org/10.1200/jco.2006.08.1075 Schmoll et al. 2007 (XELOXA)]
-|2003-2004
+|2003-04 to 2004-10
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#CapeOx|XELOX]]
 | style="background-color:#fc8d59" |Seems to have inferior OS<sup>2</sup>
@@ Line 826: / Line 733: @@
 ''<sup>1</sup>X-ACT was a non-inferiority study. Reported efficacy is based on the 2011 update.''<br>
 ''<sup>2</sup>Reported efficacy for XELOXA is based on the 2015 update.''<br>
-''Dosing details for PETACC-1 could not be confirmed from the abstract.''
+''Note: This was the upper bound of 5-FU dosing in PETACC-1.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''
+*[[Leucovorin (Folinic acid)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''
 '''28-day cycle for 6 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #7, 2125/100, with cycle elongation ("Mayo Clinic regimen") {{#subobject:e24014|Variant=1}}===
+===Regimen variant #9, 2125/100, with cycle elongation ("Mayo Clinic regimen") {{#subobject:e24014|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.1997.15.1.246 O'Connell et al. 1997]
+|[https://doi.org/10.1200/jco.1997.15.1.246 O'Connell et al. 1997 (CALGB 8896)]
-|1988-1989
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-| style="background-color:#1a9851" |Phase III (E-esc)
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-260-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
+|-
+|} -->
+|1988-02 to 1989-08
+| style="background-color:#1a9851" |Phase 3 (E-esc)
 |[[Colon_cancer_-_null_regimens#Observation|Observation]]
 | style="background-color:#91cf60" |Seems to have superior OS
@@ Line 854: / Line 766: @@
 | rowspan="3" |[https://doi.org/10.1200/jco.2004.00.5686 Haller et al. 2005 (Intergroup 0089)]
 |rowspan=3|1988-1992
-| rowspan="3" style="background-color:#1a9851" |Phase III (E-de-esc)
+| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-de-esc)
 |1. [[#FULV|FULV]]; high-dose
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|2. LDLV & Levamisole
+|2. [[Colon_cancer_-_historical#FULV_.26_Levamisole|FULV & Levamisole]]; LDLV
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|3. 5-FU & Levamisole
+|3. [[Colon_cancer_-_historical#Fluorouracil_.26_Levamisole|5-FU & Levamisole]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140673602098367/fulltext Punt et al. 2002 (Study 157-002)]
+| rowspan="2" |[https://doi.org/10.1016/s0140-6736(02)09836-7 Punt et al. 2002 (Study 157-002)]
 |rowspan=2|1995-1999
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
-|1. FULV & Edrecolomab
+|1. [[#FULV_.26_Edrecolomab_999|FULV & Edrecolomab]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
@@ Line 875: / Line 787: @@
 |[https://doi.org/10.1200/JCO.2008.18.5710 Fields et al. 2009 (Study 157-001)]
 |1995-1999
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|FULV & Edrecolomab
+|[[#FULV_.26_Edrecolomab_999|FULV & Edrecolomab]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''
+*[[Leucovorin (Folinic acid)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''
 '''28-day cycle for 3 cycles, then 35-day cycle for 3 cycles'''
+</div></div>
-===Regimen variant #8, 2800/400 (LV5FUs) {{#subobject:476348|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1093/annonc/mdp236 Ychou et al. 2009]
-|2001-2006
-| style="background-color:#1a9851" |Phase III (C)
-|FOLFIRI
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Complete surgical resection of colorectal liver metastases]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''14-day cycle for 12 cycles'''
 ===References===
+#'''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. [https://doi.org/10.1200/JCO.1993.11.10.1879 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8410113/ PubMed]
-#'''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. [https://doi.org/10.1200/JCO.1993.11.10.1879 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8410113 PubMed]
+##'''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. [https://doi.org/10.1245/s10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20082144/ PubMed]
-##'''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. [https://link.springer.com/article/10.1245%2Fs10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20082144 PubMed]
+#Francini G, Petrioli R, Lorenzini L, Mancini S, Armenio S, Tanzini G, Marsili S, Aquino A, Marzocca G, Civitelli S, Mariani L, De Sando D, Bovenga S, Lorenzi M. Folinic acid and 5-fluorouracil as adjuvant chemotherapy in colon cancer. Gastroenterology. 1994 Apr;106(4):899-906. [https://doi.org/10.1016/0016-5085(94)90748-x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8143995/ PubMed]
-#O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, Wieand HS. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997 Jan;15(1):246-50. [https://doi.org/10.1200/jco.1997.15.1.246 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8996149 PubMed]
+#'''CALGB 8896:''' 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. [https://doi.org/10.1200/jco.1997.15.1.246 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8996149/ PubMed]
-##'''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. [https://doi.org/10.1200/JCO.1999.17.5.1356 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10334519 PubMed]
+##'''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. [https://doi.org/10.1200/JCO.1999.17.5.1356 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10334519/ PubMed]
-#'''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. [https://academic.oup.com/jnci/article/90/23/1810/2520545 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9839521 PubMed]
+#'''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. [https://doi.org/10.1093/jnci/90.23.1810 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9839521/ PubMed]
-##'''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. [https://link.springer.com/article/10.1245%2Fs10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20082144 PubMed]
+##'''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. [https://doi.org/10.1245/s10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20082144/ PubMed]
-#'''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. [https://doi.org/10.1200/JCO.1999.17.11.3553 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10550154 PubMed]
+#'''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. [https://doi.org/10.1200/JCO.1999.17.11.3553 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10550154/ PubMed] [https://clinicaltrials.gov/study/NCT00425152 NCT00425152]
-##'''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. [https://link.springer.com/article/10.1245%2Fs10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20082144 PubMed]
+##'''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. [https://doi.org/10.1245/s10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20082144/ PubMed]
-#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. [https://www.karger.com/Article/Abstract/12105 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10765125 PubMed]
+#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. [https://doi.org/10.1159/000012105 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10765125/ PubMed]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140673602098367/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12241873 PubMed]
+#'''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. [https://doi.org/10.1016/s0140-6736(02)09836-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12241873/ PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2003.10.065 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12885807 PubMed]
+#'''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. [https://doi.org/10.1200/JCO.2003.10.065 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12885807/ PubMed]
-##'''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. [https://doi.org/10.1200/JCO.2007.12.2234 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17704423 PubMed]
+##'''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. [https://doi.org/10.1200/JCO.2007.12.2234 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17704423/ PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa032709 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15175436 PubMed] NCT00275210
+#'''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. [https://doi.org/10.1056/NEJMoa032709 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15175436/ PubMed] [https://clinicaltrials.gov/study/NCT00275210 NCT00275210]
-##'''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. [https://doi.org/10.1200/JCO.2008.20.6771 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19451431 PubMed]
+##'''Update:''' André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009 Jul 1;27(19):3109-16. Epub 2009 May 18. [https://doi.org/10.1200/JCO.2008.20.6771 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19451431/ PubMed]
-##'''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. [https://doi.org/10.1200/JCO.2015.63.4238 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26527776 PubMed]
+##'''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. [https://doi.org/10.1200/JCO.2015.63.4238 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26527776/ PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa043116 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15987918 PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa043116 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15987918/ PubMed] [https://clinicaltrials.gov/study/NCT00009737 NCT00009737]
-##'''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. [https://doi.org/10.1093/annonc/mdr366 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21896539 PubMed]
+##'''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. [https://doi.org/10.1093/annonc/mdr366 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21896539/ PubMed]
 <!-- Presented in part at the 33rd Annual Meeting of the American Society of Clinical Oncology, Denver, CO, May 20, 1997. -->
-#'''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. [https://doi.org/10.1200/jco.2004.00.5686 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16314627 PubMed]
+#'''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. [https://doi.org/10.1200/jco.2004.00.5686 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16314627/ PubMed]
 <!-- Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 13-17, 2004. -->
-#'''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. [https://doi.org/10.1200/jco.2005.04.7498 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16648506 PubMed] NCT00378716
+#'''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. [https://doi.org/10.1200/jco.2005.04.7498 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16648506/ PubMed] [https://clinicaltrials.gov/study/NCT00378716 NCT00378716]
-#'''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. [https://doi.org/10.1200/jco.2006.08.1075 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17194911 PubMed] NCT00069121
+#'''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. [https://doi.org/10.1200/jco.2006.08.1075 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17194911/ PubMed] [https://clinicaltrials.gov/study/NCT00069121 NCT00069121]
-##'''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. [https://doi.org/10.1200/jco.2010.33.6297 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21383294/ PubMed]
+##'''Update:''' Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011 Apr 10;29(11):1465-71. Epub 2011 Mar 7. [https://doi.org/10.1200/jco.2010.33.6297 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383294/ PubMed]
-##'''Update:''' Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: Final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015 Nov 10;33(32):3733-40. Epub 2015 Aug 31. [https://doi.org/10.1200/jco.2015.60.9107 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26324362 PubMed]
+##'''Update:''' Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: Final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015 Nov 10;33(32):3733-40. Epub 2015 Aug 31. [https://doi.org/10.1200/jco.2015.60.9107 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26324362/ PubMed]
-#'''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. [https://doi.org/10.1200/jco.2006.08.2974 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17470851 PubMed] NCT00004931
+#'''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. [https://doi.org/10.1200/jco.2006.08.2974 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/17470851/ PubMed] [https://clinicaltrials.gov/study/NCT00004931 NCT00004931]
-##'''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. [https://doi.org/10.1200/JCO.2011.36.4539 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188282/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21859995 PubMed]
+##'''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. [https://doi.org/10.1200/JCO.2011.36.4539 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188282/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21859995/ PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2007.11.2144 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17687149 PubMed]
+#'''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. [https://doi.org/10.1200/JCO.2007.11.2144 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17687149/ PubMed] [https://clinicaltrials.gov/study/NCT00003835 NCT00003835]
-#'''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. [https://www.ejcancer.com/article/S0959-8049(08)00535-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/18707870 PubMed]
+#'''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. [https://doi.org/10.1016/j.ejca.2008.07.002 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18707870/ PubMed]
-#'''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. [https://doi.org/10.1093/annonc/mdn680 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19179549 PubMed]
+#'''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. [https://doi.org/10.1093/annonc/mdn680 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19179549/ PubMed] [https://clinicaltrials.gov/study/NCT00005979 NCT00005979]
-#'''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. [https://doi.org/10.1200/JCO.2008.18.5710 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19273708 PubMed]
+#'''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. [https://doi.org/10.1200/JCO.2008.18.5710 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19273708/ PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2008.21.6663 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19451425 PubMed] NCT00026273
+#'''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. [https://doi.org/10.1200/JCO.2008.21.6663 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19451425/ PubMed] [https://clinicaltrials.gov/study/NCT00026273 NCT00026273]
-#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. [https://doi.org/10.1093/annonc/mdp236 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19567451 PubMed]
+#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. [https://doi.org/10.1186/1741-7015-9-10 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038965/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21281463/ PubMed] ACTRN12610000148077
-#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. [https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-10 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038965/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/21281463 PubMed] ACTRN12610000148077
+#'''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; EORTC; FFCD; GETTD. 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. [https://doi.org/10.1016/j.ejca.2013.01.030 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23571150/ PubMed] [https://clinicaltrials.gov/study/NCT00004150 NCT00004150]
-#'''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; EORTC; FFCD; GETTD. 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. [https://www.ejcancer.com/article/S0959-8049(13)00094-4/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/23571150 PubMed] NCT00004150
-==FULV (L-Leucovorin) {{#subobject:a93a7t|Regimen=1}}==
+==S-1 monotherapy {{#subobject:5gh25a|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
+===Regimen {{#subobject:8cug1c|Variant=1}}===
-|[[#top|back to top]]
-|}
-FULV (L-Leucovorin): 5-'''<u>FU</u>''' & Levo'''<u>L</u>'''euco'''<u>V</u>'''orin
-===Regimen variant #1, 370/25, weekly {{#subobject:1d257d|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02214-5/fulltext Gray et al. 2000 (QUASAR)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143094/ Yoshida et al. 2014 (ACTS-CC)]
-|rowspan=2|1994-1997
+|2008-04 to 2009-06
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|1. FULV; HDLV
+|[[#Tegafur.2C_Uracil.2C_Folinic_acid|UFT + LV]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+| style="background-color:#eeee01" |Non-inferior DFS36 (primary endpoint)<br>DFS36: 75.5% vs 72.5%<br>(HR 0.85, 95% CI 0.70-1.03)
-|-
-|2. FULV & Levamisole; LDLV<br> 3. FULV & Levamisole; HDLV
-| style="background-color:#d9ef8b" |Might have superior OS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV bolus once on day 1
-*[[Levoleucovorin (Fusilev)]] 25 mg/m<sup>2</sup> IV bolus once on day 1
-'''7-day cycle for 30 cycles'''
-===Regimen variant #2, 1850/125, q4wk {{#subobject:acc8d1|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02214-5/fulltext Gray et al. 2000 (QUASAR)]
-|rowspan=2|1994-1997
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. FULV; HDLV
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|2. FULV & Levamisole; LDLV<br> 3. FULV & Levamisole; HDLV
-| style="background-color:#d9ef8b" |Might have superior OS
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
-*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 28
-*[[Levoleucovorin (Fusilev)]] 25 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+**BSA between 1.25 m<sup>2</sup> and 1.50 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 28
+**BSA greater than 1.50 m<sup>2</sup>: 60 mg PO twice per day on days 1 to 28
-'''28-day cycle for 6 cycles'''
+'''42-day cycle for 4 cycles'''
+</div></div>
 ===References===
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02214-5/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10821362 PubMed]
+#'''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. [https://doi.org/10.1093/annonc/mdu232 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143094/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24942277/ PubMed] [https://clinicaltrials.gov/study/NCT00660894 NCT00660894]
-##'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61866-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/18083404 PubMed]
 ==SOX {{#subobject:617cc1|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 SOX: '''<u>S</u>'''-1, '''<u>OX</u>'''aliplatin
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:c80e20|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.clinical-colorectal-cancer.com/article/S1533-0028(19)30449-9/abstract Sunami et al. 2019 (ACTS-CC 02)]
+|[https://doi.org/10.1016/j.clcc.2019.10.002 Sunami et al. 2019 (ACTS-CC 02)]
 |2010-2014
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
 |[[Colon_cancer#Tegafur.2C_Uracil.2C_Folinic_acid|Tegafur, Uracil, Folinic Acid]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 *[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV once on day 1
 '''21-day cycle for 8 cycles'''
+</div></div>
 ===References===
+#'''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. Clin Colorectal Cancer. 2020 Mar;19(1):22-31.e6. Epub 2019 Oct 18. [https://doi.org/10.1016/j.clcc.2019.10.002 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31917122/ PubMed] JapicCTI-101073
-#'''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. [https://www.clinical-colorectal-cancer.com/article/S1533-0028(19)30449-9/fulltext link to original article]
+##'''Update:''' Watanabe J, Sasaki S, Kusumoto T, Sakamoto Y, Yoshida K, Tomita N, Maeda A, Teshima J, Yokota M, Tanaka C, Yamauchi J, Uetake H, Itabashi M, Takahashi K, Baba H, Kotake K, Boku N, Aiba K, Morita S, Takenaka N, Sugihara K. S-1 and oxaliplatin versus tegafur-uracil and leucovorin as post-operative adjuvant chemotherapy in patients with high-risk stage III colon cancer: updated 5-year survival of the phase III ACTS-CC 02 trial. ESMO Open. 2021 Apr;6(2):100077. Epub 2021 Mar 11. [https://doi.org/10.1016/j.esmoop.2021.100077 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7966838/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33714860/ PubMed]
 ==Tegafur, Uracil, Folinic acid {{#subobject:5ed2aa|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 UFT + LV: '''<u>UFT</u>''' (Tegafur and uracil) & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid)
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #1, 300/75 {{#subobject:8cc7d8|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ejcancer.com/article/S0959-8049(14)00724-2/fulltext Shimada et al. 2014 (JCOG0205)]
-|2003-2006
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FULV|FULV]]
-| style="background-color:#eeee01" |Non-inferior DFS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010179/ Hasegawa et al. 2016]
-|2004-2010
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Colon_cancer_-_null_regimens#Observation|Observation]]
-| style="background-color:#1a9850" |Superior RFS
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621030/ Sadahiro et al. 2015 (JFMC33-0502)]
 |2005-2007
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|UFT + LV weekly x 18 mo
+|[[#Tegafur.2C_Uracil.2C_Folinic_acid|UFT + LV]]; weekly x 18 mo
 | style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143094/ Yoshida et al. 2014 (ACTS-CC)]
-|2008-2009
+|2008-04 to 2009-06
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|S-1
+|[[#S-1_monotherapy|S-1]]
-| style="background-color:#eeee01" |Non-inferior DFS
+| style="background-color:#eeee01" |Non-inferior DFS36
 |-
-|[https://link.springer.com/article/10.1007%2Fs00595-017-1555-1 Miyake et al. 2018 (MCSGO-CCTG-0501)]
+|[https://doi.org/10.1016/j.clcc.2019.10.002 Sunami et al. 2019 (ACTS-CC 02)]
-|2006-2010
+|2010-2014
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|UFT/PSK
+|[[#SOX|SOX]]
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior DFS36
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
 |}
 ''Note: Miyake et al. 2018 does not contain treatment details in the abstract.''
-====Preceding treatment====
+<div class="toccolours" style="background-color:#b3e2cd">
-*JCOG0205: [[Surgery#Colorectal_cancer_surgery|Surgery]] with D2/D3 lymph node dissection
-*Hasegawa et al. 2016: [[Surgery#Metastasectomy|Surgical resection of colorectal cancer liver metastases]], within 8 weeks
 ====Chemotherapy====
 *[[Tegafur and uracil (UFT)]] 100 mg/m<sup>2</sup> PO every 8 hours on days 1 to 28
-*[[Folinic acid (Leucovorin)]] 25 mg PO every 8 hours on days 1 to 28
+*[[Leucovorin (Folinic acid)]] 25 mg PO every 8 hours on days 1 to 28
 '''35-day cycle for 5 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2, 300/90 {{#subobject:643dbb|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 20%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
@@ Line 1,127: / Line 951: @@
 |[https://doi.org/10.1200/jco.2005.04.7498 Lembersky et al. 2006 (NSABP C-06)]
 |1997-1999
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 |[[#FULV|FULV]]
-| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS/OS
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of DFS/OS
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *A potentially curative [[Surgery#Colorectal_cancer_surgery|resection]] of stage II or stage III colon cancer
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Tegafur and uracil (UFT)]] 100 mg/m<sup>2</sup> PO every 8 hours on days 1 to 28
-*[[Folinic acid (Leucovorin)]] 30 mg PO every 8 hours on days 1 to 28
+*[[Leucovorin (Folinic acid)]] 30 mg PO every 8 hours on days 1 to 28
 *No food for 1 hour before and after each dose of medication.
 '''35-day cycle for 5 cycles'''
+</div></div>
 ===References===
 <!-- Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 13-17, 2004. -->
+#'''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. [https://doi.org/10.1200/jco.2005.04.7498 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16648506/ PubMed] [https://clinicaltrials.gov/study/NCT00378716 NCT00378716]
+#'''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. [https://doi.org/10.1093/annonc/mdu232 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143094/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24942277/ PubMed] [https://clinicaltrials.gov/study/NCT00660894 NCT00660894]
+#'''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. [https://doi.org/10.1093/annonc/mdv358 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621030/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26347106/ PubMed] UMIN C000000245
+#'''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. Clin Colorectal Cancer. 2020 Mar;19(1):22-31.e6. Epub 2019 Oct 18. [https://doi.org/10.1016/j.clcc.2019.10.002 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31917122/ PubMed] JapicCTI-101073
+##'''Update:''' Watanabe J, Sasaki S, Kusumoto T, Sakamoto Y, Yoshida K, Tomita N, Maeda A, Teshima J, Yokota M, Tanaka C, Yamauchi J, Uetake H, Itabashi M, Takahashi K, Baba H, Kotake K, Boku N, Aiba K, Morita S, Takenaka N, Sugihara K. S-1 and oxaliplatin versus tegafur-uracil and leucovorin as post-operative adjuvant chemotherapy in patients with high-risk stage III colon cancer: updated 5-year survival of the phase III ACTS-CC 02 trial. ESMO Open. 2021 Apr;6(2):100077. Epub 2021 Mar 11. [https://doi.org/10.1016/j.esmoop.2021.100077 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7966838/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33714860/ PubMed]
-#'''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. [https://doi.org/10.1200/jco.2005.04.7498 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16648506 PubMed] NCT00378716
+=Advanced or metastatic disease=
-#'''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. [https://doi.org/10.1093/annonc/mdu232 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143094/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24942277 PubMed] NCT00660894
+''See the [[Colorectal cancer|colorectal cancer page]] for colorectal cancer regimens.''
-#'''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. [https://www.ejcancer.com/article/S0959-8049(14)00724-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24958736 PubMed] UMIN C000000193
-#'''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. [https://doi.org/10.1093/annonc/mdv358 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621030/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/26347106 PubMed] UMIN C000000245
-#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. [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162400 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010179/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27588959 PubMed] UMIN C000000013
-#'''MCSGO-CCTG-0501:''' 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. [https://link.springer.com/article/10.1007%2Fs00595-017-1555-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28634730 PubMed] NCT00385970
-=Therapy for oligometastatic disease, including perioperative therapy and hyperthermic intra-peritoneal chemotherapy=
-==FOLFIRI {{#subobject:a051ec|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
-===Regimen {{#subobject:0e95b6|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://ar.iiarjournals.org/content/32/4/1387.long Fiorentini et al. 2012]
-|2006-2008
-| style="background-color:#1a9851" |Phase III (C)
-|DEBIRI
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second on day 1''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 100 mg/m<sup>2</sup> IV over 120 minutes once on day 1, '''given first, with irinotecan'''
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 120 minutes once on day 1, '''given first, with leucovorin'''
-'''14-day cycle for 8 cycles'''
-===References===
-#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. [http://ar.iiarjournals.org/content/32/4/1387.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/22493375 PubMed]
-==FOLFOX4 {{#subobject:58d3ec|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:dfc57d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277487/ Nordlinger et al. 2008 (EORTC 40983)]
-|2000-2004
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Colon_cancer_-_null_regimens#Observation_3|Observation]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|[https://doi.org/10.1093/annonc/mdu539 Hebbar et al. 2014 (MIROX)]
-|2004-2010
-| style="background-color:#1a9851" |Phase III (C)
-|FOLFOX7-FOLFIRI
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS24
-|-
-|}
-''Note: this is the regimen as described by de Gramont et al. 2000; [[Study_Groups#EORTC|EORTC]] 40983 refers to this protocol. In MIROX, the treatment could be given perioperatively or postoperatively.''
-====Preceding treatment====
-*[[Surgery#Surgical_resection|Surgical resection of oligometastatic disease]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> 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===
-#'''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; [[Study_Groups#EORTC|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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60455-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277487/ link to PMC article] '''does not contain protocol''' [https://pubmed.ncbi.nlm.nih.gov/18358928 PubMed] NCT00006479
-##'''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; [[Study_Groups#EORTC|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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70447-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/24120480 PubMed]
-#'''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]. [https://doi.org/10.1093/annonc/mdu539 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25403578 PubMed] NCT00268398
-==mFOLFOX6 {{#subobject:328g5a|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:2057uf|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.20.00174 Tang et al. 2020 (BECOME)]
-|2013-2017
-| style="background-color:#1a9851" |Phase III (C)
-|[[#mFOLFOX6-B|mFOLFOX6-B]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
-'''14-day cycles'''
-===References===
-#'''BECOME:''' Tang W, Ren L, Liu T, Ye Q, Wei Y, He G, Lin Q, Wang X, Wang M, Liang F, Cui Y, Xu J. Bevacizumab Plus mFOLFOX6 Versus mFOLFOX6 Alone as First-Line Treatment for RAS Mutant Unresectable Colorectal Liver-Limited Metastases: The BECOME Randomized Controlled Trial. J Clin Oncol. 2020 Sep 20;38(27):3175-3184. Epub 2020 Aug 4. [https://doi.org/10.1200/jco.20.00174 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32749938 PubMed] NCT01972490
-==mFOLFOX6 (L-Leucovorin) {{#subobject:8fig59|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:e300fa|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1016/j.ejca.2015.09.017 Cashin et al. 2016 (SPS-1)]
-|2004-2011
-| style="background-color:#1a9851" |Randomized (C)
-|[[#Intraperitoneal_5-FU|IP 5-FU & LV]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV once on day 1
-'''14-day cycle for 12 cycles'''
-===References===
-#'''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. [https://doi.org/10.1016/j.ejca.2015.09.017 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26751236 PubMed] NCT01524094
-==mFOLFOX6-B {{#subobject:391jga|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6-B: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-===Regimen {{#subobject:208nzf|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.20.00174 Tang et al. 2020 (BECOME)]
-|2013-2017
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#mFOLFOX6_2|mFOLFOX6]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given first'''
-'''14-day cycles'''
-===References===
-#'''BECOME:''' Tang W, Ren L, Liu T, Ye Q, Wei Y, He G, Lin Q, Wang X, Wang M, Liang F, Cui Y, Xu J. Bevacizumab Plus mFOLFOX6 Versus mFOLFOX6 Alone as First-Line Treatment for RAS Mutant Unresectable Colorectal Liver-Limited Metastases: The BECOME Randomized Controlled Trial. J Clin Oncol. 2020 Sep 20;38(27):3175-3184. Epub 2020 Aug 4. [https://doi.org/10.1200/jco.20.00174 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32749938 PubMed] NCT01972490
-==FULV {{#subobject:e9bcc2|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FULV: 5-'''<u>FU</u>''' & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid)
-===Regimen {{#subobject:12cfb6|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2006.06.8353 Portier et al. 2006 (FFCD 9002)]
-|1991-2001
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Colon_cancer_-_null_regimens#Observation_3|Observation]]
-| style="background-color:#d9ef8b" |Might have superior PFS<sup>1</sup>
-|-
-|}
-''<sup>1</sup>Reported efficacy is based on the 2008 pooled update.''
-====Preceding treatment====
-*[[Surgery#Surgical_resection|Surgical resection of oligometastatic disease]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second'''
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given first'''
-'''28-day cycle for 6 cycles'''
-===References===
-#'''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. [https://doi.org/10.1200/JCO.2006.06.8353 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17075115 PubMed]
-##'''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. [https://doi.org/10.1200/JCO.2008.17.3781 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18794541 PubMed]
-==Hepatic arterial chemotherapy==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673694907501/fulltext Allen-Mersh et al. 1994]
-|1988-1993
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Colon_cancer_-_null_regimens#Observation_3|Observation]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJM199912303412702 Kemeny et al. 1999]
-|NR
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Colon_cancer_-_null_regimens#Observation_3|Observation]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-''Of historic interest; unlikely to be completed.''
-====Preceding treatment====
-*[[Surgery#Surgical_resection|Surgical resection of oligometastatic disease]]
-====Chemotherapy====
-*[[Floxuridine (FUDR)]]
-====Supportive medications====
-*[[Dexamethasone (Decadron)]]
-===References===
-#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. [https://www.thelancet.com/journals/lancet/article/PIIS0140673694907501/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/7526096 PubMed]
-#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. [https://www.nejm.org/doi/full/10.1056/NEJM199912303412702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10615075 PubMed]
-==Intraperitoneal 5-FU {{#subobject:581aec|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:1ac57d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1016/j.ejca.2015.09.017 Cashin et al. 2016 (SPS-1)]
-|2004-2011
-| style="background-color:#1a9851" |Randomized (E-switch-ooc)
-|[[#mFOLFOX6_3|mFOLFOX6]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-====Preceding treatment====
-*Cytoreductive surgery
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 550 mg/m<sup>2</sup>/day IP continuous infusion over 6 days, started on day 1 (total dose per cycle: 3300 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 30 mg/m<sup>2</sup>/day IV once on day 1, '''given 60 minutes after start of 5-FU IP infusion'''
-'''1-month cycle for 6 cycles'''
-===References===
-#'''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. [https://doi.org/10.1016/j.ejca.2015.09.017 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26751236 PubMed] NCT01524094
-==Intraperitoneal hyperthermic mitomycin {{#subobject:c049cb|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:f86ab6|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2003.04.187 Verwaal et al. 2003]
-|1998-2001
-| style="background-color:#1a9851" |Phase III (E-switch-ooc)
-|[[#FULV_3|FULV]]; modified Laufman regimen
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-====Preceding treatment====
-*Cytoreductive surgery
-====Chemotherapy====
-*Hyperthermic [[Mitomycin (Mutamycin)]] 17.5 mg/m<sup>2</sup> IP once, then 8.8 mg/m<sup>2</sup> every 30 minutes (maximum dose of 70 mg)
-'''One treatment'''
-===References===
-#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. [https://doi.org/10.1200/JCO.2003.04.187 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14551293 PubMed]
-==Intraperitoneal hyperthermic oxaliplatin {{#subobject:c049cb|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:f86ab6|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30599-4/fulltext Quenet et al. 2021]
-|2008 - 2014
-| style="background-color:#1a9851" |Phase III
-| cytoreductive surgery without HIPEC
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|}
-''Patients enrolled had a peritoneal cancer index of 25 or less''
-====Preceding treatment====
-*Cytoreductive surgery
-====Chemotherapy====
-*Hyperthermic [[Oxaliplatin_(Eloxatin)|Oxaliplatin]] 360 mg/m<sup>2</sup> (closed) or 460 mg/m<sup>2</sup> (open) IP once, systemic chemotherapy 5FU mg/m<sup>2</sup> and folinic acid 20 mg/m<sup>2</sup> delivered IV 20 minutes before HIPEC
-'''One treatment'''
-===References===
-# Quénet F, Elias D, Roca L, Goéré D, Ghouti L, Pocard M, Facy O, Arvieux C, Lorimier G, Pezet D, Marchal F, Loi V, Meeus P, Juzyna B, de Forges H, Paineau J, Glehen O; UNICANCER-GI Group and BIG Renape Group. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):256-266. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30599-4/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/33476595/ PubMed]
-=Advanced or metastatic disease, first-line=
-==Capecitabine monotherapy {{#subobject:6816ee|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-C: '''<u>C</u>'''apecitabine
-===Regimen variant #1, 2000 mg/m<sup>2</sup>/day {{#subobject:b1642a|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 17%"|Study
-!style="width: 15%"|Years of enrollment
-!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 17%"|Comparator
-!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-|[https://doi.org/10.1093/annonc/mdx122 Kwakman et al. 2017 (SALTO)]
-|2014-2015
-| style="background-color:#1a9851" |Phase III (C)
-|[[#S-1_monotherapy|S-1]]
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints<sup>1</sup>
-| style="background-color:#d73027" |Higher incidence of hand-foot syndrome
-|-
-|}
-''<sup>1</sup>Reported efficacy is based on the 2019 update.''<br>
-''Note: this trial had a primary toxicity endpoint; this dose was intended for patients at least 70 years old.''
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-'''21-day cycles'''
-===Regimen variant #2, 2500 mg/m<sup>2</sup>/day {{#subobject:303fab|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 17%"|Study
-!style="width: 15%"|Years of enrollment
-!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 17%"|Comparator
-!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-|[https://doi.org/10.1200/jco.2001.19.8.2282 Hoff et al. 2001]
-|1996-1998
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
-|[[#FULV_3|FULV]]
-| style="background-color:#1a9850" |Superior ORR
-|
-|-
-|[https://doi.org/10.1200/jco.2001.19.21.4097 Van Cutsem et al. 2001]
-|1996-1998
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
-|[[#FULV_3|FULV]]
-| style="background-color:#eeee01" |Equivalent ORR
-|
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext Koopman et al. 2007 (CAIRO)]
-|2003-2004
-| style="background-color:#1a9851" |Phase III (C)
-|[[Complex_multipart_regimens#CAIRO|See link]]
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#CAIRO|See link]]
-|
-|-
-| rowspan="2" |[https://doi.org/10.1200/JCO.2009.27.7723 Tebbutt et al. 2010 (AGITG MAX)]
-|rowspan=2|2005-2007
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]
-| style="background-color:#d73027" |Inferior PFS
-|
-|-
-|2. [[Stub#CBM|CBM]]
-| style="background-color:#d73027" |Inferior PFS
-|
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70154-2/fulltext Cunningham et al. 2013 (AVEX)]
-|2007-2010
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]
-| style="background-color:#d73027" |Inferior PFS
-|
-|-
-|[https://doi.org/10.1093/annonc/mdx122 Kwakman et al. 2017 (SALTO)]
-|2014-2015
-| style="background-color:#1a9851" |Phase III (C)
-|[[#S-1_monotherapy|S-1]]
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints<sup>1</sup>
-| style="background-color:#d73027" |Higher incidence of hand-foot syndrome
-|-
-|}
-''<sup>1</sup>Reported efficacy for SALTO is based on the 2019 update.''<br>
-''Note: SALTO had a primary toxicity endpoint; this dose was intended for patients less than 70 years old.''
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-'''21-day cycles'''
-====Subsequent treatment====
-*CAIRO, upon progression: [[#Irinotecan_monotherapy_2|Irinotecan]]
-===References===
-<!-- Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, Georgia, May 15-18, 1999. -->
-#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. [https://doi.org/10.1200/jco.2001.19.8.2282 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11304782 PubMed]
-##'''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. [https://www.nature.com/articles/6601676 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409640/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/15026800 PubMed]
-<!-- This study was presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999. -->
-#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. [https://doi.org/10.1200/jco.2001.19.21.4097 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11689577 PubMed]
-##'''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. [https://www.nature.com/articles/6601676 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409640/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/15026800 PubMed]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17630036 PubMed] NCT00312000
-#'''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. [https://doi.org/10.1200/JCO.2009.27.7723 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20516443 PubMed]
-<!--
-# '''Abstract:''' David Cunningham, Istvan Lang, Vito Lorusso, Janja Ocvirk, Dongbok Shin, Derek J. Jonker, Stuart Osborne, Niko Alexander Andre, Daniel Waterkamp, Mark P. Saunders. Bevacizumab (bev) in combination with capecitabine (cape) for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): Results of a randomized international phase III trial (AVEX). 2013 ASCO Gastrointestinal Cancers Symposium abstract 337. [http://meetinglibrary.asco.org/content/106233-133 link to abstract] -->
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70154-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/24028813 PubMed] NCT00484939
-#'''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. [https://doi.org/10.1093/annonc/mdx122 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/28383633 PubMed] NCT01918852
-##'''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. [https://www.clinical-colorectal-cancer.com/article/S1533-0028(18)30531-0/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/30782413 PubMed]
-==Capecitabine & Bevacizumab {{#subobject:408d3d|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CB: '''<u>C</u>'''apecitabine & '''<u>B</u>'''evacizumab
-===Regimen variant #1, 1000/7.5 {{#subobject:f9f237|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70154-2/fulltext Cunningham et al. 2013 (AVEX)]
-|2007-2010
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Capecitabine_monotherapy_2|Capecitabine]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===Regimen variant #2, 1250/7.5 {{#subobject:94ef02|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-||[https://doi.org/10.1200/JCO.2009.27.7723 Tebbutt et al. 2010 (AGITG MAX)]
-|2005-2007
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Capecitabine_monotherapy_2|Capecitabine]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===References===
-#'''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. [https://doi.org/10.1200/JCO.2009.27.7723 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20516443 PubMed]
-<!--
-# '''Abstract:''' David Cunningham, Istvan Lang, Vito Lorusso, Janja Ocvirk, Dongbok Shin, Derek J. Jonker, Stuart Osborne, Niko Alexander Andre, Daniel Waterkamp, Mark P. Saunders. Bevacizumab (bev) in combination with capecitabine (cape) for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): Results of a randomized international phase III trial (AVEX). 2013 ASCO Gastrointestinal Cancers Symposium abstract 337. [http://meetinglibrary.asco.org/content/106233-133 link to abstract] -->
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70154-2/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24028813 PubMed] NCT00484939
-#'''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. [https://doi.org/10.1200/JCO.18.00052 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30388045 PubMed] NCT01249638
-==CapeOx {{#subobject:b4a5f5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CapeOX: '''<u>Cape</u>'''citabine & '''<u>OX</u>'''aliplatin
-<br>XELOX: '''<u>XEL</u>'''oda & '''<u>OX</u>'''aliplatin
-<br>COX: '''<u>C</u>'''apecitabine & '''<u>OX</u>'''aliplatin
-===Example orders===
-*[[Example orders for CapeOx (XELOX) in colon cancer]]
-===Regimen variant #1, 850/130 {{#subobject:d1897d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://doi.org/10.1200/jco.2007.15.4138 Hochster et al. 2008 (TREE-1)]
-|rowspan=2|2002-2003
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. bFOL
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints
-|-
-|2. [[#mFOLFOX6_4|mFOLFOX6]]
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints
-|-
-|}
-''Note: TREE-1 did not have any primary endpoints.''
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 850 mg/m<sup>2</sup> 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/m<sup>2</sup> PO twice per day. Patients with a CrCl of 30 to 50 mL/min/1.73m<sup>2</sup> received 650 mg/m<sup>2</sup> PO twice per day
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''21-day cycles'''
-===Regimen variant #2, 1000/70 {{#subobject:b301d1|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.2006.09.2684 Porschen et al. 2007]
-|2002-2004
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|FUFOX
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 70 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 8
-'''21-day cycles'''
-===Regimen variant #3, 1000/130 {{#subobject:162a54|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.2006.09.8467 Díaz-Rubio et al. 2007]
-|2002-2004
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FUOX|FUOX]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
-|-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.25369 Ducreux et al. 2011]
-|2003-2004
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#mFOLFOX6_4|mFOLFOX6]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-| rowspan="2" |[https://doi.org/10.1200/jco.2007.14.9898 Cassidy et al. 2008 (NO16966)]
-|rowspan=2|2003-2005
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#FOLFOX4_3|FOLFOX4]]<br> 2. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|3. [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-| rowspan="2" |[https://doi.org/10.1200/jco.2007.14.9930 Saltz et al. 2008 (NO16966)]
-|rowspan=2|2003-2005
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]<br> 2. [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|3. [[#FOLFOX4_3|FOLFOX4]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159415/ Maughan et al. 2011 (UK MRC COIN)]
-|2005-2008
-| style="background-color:#1a9851" |Phase III (C)
-|CapeOx & Cetuximab
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup>
-|-
-|[https://doi.org/10.1200/jco.2012.42.6031 Hoff et al. 2012 (HORIZON II)]
-|2006-NR
-| style="background-color:#1a9851" |Phase III (C)
-|1. CAPOX & Cediranib<br> 2. FOLFOX4 & Cediranib<br> 3. mFOLFOX6 & Cediranib
-| style="background-color:#fc8d59" |Seems to have inferior PFS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext Hong et al. 2012 (SMC 2008-03-012)]
-|2008-2009
-| style="background-color:#1a9851" |Phase III (C)
-|[[#SOX_2|SOX]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|}
-''<sup>1</sup>Reported efficacy for UK MRC COIN is for KRAS wild-type patients.''<br>
-''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.''
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> 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/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''21-day cycles (see note)'''
-====Subsequent treatment====
-*SMC 2008-03-012: Optional [[#Capecitabine_monotherapy|capecitabine maintenance]] after 9 cycles
-===References===
-#Porschen R, Arkenau HT, Kubicka S, Greil R, Seufferlein T, Freier W, Kretzschmar A, Graeven U, Grothey A, Hinke A, Schmiegel W, Schmoll HJ; AIO Colorectal Study Group. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol. 2007 Sep 20;25(27):4217-23. Epub 2007 Jun 4. [https://doi.org/10.1200/jco.2006.09.2684 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17548840 PubMed]
-<!-- Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2005, Atlanta, GA; and the Annual Meeting of the European Society for Medical Oncology, Istanbul, Turkey, September 29-October 3, 2006. -->
-#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. [https://doi.org/10.1200/jco.2006.09.8467 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17548839 PubMed]
-<!-- Presented in part at the 31st European Society of Medical Oncology Congress, Istanbul, Turkey, September 29- October 3, 2006; the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Orlando, FL, January 19-21, 2007; and the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007. -->
-#'''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. [https://doi.org/10.1200/jco.2007.14.9898 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18421053 PubMed]
-##'''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. [https://doi.org/10.1200/jco.2007.14.9930 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18421054 PubMed]
-##'''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. [https://www.nature.com/articles/bjc2011201 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137415/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21673685 PubMed]
-#'''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. [https://doi.org/10.1200/jco.2007.15.4138 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18640933 PubMed]
-#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. [https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.25369 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20473862 PubMed]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60613-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159415/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21641636 PubMed] ISRCTN27286448
-##'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70102-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159416/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21641867 PubMed]
-#'''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. [https://doi.org/10.1200/jco.2012.42.6031 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22965965 PubMed] NCT00399035
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23062232 PubMed] NCT00677443
-##'''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. [https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-14-883 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289339/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25424120 PubMed]
-==CapeOx & Bevacizumab {{#subobject:62d39f|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CapeOX & Bevacizumab: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin, Bevacizumab
-<br>CAPOX-B: '''<u>CAP</u>'''ecitabine, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-<br>XELOX & Bevacizumab: '''<u>XEL</u>'''oda, '''<u>OX</u>'''aliplatin, Bevacizumab
-===Regimen variant #1, 850/130/7.5 {{#subobject:618554|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 17%"|Study
-!style="width: 15%"|Years of enrollment
-!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 17%"|Comparator
-!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-| rowspan="2" |[https://doi.org/10.1200/jco.2007.15.4138 Hochster et al. 2008 (TREE-2)]
-|rowspan=2|2003-2004
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. bFOL & Bevacizumab
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints
-| style="background-color:#ffffbf" |Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
-|-
-|2. [[#mFOLFOX6-B_2|mFOLFOX6-B]]
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints
-| style="background-color:#ffffbf" |Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 850 mg/m<sup>2</sup> 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/1.73m<sup>2</sup> received 650 mg/m<sup>2</sup> PO twice per day
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===Regimen variant #2, 1000/130/7.5 x 6 {{#subobject:e7bd8e|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa0808268 Tol et al. 2009 (CAIRO2)]
-|2005-2006
-| style="background-color:#1a9851" |Phase III (C)
-|CapeOx, Bevacizumab, Cetuximab
-| style="background-color:#1a9850" |Superior PFS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267817/ Díaz-Rubio et al. 2012 (MACRO)]
-|2006-2008
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://doi.org/10.1093/annonc/mdt236 Johnsson et al. 2013 (Nordic ACT)]
-|2007-2009
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62004-3/fulltext Simkens et al. 2015 (CAIRO3)]
-|2007-2012
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycle for 6 cycles'''
-====Subsequent treatment====
-*CAIRO2: [[#Capecitabine_.26_Bevacizumab_2|Capecitabine & Bevacizumab maintenance]]
-*MACRO: [[#Bevacizumab_monotherapy|Bevacizumab]] versus XELOX & Bevacizumab maintenance
-*Nordic ACT: [[#Bevacizumab_monotherapy|Bevacizumab]] versus Erlotinib & Bevacizumab maintenance
-*CAIRO3: [[#Capecitabine_.26_Bevacizumab_2|Capecitabine & Bevacizumab maintenance]] versus [[Colon_cancer_-_null_regimens#Observation_4|Observation]]
-===Regimen variant #3, 1000/130/7.5, indefinite {{#subobject:e7bd8e|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://doi.org/10.1200/jco.2007.14.9898 Cassidy et al. 2008 (NO16966)]
-|rowspan=2|2003-2005
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[#FOLFOX4_3|FOLFOX4]]<br> 2. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|3. [[#CapeOx_2|XELOX]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-| rowspan="2" |[https://doi.org/10.1200/jco.2007.14.9930 Saltz et al. 2008 (NO16966)]
-|rowspan=2|2003-2005
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[#FOLFOX4_3|FOLFOX4]]<br> 2. [[#CapeOx_2|XELOX]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|3. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889030/ Yamada et al. 2018 (TRICOLORE)]
-|2012-2014
-| style="background-color:#1a9851" |Phase III (C)
-|[[#IRIS_.26_Bevacizumab|IRIS & Bevacizumab]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|[http://theoncologist.alphamedpress.org/content/23/8/919.long Nakayama 2018 (CCOG-1201)]
-|2012-2016
-| style="background-color:#1a9851" |Randomized Phase II (C)
-|[[#CAPIRI-Bev|CAPIRI & Bevacizumab]]
-| style="background-color:#ffffbf" |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/m<sup>2</sup> 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/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV over 30 to 90 minutes once on day 1, '''given first'''
-'''21-day cycles'''
-===References===
-<!-- Presented in part at the 31st European Society of Medical Oncology Congress, Istanbul, Turkey, September 29- October 3, 2006; the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Orlando, FL, January 19-21, 2007; and the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007. -->
-#'''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. [https://doi.org/10.1200/jco.2007.14.9898 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18421053 PubMed]
-##'''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. [https://doi.org/10.1200/jco.2007.14.9930 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18421054 PubMed]
-##'''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. [https://www.nature.com/articles/bjc2011201 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137415/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21673685 PubMed]
-#'''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. [https://doi.org/10.1200/jco.2007.15.4138 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18640933 PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa0808268 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19196673 PubMed] NCT00208546
-##'''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. [https://www.nejm.org/doi/10.1056/NEJMc0904160 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19571295 PubMed]
-#'''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. [http://theoncologist.alphamedpress.org/content/17/1/15.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267817/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22234633 PubMed] NCT00335595
-#'''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. [https://doi.org/10.1093/annonc/mdt236 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23788755 PubMed] NCT00598156
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62004-3/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25862517 PubMed] NCT00442637
-##'''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. [https://doi.org/10.1093/annonc/mdx322 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28911067 PubMed]
-#'''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. [https://doi.org/10.1093/annonc/mdx816 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889030/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29293874 PubMed] UMIN000007834
-#'''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. [http://theoncologist.alphamedpress.org/content/23/8/919.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/30049885 PubMed] UMIN000006478
-==CAPIRI {{#subobject:793efd|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CapeIRI: '''<u>Cape</u>'''citabine and '''<u>IRI</u>'''notecan
-<br>CAPIRI: '''<u>CAP</u>'''ecitabine and '''<u>IRI</u>'''notecan
-<br>XELIRI: '''<u>XEL</u>'''ox (Capecitabine) and '''<u>IRI</u>'''notecan
-===Regimen {{#subobject:0ec52b|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366 Moehler et al. 2009a]
-|2001-2006
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext Koopman et al. 2007 (CAIRO)]
-|2003-2004
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[Complex_multipart_regimens#CAIRO|See link]]
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#CAIRO|See link]]
-|-
-| rowspan="2" |[https://doi.org/10.1200/jco.2007.11.3357 Fuchs et al. 2007 (BICC-C)]
-|rowspan=2|2003-2004
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. [[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#fc8d59" |Seems to have inferior PFS
-|-
-|2. [[#IFL|mIFL]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|[https://doi.org/10.1093/annonc/mdm544 Köhne et al. 2007 (EORTC 40015)]
-|2003-2005
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FOLFIRI_2|FOLFIRI]] +/- Celecoxib
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
-|-
-|}
-''Note: EORTC 40015 was closed prematurely.''
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-'''21-day cycles'''
-====Subsequent treatment====
-*CAIRO, with progression: [[#CapeOx_3|CapeOx]]
-===References===
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17630036 PubMed] NCT00312000
-<!-- Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA. -->
-#'''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. [https://doi.org/10.1200/jco.2007.11.3357 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17947725 PubMed]
-##'''Update:''' Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. [https://doi.org/10.1200/jco.2007.15.5390 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18235136 PubMed]
-#'''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. [https://doi.org/10.1093/annonc/mdm544 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18065406 PubMed]
-#Moehler M, Sprinzl MF, Abdelfattah M, Schimanski CC, Adami B, Godderz W, Majer K, Flieger D, Teufel A, Siebler J, Hoehler T, Galle PR, Kanzler S. Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients. World J Gastroenterol. 2009 Jan 28;15(4):449-56. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366 link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19152449 PubMed]
-==CAPIRI-Bev {{#subobject:cd6750|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CAPIRI-Bev: '''<u>CAP</u>'''ecitabine, '''<u>IRI</u>'''notecan, '''<u>Bev</u>'''acizumab
-<br>XELIRI-Bev: '''<u>XEL</u>'''oda (Capecitabine), '''<u>IRI</u>'''notecan, '''<u>Bev</u>'''acizumab
-===Regimen variant #1, 750/150/7.5 {{#subobject:ed3172|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1093/annonc/mdt236 Johnsson et al. 2013 (Nordic ACT)]
-|2007-2009
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-''This dose was recommended for patients older than 65 years.''
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycle for 6 cycles'''
-====Subsequent treatment====
-*[[#Bevacizumab_monotherapy|Bevacizumab]] versus Erlotinib & Bevacizumab maintenance
-===Regimen variant #2, 800/200/7.5 {{#subobject:f6bf78|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.18.00052 Modest et al. 2018 (XELAVIRI)]
-|2010-2016
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Capecitabine_.26_Bevacizumab|Cape-Bev]]
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior TFS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===Regimen variant #3, 1000/180/7.5 {{#subobject:852626|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1093/annonc/mdt236 Johnsson et al. 2013 (Nordic ACT)]
-|2007-2009
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycle for 6 cycles'''
-====Subsequent treatment====
-*[[#Bevacizumab_monotherapy|Bevacizumab]] versus Erlotinib & Bevacizumab maintenance
-===Regimen variant #4, 1000/200/7.5 {{#subobject:88c136|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366 Moehler et al. 2009a]
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===Regimen variant #5, 1000/240/7.5 {{#subobject:a19b6d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466131/ Pectasides et al. 2012]
-|2006-2008
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI-Bev]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 240 mg/m<sup>2</sup> IV once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycle for 6 cycles'''
-===References===
-#Moehler M, Sprinzl MF, Abdelfattah M, Schimanski CC, Adami B, Godderz W, Majer K, Flieger D, Teufel A, Siebler J, Hoehler T, Galle PR, Kanzler S. Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients. World J Gastroenterol. 2009 Jan 28;15(4):449-56. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366 link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19152449 PubMed]
-#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. [https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-12-271 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466131/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22748098 PubMed] ACTRN12610000270011
-#'''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. [https://doi.org/10.1093/annonc/mdt236 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23788755 PubMed] NCT00598156
-#'''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. [https://doi.org/10.1200/JCO.18.00052 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30388045 PubMed] NCT01249638
-==Fluorouracil monotherapy {{#subobject:a3995f|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen variant #1, 400 mg/m<sup>2</sup> intermittent bolus {{#subobject:323429|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1023/a:1008270916325 Borner et al. 1998]
-|1991-1995
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FULV_3|FULV]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
-'''1-month cycles'''
-===Regimen variant #2, 450 mg/m<sup>2</sup> intermittent bolus {{#subobject:54acz9|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1097/00000421-198908000-00011 Molinaro et al. 1989]
-|1984-1985
-| style="background-color:#1a9851" |Phase III (C)
-|Epirubicin
-| style="background-color:#1a9850" |Superior ORR
-|-
-|}
-''Note: this dose was used for those who had previously been exposed to radiotherapy.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 450 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
-'''28-day cycles'''
-===Regimen variant #3, 500 mg/m<sup>2</sup> intermittent bolus {{#subobject:545429|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1097/00000421-198908000-00011 Molinaro et al. 1989]
-|1984-1985
-| style="background-color:#1a9851" |Phase III (C)
-|Epirubicin
-| style="background-color:#1a9850" |Superior ORR
-|-
-|[https://doi.org/10.1200/JCO.1989.7.4.425 Lokich et al. 1989]
-|1984-1986
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Fluorouracil_monotherapy|5-FU]]; PVI
-| style="background-color:#d73027" |Inferior ORR
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
-'''4- to 5-week cycles'''
-===Regimen variant #4, 600 mg/m<sup>2</sup>/week {{#subobject:768cajb|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1093/oxfordjournals.annonc.a059365 Smyth et al. 1995 (F-trial)]
-|1989-1992
-| style="background-color:#1a9851" |Phase III (C)
-|TCNU
-| style="background-color:#ffffbf" |Did not meet efficacy endpoint
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
-'''7-day cycles'''
-===Regimen variant #5, 600 mg/m<sup>2</sup>/week, 6 out of 8 weeks {{#subobject:76acae|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.1986.4.4.565 Richards et al. 1986]
-|1977-1980
-| style="background-color:#1a9851" |Phase III (C)
-|[[Stub#MMF|MMF]]
-| style="background-color:#ffffbf" |Did not meet efficacy endpoints
-|-
-|[https://journals.lww.com/amjclinicaloncology/Fulltext/2002/02000/A_Phase_III_Study_of_5_Fluorouracil_Versus.4.aspx Kalofonos et al. 2002]
-|1993-1998
-| style="background-color:#1a9851" |Phase III (C)
-|1. 5-FU & IFN alfa<br> 2. [[#FULV_3|FULV]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, 29, 36
-'''8-week cycles'''
-===Regimen variant #6, weekly bolus with CI lead-in {{#subobject:b3b13d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.1996.14.10.2674 Greco et al. 1996]
-|1989-1992
-| style="background-color:#1a9851" |Phase III (C)
-|5-FU & IFN alfa-2a
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|[https://doi.org/10.1200/JCO.1995.13.6.1297 Hill et al. 1995]
-|1990-1992
-| style="background-color:#1a9851" |Phase III (C)
-|5-FU & IFN alfa-2b
-| style="background-color:#ffffbf" |Did not meet efficacy endpoints
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] as follows:
-**Cycle 1: 750 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose: 3750 mg/m<sup>2</sup>)
-**Cycle 2 onwards: 750 mg/m<sup>2</sup> IV once on day 1
-'''7-day cycles'''
-===Regimen variant #7, weekly CI {{#subobject:cbf24c|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1023/a:1008282824860 Aranda et al. 1998]
-|1994-1996
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FULV_3|FULV]]; Mayo Clinic regimen
-| style="background-color:#91cf60" |Seems to have superior ORR
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 1750 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 3500 mg/m<sup>2</sup>)
-'''7-day cycles'''
-===Regimen variant #8, PVI ("Lokich regimen") {{#subobject:88b2a1|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.1989.7.4.425 Lokich et al. 1989]
-|1984-1986
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Fluorouracil_monotherapy|5-FU]]; bolus
-| style="background-color:#1a9850" |Superior ORR
-|-
-|[https://academic.oup.com/jnci/article/88/10/668/894396 Hansen et al. 1996 (ECOG E2286)]
-|1987-1990
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Fluorouracil_monotherapy|5-FU]]; bolus
-| style="background-color:#1a9850" |Superior TTP
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08514-8/fulltext Maughan et al. 2002]
-|rowspan=2|1996-1998
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#FULV_3|FULV]]; de Gramont regimen
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|2. Raltitrexed
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion
-'''Continued indefinitely'''
-===Regimen variant #9, load to toxicity {{#subobject:31493b|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010301%2991%3A5%3C1020%3A%3AAID-CNCR1093%3E3.0.CO%3B2-V Witte et al. 2001]
-|1982-NR
-| style="background-color:#1a9851" |Phase III (C)
-|5-FU & Levamisole
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] as follows:
-**Cycle 1: 480 mg/m<sup>2</sup> IV once per day on days 1 to 5, then 240 mg/m<sup>2</sup> every other day to toxicity or six additional doses
-**Cycle 2 onwards: 480 mg/m<sup>2</sup> IV once per day on days 1 to 5
-'''6-week cycle for 1 cycle, then 5-week cycles'''
-===References===
-#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. [https://doi.org/10.1200/JCO.1986.4.4.565 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3514806 PubMed]
-#Lokich JJ, Ahlgren JD, Gullo JJ, Philips JA, Fryer JG; MAOP. 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. [https://doi.org/10.1200/JCO.1989.7.4.425 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2926468 PubMed]
-#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. [https://doi.org/10.1097/00000421-198908000-00011 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2667324 PubMed]
-#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. [https://doi.org/10.1200/JCO.1995.13.6.1297 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/7751874 PubMed]
-#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. [https://doi.org/10.1093/oxfordjournals.annonc.a059365 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8624301 PubMed]
-#'''ECOG E2286:''' 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. [https://academic.oup.com/jnci/article/88/10/668/894396 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8627643 PubMed]
-#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. [https://doi.org/10.1200/JCO.1996.14.10.2674 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/8874326 PubMed]
-#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. [https://doi.org/10.1023/a:1008282824860 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/9739438 PubMed]
-#Witte RS, Cnaan A, Mansour EG, Barylak E, Harris JE, Schutt AJ; ECOG. 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. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010301%2991%3A5%3C1020%3A%3AAID-CNCR1093%3E3.0.CO%3B2-V link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11251955 PubMed]
-#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. [https://journals.lww.com/amjclinicaloncology/Fulltext/2002/02000/A_Phase_III_Study_of_5_Fluorouracil_Versus.4.aspx link to original article] [https://pubmed.ncbi.nlm.nih.gov/11823690 PubMed]
-#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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08514-8/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/12047964 PubMed]
-==FOLFIRI {{#subobject:ebcf30|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
-<br>FUFIRI: 5-'''<u>FU</u>''' (Fluorouracil), '''<u>F</u>'''olinic acid, '''<u>IRI</u>'''notecan
-===Example orders===
-*[[Example orders for FOLFIRI in colon cancer]]
-===Regimen variant #1, 400/2000/180, bi-weekly ("Lv5FU2-Iri") {{#subobject:048237|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1023/a:1008282824860 Aranda et al. 2008]
-|1994-1996
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FUIRI|FUIRI]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<sup>1</sup>
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext Douillard et al. 2000]
-|1997-1998
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#FULV_3|FULV]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361370/ Souglakos et al. 2006]
-|2000-2004
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFIRINOX|FOLFOXIRI]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://doi.org/10.1093/annonc/mdm588 Glimelius et al. 2008]
-|2001-2004
-| style="background-color:#1a9851" |Phase III (C)
-|FLIRI
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|[https://doi.org/10.1093/annonc/mdm544 Köhne et al. 2007 (EORTC 40015)]
-|2003-2005
-| style="background-color:#1a9851" |Phase III (C)
-|[[#CAPIRI|CAPIRI]]
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
-|-
-|[https://doi.org/10.1093/annonc/mdv130 Passardi et al. 2015 (ITACa)]
-|2007-2012
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-''<sup>1</sup>Aranda et al. 2008 is described by the authors as a non-inferiority trial but the statistics used are superiority-based.''<br>
-''Note: EORTC 40015 was closed prematurely.''
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 120 minutes once per day on days 1 & 2, '''given second'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given third''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first'''
-'''14-day cycles'''
-===Regimen variant #2, 400/2800/180 {{#subobject:abe1bd|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.2006.09.0928 Falcone et al. 2007]
-|2001-2005
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFIRINOX|FOLFOXIRI]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-| rowspan="2" |[https://doi.org/10.1200/jco.2007.11.3357 Fuchs et al. 2007 (BICC-C)]
-|rowspan=2|2003-2004
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. [[#CAPIRI|CapeIRI]]
-| style="background-color:#91cf60" |Seems to have superior PFS
-|-
-|2. [[#IFL|mIFL]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa0805019 Van Cutsem et al. 2009 (CRYSTAL)]
-|2004-2005
-| style="background-color:#1a9851" |Phase III (C)
-|[[Colon_cancer,_RAS_wild-type#FOLFIRI_.26_Cetuximab_2|FOLFIRI & Cetuximab]]
-| style="background-color:#d73027" |Inferior OS<sup>1</sup>
-|-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.31552 Sanoff et al. 2018 (LCCC 1029)]
-|2011-2015
-| style="background-color:#1a9851" |Randomized Phase II (C)
-|FOLFIRI & Regorafenib
-| style="background-color:#fee08b" |Might have inferior PFS
-|-
-|[https://doi.org/10.1056/nejmoa2017699 André et al. 2020 (KEYNOTE-177)]
-|2016-2018
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Pembrolizumab_monotherapy|Pembrolizumab]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|}
-''<sup>1</sup>Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.''
-====Biomarker eligibility criteria====
-*KEYNOTE-177: MSI-H/dMMR mCRC as determined locally
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> 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") {{#subobject:310a1a|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2005.05.546 Köhne et al. 2005 (EORTC 40986)]
-|1999-2001
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#FULV_3|FULV]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|[https://doi.org/10.1016/j.ejca.2010.09.022 Fischer von Weikersthal et al. 2011]
-|2000-2004
-| style="background-color:#1a9851" |Phase III (C)
-|mIROX
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
-*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36
-*[[Irinotecan (Camptosar)]] 80 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36
-'''7-week cycles'''
-===Regimen variant #4, 500/2300/80, weekly {{#subobject:355f88|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext Douillard et al. 2000]
-|1997-1998
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#FULV_3|FULV]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[https://doi.org/10.1093/annonc/mdv130 Passardi et al. 2015 (ITACa)]
-|2007-2012
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 2300 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
-*[[Irinotecan (Camptosar)]] 80 mg/m<sup>2</sup> IV once on day 1
-'''7-day cycles'''
-===References===
-#Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10744089 PubMed]
-#'''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; [[Study_Groups#EORTC|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. [https://doi.org/10.1200/JCO.2005.05.546 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15939923 PubMed]
-#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. [https://www.nature.com/articles/6603011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361370/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16508637 PubMed]
-<!-- Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006, and at the American Society of Clinical Oncology 2006 Gastrointestinal Cancers Symposium, San Francisco, CA, January 24-27, 2006. -->
-#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. [https://doi.org/10.1200/jco.2006.09.0928 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17470860 PubMed]
-<!-- Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA. -->
-#'''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. [https://doi.org/10.1200/jco.2007.11.3357 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17947725 PubMed]
-##'''Update:''' Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. [https://doi.org/10.1200/jco.2007.15.5390 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18235136 PubMed]
-#'''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. [https://doi.org/10.1093/annonc/mdm544 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18065406 PubMed]
-#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. [https://doi.org/10.1093/annonc/mdm588 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18209013 PubMed]
-#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. [https://doi.org/10.1023/a:1008282824860 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18718892 PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa0805019 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19339720 PubMed] NCT00154102
-<!-- ## '''Update: Abstract:''' E. Van Cutsem, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D. Cunningham, I. Celik, C. Kohne. Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome. 2010 ASCO Annual Meeting abstract 3570. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=54429 link to abstract] -->
-##'''Update:''' Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. [https://doi.org/10.1200/jco.2010.33.5091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21502544 PubMed]
-##'''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. [https://www.ejcancer.com/article/S0959-8049(12)00209-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/22446022 PubMed]
-##'''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. [https://doi.org/10.1200/JCO.2014.59.4812 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25605843 PubMed]
-#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. [https://doi.org/10.1016/j.ejca.2010.09.022 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20971632 PubMed]
-#'''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. [https://doi.org/10.1093/annonc/mdv130 link to original article] '''refers to Douillard et al. 2000''' [https://pubmed.ncbi.nlm.nih.gov/25735317 PubMed] NCT01878422
-#'''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. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.31552 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29905927 PubMed] NCT01298570
-# '''KEYNOTE-177:''' André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. [https://doi.org/10.1056/nejmoa2017699 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33264544 33264544] NCT02563002
-==FOLFIRI (L-Leucovorin) {{#subobject:e98yb0|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
-===Regimen variant #1, 200/2000/150 {{#subobject:ad9b82|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2005.07.113 Colucci et al. 2005 (GOIM 9901)]
-|1999-2002
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFOX4_3|FOLFOX4]]
-| style="background-color:#ffffbf" |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/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given second'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given third''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given first'''
-'''14-day cycles'''
-===Regimen variant #2, 200/2000/180 {{#subobject:87b4fe|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2005.07.113 Colucci et al. 2005 (GOIM 9901)]
-|1999-2002
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFOX4_3|FOLFOX4]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|[https://doi.org/10.1093/annonc/mdq580 Labianca et al. 2010]
-|2001-2005
-| style="background-color:#1a9851" |Phase III (C)
-|Intermittent FOLFIRI
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Chemotherapy====
-*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given second'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given third''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given first'''
-'''14-day cycles'''
-===Regimen variant #3, 200/2800/180 {{#subobject:a3c9bd|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa0805019 Van Cutsem et al. 2009 (CRYSTAL)]
-|2004-2005
-| style="background-color:#1a9851" |Phase III (C)
-|[[Colon_cancer,_RAS_wild-type#FOLFIRI_.26_Cetuximab_2|FOLFIRI & Cetuximab]]
-| style="background-color:#d73027" |Inferior OS<sup>1</sup>
-|-
-|[https://doi.org/10.1200/JCO.2012.45.1930 Carrato et al. 2013 (SUN 1122)]
-|2007-NR
-| style="background-color:#1a9851" |Phase III (C)
-|FOLFIRI & Sunitinib
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-''<sup>1</sup>Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.''
-====Chemotherapy====
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1, '''given first, with levoleucovorin'''
-'''14-day cycles'''
-===References===
-#'''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. [https://doi.org/10.1200/JCO.2005.07.113 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15939922 PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa0805019 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19339720 PubMed] NCT00154102
-<!-- ## '''Update: Abstract:''' E. Van Cutsem, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D. Cunningham, I. Celik, C. Kohne. Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome. 2010 ASCO Annual Meeting abstract 3570. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=54429 link to abstract] -->
-##'''Update:''' Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. [https://doi.org/10.1200/jco.2010.33.5091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21502544 PubMed]
-##'''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. [https://www.ejcancer.com/article/S0959-8049(12)00209-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/22446022 PubMed]
-##'''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. [https://doi.org/10.1200/JCO.2014.59.4812 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25605843 PubMed]
-#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. [https://doi.org/10.1093/annonc/mdq580 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21078826 PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2012.45.1930 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23358972 PubMed] NCT00457691
-==FOLFIRI & Bevacizumab {{#subobject:80d6b8|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI & Bevacizumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Bevacizumab
-===Regimen variant #1, indefinite {{#subobject:28b67a|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.2007.11.3357 Fuchs et al. 2007 (BICC-C)]
-|2003-2004
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#IFL_.26_Bevacizumab|mIFL & Bevacizumab]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[https://doi.org/10.1093/annonc/mdw206 Yamazaki et al. 2016 (WJOG4407G)]
-|2008-2012
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#mFOLFOX6-B_2|mFOLFOX6-B]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|[https://doi.org/10.1056/nejmoa2017699 André et al. 2020 (KEYNOTE-177)]
-|2016-2018
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Pembrolizumab_monotherapy|Pembrolizumab]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|}
-====Biomarker eligibility criteria====
-*KEYNOTE-177: MSI-H/dMMR mCRC as determined locally
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first, with leucovorin'''
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given second'''
-'''14-day cycles'''
-===Regimen variant #2, lower dose leucovorin {{#subobject:1bfcd9|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1093/annonc/mdt236 Johnsson et al. 2013 (Nordic ACT)]
-|2007-2009
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 120 minutes once on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 44 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1
-'''14-day cycle for 9 cycles'''
-====Subsequent treatment====
-*Nordic ACT: [[#Bevacizumab_monotherapy|Bevacizumab]] versus Erlotinib & Bevacizumab maintenance
-===References===
-<!-- Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA. -->
-#'''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. [https://doi.org/10.1200/jco.2007.11.3357 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17947725 PubMed]
-##'''Update:''' Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. [https://doi.org/10.1200/jco.2007.15.5390 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18235136 PubMed]
-#'''Observational cohort:''' Bendell JC, Bekaii-Saab TS, Cohn AL, Hurwitz HI, Kozloff M, Tezcan H, Roach N, Mun Y, Fish S, Flick ED, Dalal D, Grothey A. Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-bevacizumab or FOLFIRI-bevacizumab: results from ARIES, a bevacizumab observational cohort study. Oncologist. 2012;17(12):1486-95. [http://theoncologist.alphamedpress.org/content/17/12/1486.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528380/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23015662 PubMed]
-#'''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. [https://doi.org/10.1093/annonc/mdt236 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23788755 PubMed] NCT00598156
-#'''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. [https://doi.org/10.1093/annonc/mdw206 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27177863 PubMed] UMIN000001396
-# '''KEYNOTE-177:''' André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. [https://doi.org/10.1056/nejmoa2017699 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33264544 33264544] NCT02563002
-==FOLFIRI & Bevacizumab (L-Leucovorin) {{#subobject:92d6b8|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI & Bevacizumab: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Bevacizumab
-===Regimen {{#subobject:58ae38|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1403108 Loupakis et al. 2014 (TRIBE)]
-|2008-2011
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFIRINOX_.26_Bevacizumab_.28L-Leucovorin.29|FOLFOXIRI & Bevacizumab (L-Leucovorin)]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-''Note: Loupakis et al. 2014 listed folinic acid 200 mg/m<sup>2</sup> in the body of the paper, whereas the protocol in the supplementary material stated that levoleucovorin 200 mg/m<sup>2</sup> was used. We have contacted NEJM regarding this suspected error.''
-====Chemotherapy====
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 60 minutes once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV over 30 minutes once on day 1
-'''14-day cycle for up to 12 cycles'''
-====Subsequent treatment====
-*Fluorouracil, leucovorin, bevacizumab maintenance
-===References===
-<!-- # Fotios Loupakis, Chiara Cremolini, Gianluca Masi, Sara Lonardi, Vittorina Zagonel, Patrizia Trenta, Gianluca Tomasello, Monica Ronzoni, Libero Ciuffreda, Alberto Zaniboni, Giuseppe Tonini, Angela Buonadonna, Chiara Valsuani, Silvana Chiara, Chiara Carlomagno, Corrado Boni, Lorenzo Marcucci, Luca Boni, Alfredo Falcone. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (MCRC): Results of the phase III randomized TRIBE trial. 2013 ASCO Gastrointestinal Cancers Symposium abstract 336. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=105744 link to abstract] [http://meetinglibrary.asco.org/presentationBySession/5250/1300 link to video presentation] -->
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1403108 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1403108/suppl_file/nejmoa1403108_protocol.pdf link to protocol in supplementary material] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25337750 PubMed] NCT00719797
-##'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00122-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/26338525 PubMed]
-==FOLFIRINOX {{#subobject:7c3585|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRINOX: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin
-<br>FOLFOXIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>IRI</u>'''notecan
-===Regimen {{#subobject:4620e1|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361370/ Souglakos et al. 2006]
-|2000-2004
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://doi.org/10.1200/jco.2006.09.0928 Falcone et al. 2007]
-|2001-2005
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-''Note: In contrast to Falcone et al. 2007, some guidelines list the dose of folinic acid as 400 mg/m<sup>2</sup> IV on day 1. No primary reference could be found for this.''
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 1600 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 3200 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
-*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV once on day 1
-'''14-day cycles'''
-===References===
-#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. [https://www.nature.com/articles/6603011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361370/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16508637 PubMed]
-<!-- Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006, and at the American Society of Clinical Oncology 2006 Gastrointestinal Cancers Symposium, San Francisco, CA, January 24-27, 2006. -->
-#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. [https://doi.org/10.1200/jco.2006.09.0928 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17470860 PubMed]
-==FOLFIRINOX & Bevacizumab (L-Leucovorin) {{#subobject:9bf7|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRINOX & Bevacizumab: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin, Bevacizumab
-<br>FOLFOXIRI & Bevacizumab: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>IRI</u>'''notecan, Bevacizumab
-===Regimen {{#subobject:19365|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1016/s1470-2045(10)70175-3 Masi et al. 2010 (FOIB)]
-|2007-2008
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1403108 Loupakis et al. 2014 (TRIBE)]
-|2008-2011
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#FOLFIRI_.26_Bevacizumab_.28L-Leucovorin.29|FOLFIRI & Bevacizumab (L-Leucovorin)]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-''Note: Loupakis et al. 2014 listed folinic acid 200 mg/m<sup>2</sup> in the body of the paper, whereas the protocol in the supplementary material stated that levoleucovorin 200 mg/m<sup>2</sup> was used. We have contacted NEJM regarding this suspected error. Some guidelines list either folinic acid 400 mg/m<sup>2</sup> IV once on day 1 or levoleucovorin 200 mg/m<sup>2</sup> IV once on day 1 as options.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 1600 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1, '''given fourth''' (total dose per cycle: 3200 mg/m<sup>2</sup>)
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given third, with oxaliplatin'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given third, with levoleucovorin'''
-*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given second'''
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV over 30 minutes once on day 1, '''given first'''
-'''14-day cycle for up to 12 cycles'''
-====Subsequent treatment====
-*FULV & Bevacizumab maintenance (specific details not provided)
-===References===
-# '''FOIB:''' Masi G, Loupakis F, Salvatore L, Fornaro L, Cremolini C, Cupini S, Ciarlo A, Del Monte F, Cortesi E, Amoroso D, Granetto C, Fontanini G, Sensi E, Lupi C, Andreuccetti M, Falcone A. Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Lancet Oncol. 2010 Sep;11(9):845-52. Epub 2010 Aug 9. [https://doi.org/10.1016/s1470-2045(10)70175-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20702138 PubMed] NCT01163396
-<!-- # Fotios Loupakis, Chiara Cremolini, Gianluca Masi, Sara Lonardi, Vittorina Zagonel, Patrizia Trenta, Gianluca Tomasello, Monica Ronzoni, Libero Ciuffreda, Alberto Zaniboni, Giuseppe Tonini, Angela Buonadonna, Chiara Valsuani, Silvana Chiara, Chiara Carlomagno, Corrado Boni, Lorenzo Marcucci, Luca Boni, Alfredo Falcone. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (MCRC): Results of the phase III randomized TRIBE trial. 2013 ASCO Gastrointestinal Cancers Symposium abstract 336. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=105744 link to abstract] [http://meetinglibrary.asco.org/presentationBySession/5250/1300 link to video presentation] -->
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1403108 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1403108/suppl_file/nejmoa1403108_protocol.pdf link to protocol in supplementary material] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25337750 PubMed] NCT00719797
-##'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00122-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/26338525 PubMed]
-==FOLFOX2 {{#subobject:429ff9|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX2: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:d356da|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2006.06.1440 Giacchetti et al. 2006]
-|1998-2002
-| style="background-color:#1a9851" |Phase III (C)
-|chronoFLO4
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 600 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
-*[[Fluorouracil (5-FU)]] 1500 mg/m<sup>2</sup> IV continuous infusion over 22 hours once per day, started on days 1 & 2, '''given second''' (total dose per cycle: 3000 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''14-day cycles'''
-===References===
-#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; [[Study_Groups#EORTC|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. [https://doi.org/10.1200/JCO.2006.06.1440 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16877722 PubMed]
-==FOLFOX4 {{#subobject:7239a0|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:ab483a|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.2000.18.16.2938 de Gramont et al. 2000]
-|1995-1997
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#FULV_3|FULV]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-| rowspan="2" |[https://doi.org/10.1200/JCO.2004.09.046 Goldberg et al. 2003 (NCCTG N9741)]
-|rowspan=2|1999-2001
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
-|1. [[#IFL|IFL]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|2. [[#IROX|IROX]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
-|-
-|[https://doi.org/10.1200/jco.2005.03.0106 Tournigand et al. 2006 (OPTIMOX1)]
-|2000-2002
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFOX_7.2FsLV5FU2|FOLFOX7/LV5FU2]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DDC
-|-
-|[https://doi.org/10.1200/JCO.2010.29.4496 Hecht et al. 2011 (CONFIRM 1)]
-|2003-2004
-| style="background-color:#1a9851" |Phase III (C)
-|FOLFOX4 & Vatalanib
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-| rowspan="2" |[https://doi.org/10.1200/jco.2007.14.9898 Cassidy et al. 2008 (NO16966)]
-|rowspan=2|2003-2005
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-|2. [[#CapeOx_2|XELOX]]<br> 3. [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-| rowspan="2" |[https://doi.org/10.1200/jco.2007.14.9930 Saltz et al. 2008 (NO16966)]
-|rowspan=2|2003-2005
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]<br> 2. [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|3. [[#CapeOx_2|XELOX]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-|[https://doi.org/10.1200/JCO.2008.20.8397 Bokemeyer et al. 2008 (OPUS)]
-|2005-2006
-| style="background-color:#1a9851" |Randomized Phase II (C)
-|[[Colon_cancer,_RAS_wild-type#FOLFOX4_.26_Cetuximab|FOLFOX4 & Cetuximab]]
-| style="background-color:#d73027" |Inferior OS<sup>1</sup>
-|-
-|[https://doi.org/10.1200/jco.2009.27.4860 Douillard et al. 2010 (PRIME)]
-|2006-2008
-| style="background-color:#1a9851" |Phase III (C)
-|[[Colon_cancer,_RAS_wild-type#FOLFOX4_.26_Panitumumab|FOLFOX4 & Panitumumab]]
-| style="background-color:#91cf60" |Seems to have superior PFS<sup>2</sup>
-|-
-|[https://doi.org/10.1200/jco.2012.42.6031 Hoff et al. 2012 (HORIZON II)]
-|2006-NR
-| style="background-color:#1a9851" |Phase III (C)
-|1. CAPOX & Cediranib<br> 2. FOLFOX4 & Cediranib<br> 3. mFOLFOX6 & Cediranib
-| style="background-color:#fc8d59" |Seems to have inferior PFS
-|-
-|[https://doi.org/10.1093/annonc/mdv130 Passardi et al. 2015 (ITACa)]
-|2007-2012
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-''<sup>1</sup>Reported efficacy for OPUS is based on the 2012 pooled update and is only for KRAS wild-type tumors.''<br>
-''<sup>2</sup>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.''
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''14-day cycles'''
-===References===
-#de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. [https://doi.org/10.1200/jco.2000.18.16.2938 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10944126 PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2004.09.046 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14665611 PubMed]
-#'''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. [https://doi.org/10.1200/jco.2005.03.0106 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16421419 PubMed]
-#'''Retrospective:''' Goldberg RM, Tabah-Fisch I, Bleiberg H, de Gramont A, Tournigand C, Andre T, Rothenberg ML, Green E, Sargent DJ. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol. 2006 Sep 1;24(25):4085-91. [https://doi.org/10.1200/jco.2006.06.9039 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16943526 PubMed] content property of [http://hemonc.org HemOnc.org]
-<!-- Presented in part at the 31st European Society of Medical Oncology Congress, Istanbul, Turkey, September 29- October 3, 2006; the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Orlando, FL, January 19-21, 2007; and the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007. -->
-#'''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. [https://doi.org/10.1200/jco.2007.14.9898 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18421053 PubMed]
-##'''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. [https://doi.org/10.1200/jco.2007.14.9930 link to original article] '''refers to de Gramont et al. 2000 for protocol''' [https://pubmed.ncbi.nlm.nih.gov/18421054 PubMed]
-##'''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. [https://www.nature.com/articles/bjc2011201 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137415/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21673685 PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2008.20.8397 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19114683 PubMed]
-##'''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. [https://doi.org/10.1093/annonc/mdq632 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21228335 PubMed]
-##'''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. [https://www.ejcancer.com/article/S0959-8049(12)00209-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/22446022 PubMed]
-#'''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. [https://doi.org/10.1200/jco.2009.27.4860 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20921465 PubMed] NCT00364013
-##'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1305275 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24024839 PubMed]
-##'''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. [https://doi.org/10.1093/annonc/mdu141 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24718886 PubMed]
-#'''CONFIRM 1:''' 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. [https://doi.org/10.1200/JCO.2010.29.4496 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21464406 PubMed] NCT00056459
-#'''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. [https://doi.org/10.1200/jco.2012.42.6031 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22965965 PubMed] NCT00399035
-#'''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. [https://doi.org/10.1093/annonc/mdv130 link to original article] '''refers to de Gramont et al. 2000''' [https://pubmed.ncbi.nlm.nih.gov/25735317 PubMed] NCT01878422
-==FOLFOX4 (L-Leucovorin) {{#subobject:73uba0|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX4: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:0af678|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2005.07.113 Colucci et al. 2005 (GOIM 9901)]
-|1999-2002
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|[https://doi.org/10.1200/JCO.2010.29.4496 Hecht et al. 2011 (CONFIRM 1)]
-|2003-2004
-| style="background-color:#1a9851" |Phase III (C)
-|FOLFOX4 & Vatalanib
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|[https://insights.ovid.com/pubmed?pmid=24316553 Correale et al. 2014 (GOLFIG-2)]
-|2005-2010
-| style="background-color:#1a9851" |Phase III (C)
-|GOLFIG
-| style="background-color:#d73027" |Inferior PFS
-|-
-|}
-====Chemotherapy====
-*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with leucovorin'''
-'''14-day cycles'''
-===References===
-#'''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. [https://doi.org/10.1200/JCO.2005.07.113 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15939922 PubMed]
-#'''CONFIRM 1:''' 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. [https://doi.org/10.1200/JCO.2010.29.4496 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21464406 PubMed] NCT00056459
-#'''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. [https://insights.ovid.com/pubmed?pmid=24316553 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24316553 PubMed] EudraCT 2005-003458-81
-==mFOLFOX6 {{#subobject:e4bda7|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-<br>OxMdG: '''<u>Ox</u>'''aliplatin '''<u>M</u>'''odified '''<u>d</u>'''e '''<u>G</u>'''ramont
-===Example orders===
-*[[Example orders for mFOLFOX 6 in colon cancer]]
-===Regimen variant #1, LCV 200 mg/m<sup>2</sup> {{#subobject:792d00|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2015.66.1181 van Hazel et al. 2016 (SIRFLOX)]
-|2006-2013
-| style="background-color:#1a9851" |Phase III (C)
-|mFOLFOX6 plus SIRT
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext Wasan et al. 2017 (FOXFIRE-Global)]
-|2013-2014
-| style="background-color:#1a9851" |Phase III (C)
-|mFOLFOX6 plus SIRT
-| style="background-color:#ffffbf" |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/m<sup>2</sup>; the authors were contacted for clarification.''
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''14-day cycles'''
-===Regimen variant #2, LCV 350 mg/m<sup>2</sup> {{#subobject:90f8fc|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376131/ Cheeseman et al. 2002]
-|NR
-| style="background-color:#91cf61" |Non-randomized
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-| rowspan="2" |[https://doi.org/10.1200/jco.2007.15.4138 Hochster et al. 2008 (TREE-1)]
-|rowspan=2|2002-2003
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. bFOL
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints
-|-
-|2. [[#CapeOx_2|CapeOx]]
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159415/ Maughan et al. 2011 (UK MRC COIN)]
-|2005-2008
-| style="background-color:#1a9851" |Phase III (C)
-|mFOLFOX6 & Cetuximab
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup>
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext Wasan et al. 2017 (FOXFIRE)]
-|2009-2014
-| style="background-color:#1a9851" |Phase III (C)
-|OxMdG plus SIRT
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-''<sup>1</sup>Reported efficacy for UK MRC COIN is as reported for KRAS wild-type patients.''<br>
-''Note: TREE-1 did not have any primary endpoints.''
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 350 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''14-day cycles'''
-===Regimen variant #3, LCV 400 mg/m<sup>2</sup> {{#subobject:db877a|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.2012.42.6031 Hoff et al. 2012 (HORIZON II)]
-|2006-NR
-| style="background-color:#1a9851" |Phase III (C)
-|1. CAPOX & Cediranib<br> 2. FOLFOX4 & Cediranib<br> 3. mFOLFOX6 & Cediranib
-| style="background-color:#fc8d59" |Seems to have inferior PFS
-|-
-|[https://doi.org/10.1056/nejmoa2017699 André et al. 2020 (KEYNOTE-177)]
-|2016-2018
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Pembrolizumab_monotherapy|Pembrolizumab]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|}
-====Biomarker eligibility criteria====
-*KEYNOTE-177: MSI-H/dMMR mCRC as determined locally
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''14-day cycles'''
-===References===
-#Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12;87(4):393-9. [https://doi.org/10.1038/sj.bjc.6600467 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376131/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/12177775 PubMed]
-#'''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. [https://doi.org/10.1200/jco.2007.15.4138 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18640933 PubMed]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60613-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159415/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21641636 PubMed] ISRCTN27286448
-##'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70102-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159416/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21641867 PubMed]
-#'''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. [https://doi.org/10.1200/jco.2012.42.6031 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22965965 PubMed] NCT00399035
-#'''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. [https://doi.org/10.1200/JCO.2015.66.1181 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26903575 PubMed] NCT00724503
-##'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28781171 PubMed]
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28781171 PubMed] NCT01721954
-# '''KEYNOTE-177:''' André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. [https://doi.org/10.1056/nejmoa2017699 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33264544 33264544] NCT02563002
-==mFOLFOX6 (L-Leucovorin) {{#subobject:e46gn7|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:8c4386|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159415/ Maughan et al. 2011 (UK MRC COIN)]
-|2005-2008
-| style="background-color:#1a9851" |Phase III (C)
-|mFOLFOX6 & Cetuximab
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup>
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext Wasan et al. 2017 (FOXFIRE)]
-|2009-2014
-| style="background-color:#1a9851" |Phase III (C)
-|OxMdG plus SIRT
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-''<sup>1</sup>Reported efficacy for UK MRC COIN is as reported for KRAS wild-type patients.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Levoleucovorin (Fusilev)]] 175 mg IV over 2 hours once on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''14-day cycles'''
-===References===
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60613-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159415/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21641636 PubMed] ISRCTN27286448
-##'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70102-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159416/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21641867 PubMed]
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28781171 PubMed] NCT01721954
-==FOLFOX 7/sLV5FU2 {{#subobject:5513db|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX 7/sLV5FU2: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin alternating with '''<u>s</u>'''implified '''<u>L</u>'''euco'''<u>V</u>'''orin, '''<u>5-FU</u>''', '''<u>2</u>'''-weekly (every 2 weeks)
-===Protocol {{#subobject:b39a65|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.2005.03.0106 Tournigand et al. 2006 (OPTIMOX1)]
-|2000-2002
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FOLFOX4_3|FOLFOX4]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DDC
-|-
-|}
-''Note: this regimen has an unusual alternating schedule; see paper for more details.''
-====Chemotherapy, FOLFOX 7 portion====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, started on day 1, '''given third'''
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
-'''14-day cycle for up to 6 cycles, then proceed to sLV5FU2:'''
-====Chemotherapy, sLV5FU2 portion====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1500 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 3000 mg/m<sup>2</sup>)
-'''14-day cycle for up to 12 cycles, then resume FOLFOX 7 for 6 additional cycles as described above'''
-===References===
-#'''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. [https://doi.org/10.1200/jco.2005.03.0106 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16421419 PubMed]
-==FOLFOX 7/sLV5FU2 (L-Leucovorin) {{#subobject:66b3db|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX 7/sLV5FU2: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin alternating with '''<u>s</u>'''implified L-'''<u>L</u>'''euco'''<u>V</u>'''orin, '''<u>5-FU</u>''', '''<u>2</u>'''-weekly (every 2 weeks)
-===Protocol {{#subobject:b39a65|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.2005.03.0106 Tournigand et al. 2006 (OPTIMOX1)]
-|2000-2002
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FOLFOX4_3|FOLFOX4]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DDC
-|-
-|}
-''Note: this regimen has an unusual alternating schedule; see paper for more details.''
-====Chemotherapy, FOLFOX 7 portion====
-*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, started on day 1, '''given third'''
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
-'''14-day cycle for up to 6 cycles, then proceed to sLV5FU2:'''
-====Chemotherapy, sLV5FU2 portion====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1500 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 3000 mg/m<sup>2</sup>)
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> 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===
-#'''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. [https://doi.org/10.1200/jco.2005.03.0106 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16421419 PubMed]
-==mFOLFOX7 {{#subobject:7ff5f5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX7: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:d39fe0|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/JCO.2009.23.4344 Chibaudel et al. 2009 (OPTIMOX2)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
-*[[Fluorouracil (5-FU)]] 3000 mg/m<sup>2</sup> IV continuous infusion over 46 hours, started on day 1, '''given second'''
-*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with leucovorin'''
-'''14-day cycle for 6 cycles'''
-====Subsequent treatment====
-*sLV5FU2 versus no further treatment
-===References===
-#'''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. [https://doi.org/10.1200/JCO.2009.23.4344 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19786657 PubMed]
-==mFOLFOX7 (L-Leucovorin) {{#subobject:7f8nb5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX7: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:d39g0k|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/JCO.2009.23.4344 Chibaudel et al. 2009 (OPTIMOX2)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 3000 mg/m<sup>2</sup> IV continuous infusion over 46 hours, started on day 1, '''given second'''
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
-*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with leucovorin'''
-'''14-day cycle for 6 cycles'''
-====Subsequent treatment====
-*sLV5FU2 versus no further treatment
-===References===
-#'''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. [https://doi.org/10.1200/JCO.2009.23.4344 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19786657 PubMed]
-==FOLFOX4 & Bevacizumab {{#subobject:e93745|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX4 & Bevacizumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-<br>FOLFOX-B: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-===Regimen {{#subobject:c7030b|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894803/ Emmanouilides et al. 2007]
-|2004-2005
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-| rowspan="2" |[https://doi.org/10.1200/jco.2007.14.9898 Cassidy et al. 2008 (NO16966)]
-|rowspan=2|2003-2005
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[#FOLFOX4_3|FOLFOX4]]<br> 2. [[#CapeOx_2|XELOX]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|3. [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-====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===
-#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. [http://www.biomedcentral.com/1471-2407/7/91 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894803/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17537235 PubMed]
-<!-- Presented in part at the 31st European Society of Medical Oncology Congress, Istanbul, Turkey, September 29- October 3, 2006; the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Orlando, FL, January 19-21, 2007; and the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007. -->
-#'''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. [https://doi.org/10.1200/jco.2007.14.9898 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18421053 PubMed]
-##'''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. [https://doi.org/10.1200/jco.2007.14.9930 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18421054 PubMed]
-##'''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. [https://www.nature.com/articles/bjc2011201 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137415/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21673685 PubMed]
-==mFOLFOX6-B {{#subobject:b74416|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6-B: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-<br>FOLFOX-B: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-===Example orders===
-*[[Example orders for mFOLFOX6-B in colon cancer]]
-===Regimen variant #1 {{#subobject:eeb338|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 17%"|Study
-!style="width: 15%"|Years of enrollment
-!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 17%"|Comparator
-!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-| rowspan="2" |[https://doi.org/10.1200/jco.2007.15.4138 Hochster et al. 2008 (TREE-2)]
-|rowspan=2|2003-2004
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. bFOL & Bevacizumab
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints
-| style="background-color:#ffffbf" |Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
-|-
-|2. [[#CapeOx_.26_Bevacizumab|CapeOx & Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints
-| style="background-color:#ffffbf" |Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
-|-
-|[https://doi.org/10.1200/JCO.2008.19.8135 Hecht et al. 2008 (PACCE)]
-|2005-2006
-| style="background-color:#1a9851" |Phase III (C)
-|mFOLFOX6 & Bevacizumab & Panitumumab
-| style="background-color:#1a9850" |Superior PFS
-|
-|-
-|[http://www.clinical-colorectal-cancer.com/article/S1533-0028(11)00063-6/fulltext Saltz et al. 2011]
-|NR
-| style="background-color:#1a9851" |Phase III (C)
-|[[Stub#FOLF-CB|FOLF-CB]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS12
-|
-|-
-|[https://doi.org/10.1200/jco.2012.42.5355 Schmoll et al. 2012 (HORIZON III)]
-|2006-2009
-| style="background-color:#1a9851" |Phase III (C)
-|mFOLFOX6 & Cediranib
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
-|
-|-
-|[https://doi.org/10.1093/annonc/mdw206 Yamazaki et al. 2016 (WJOG4407G)]
-|2008-2012
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70490-X/fulltext Yamada et al. 2013 (SOFT<sub>CRC</sub>)]
-|2009-2011
-| style="background-color:#1a9851" |Phase III (C)
-|[[#SOX_.26_Bevacizumab|SOX & Bevacizumab]]
-| style="background-color:#eeee01" |Seems to have non-inferior PFS
-|
-|-
-|[https://doi.org/10.1056/nejmoa2017699 André et al. 2020 (KEYNOTE-177)]
-|2016-2018
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Pembrolizumab_monotherapy|Pembrolizumab]]
-| style="background-color:#d73027" |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.''
-====Biomarker eligibility criteria====
-*KEYNOTE-177: MSI-H/dMMR mCRC as determined locally
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1
-'''14-day cycles'''
-===Regimen variant #2, lower dose leucovorin {{#subobject:3c348b|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1093/annonc/mdt236 Johnsson et al. 2013 (Nordic ACT)]
-|2007-2009
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 120 minutes once on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 44 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1
-'''14-day cycle for 9 cycles'''
-====Subsequent treatment====
-*Nordic ACT: [[#Bevacizumab_monotherapy|Bevacizumab]] versus Erlotinib & Bevacizumab maintenance
-===References===
-#'''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. [https://doi.org/10.1200/jco.2007.15.4138 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18640933 PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2008.19.8135 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19114685 PubMed]
-#Saltz L, Badarinath S, Dakhil S, Bienvenu B, Harker WG, Birchfield G, Tokaz LK, Barrera D, Conkling PR, O'Rourke MA, Richards DA, Reidy D, Solit D, Vakiani E, Capanu M, Scales A, Zhan F, Boehm KA, Asmar L, Cohn A. Phase III trial of cetuximab, bevacizumab, and 5-fluorouracil/leucovorin vs FOLFOX-bevacizumab in colorectal cancer. Clin Colorectal Cancer. 2012 Jun;11(2):101-11. Epub 2011 Nov 4. [http://www.clinical-colorectal-cancer.com/article/S1533-0028(11)00063-6/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22055112 PubMed]
-#'''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. [https://doi.org/10.1200/jco.2012.42.5355 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22965961 PubMed] NCT00384176
-#'''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. [http://theoncologist.alphamedpress.org/content/17/12/1486.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528380/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23015662 PubMed]
-#'''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. [https://doi.org/10.1093/annonc/mdt236 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23788755 PubMed] NCT00598156
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70490-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/24225157 PubMed] JapicCTI-090699
-##'''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. [https://esmoopen.bmj.com/content/2/1/e000135 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519807/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28761727 PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2015.66.1181 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26903575 PubMed] NCT00724503
-#'''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. [https://doi.org/10.1093/annonc/mdw206 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27177863 PubMed] UMIN000001396
-# '''KEYNOTE-177:''' André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. [https://doi.org/10.1056/nejmoa2017699 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33264544 33264544] NCT02563002
-==mFOLFOX6-B (L-Leucovorin) {{#subobject:b7yy26|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6-B: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-<br>FOLFOX-B: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-===Regimen {{#subobject:1d15de|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889030/ Yamada et al. 2018 (TRICOLORE)]
-|2012-2014
-| style="background-color:#1a9851" |Phase III (C)
-|[[#IRIS_.26_Bevacizumab|IRIS & Bevacizumab]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV once on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given first'''
-'''14-day cycles'''
-===References===
-#'''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. [https://doi.org/10.1093/annonc/mdx816 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889030/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29293874 PubMed] UMIN000007834
-==FUIRI {{#subobject:e8ugac|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FUIRI: 5-'''<u>FU</u>''' & '''<u>IRI</u>'''notecan
-===Regimen {{#subobject:08ucb7|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1023/a:1008282824860 Aranda et al. 2008]
-|1994-1996
-| style="background-color:#1a9851" |Phase III (E-de-esc)
-|[[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<sup>1</sup>
-|-
-|}
-''<sup>1</sup>Aranda et al. 2008 is described by the authors as a non-inferiority trial but the statistics used are superiority-based.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 1125 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1, '''given second''' (total dose per cycle: 2250 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 80 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given first'''
-'''7-day cycles'''
-===References===
-#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. [https://doi.org/10.1023/a:1008282824860 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18718892 PubMed]
-==FULV {{#subobject:e9add2|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FULV: 5-'''<u>FU</u>''' & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid)
-<br>LV5FU2: '''<u>L</u>'''euco'''<u>V</u>'''orin and '''<u>5-FU</u>''', two days out of the month
-<br>sLV5FU2: '''<u>s</u>'''implified '''<u>L</u>'''euco'''<u>V</u>'''orin and '''<u>5-FU</u>''', two days out of the month
-===Example orders===
-*[[Example orders for 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV) in colon cancer]]
-*[[Example orders for 5-FU & high-dose Leucovorin (Roswell Park regimen/HDLV) in colon cancer]]
-*[[Example orders for weekly 5-FU & Leucovorin in colon cancer]]
-*[[Example orders for simplified biweekly 5-FU & leucovorin (sLV5FU2) in colon cancer]]
-===Regimen variant #1, 400/80 ("modified Laufman regimen") {{#subobject:8f214e|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2003.04.187 Verwaal et al. 2003]
-|1998-2001
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Intraperitoneal_hyperthermic_mitomycin|HIPEC]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1
-*[[Folinic acid (Leucovorin)]] 80 mg/m<sup>2</sup> IV once on day 1
-'''7-day cycle for up to 26 cycles (6 months)'''
-===Regimen variant #2, 450/200 {{#subobject:24e32a|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.1996.14.10.2682 Kosmidis et al. 1996]
-|NR
-| style="background-color:#1a9851" |Phase III (C)
-|FULV & IFN alfa-2b
-| style="background-color:#1a9850" |Superior OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 450 mg/m<sup>2</sup> IV bolus once on day 1, '''given halfway through'''
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''7-day cycles'''
-===Regimen variant #3, 500/20 {{#subobject:a1523|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.1996.14.8.2274 Jäger et al. 1996]
-|1989-1994
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FULV_3|FULV]]; high-dose
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once on day 1, '''given second, 1 hour after start of leucovorin'''
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''7-day cycles'''
-===Regimen variant #4, 500/200, 6 out of 8 weeks {{#subobject:f7ed72|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1093/annonc/mdf043 Blanke et al. 2002]
-|1995-1999
-| style="background-color:#1a9851" |Phase III (C)
-|[[Stub#FULV_.26_Trimetrexate|FULV & Trimetrexate]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
-'''8-week cycles'''
-===Regimen variant #5, 600/500 ("Roswell Park regimen") {{#subobject:3f90af|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.1987.5.10.1559 Petrelli et al. 1987]
-|NR
-| style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[#Fluorouracil_monotherapy|5-FU]]<br> 2. 5-FU & MTX
-| style="background-color:#1a9850" |Superior ORR
-|-
-|[https://doi.org/10.1200/JCO.1989.7.10.1419 Petrelli et al. 1989]
-|NR
-| style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[#Fluorouracil_monotherapy|5-FU]]<br> 2. [[#FULV_3|FULV]]; LDLV
-| style="background-color:#d9ef8b" |Might have superior OS
-|-
-|[https://doi.org/10.1200/JCO.1994.12.1.14 Buroker et al. 1994]
-|1988-1990
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#FULV_3|FULV]]; Mayo Clinic regimen
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%
-|-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19951115)76:10%3C1709::AID-CNCR2820761006%3E3.0.CO;2-5 Jones et al. 1995]
-|1988-1991
-| style="background-color:#1a9851" |Phase III (C)
-|[[Stub#MFL|MFL]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|[https://doi.org/10.1200/jco.2003.10.066 Kabbinavar et al. 2003 (AVF0780)]
-|1998
-| style="background-color:#1a9851" |Randomized Phase II (C)
-|FULV & Bevacizumab
-| style="background-color:#fee08b" |Might have inferior OS
-|-
-|}
-''Note: the original regimen described by Petrelli et al. 1987 & 1989 used a 5-FU dose of 600 mg/m<sup>2</sup>.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 500 to 600 mg/m<sup>2</sup> 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/m<sup>2</sup> 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 {{#subobject:be5dfd|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2007.13.3934 Gamelin et al. 2008]
-|NR
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FULV_3|FULV]]; PK-guided
-| style="background-color:#fee08b" |Might have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 1500 mg/m<sup>2</sup> IV over 8 hours once on day 1
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus every 4 hours on day 1, '''given before and 4 hours into 5-FU infusion''' (total dose per cycle: 400 mg/m<sup>2</sup>)
-'''7-day cycles'''
-===Regimen variant #7, 1850/1000 {{#subobject:566afe|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.1995.13.4.921 Man et al. 1995 (Corfu-A)]
-|1990-1991
-| style="background-color:#1a9851" |Phase III (E-switch-ooc)
-|5-FU & IFN alfa-2a
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|[https://doi.org/10.1200/JCO.1997.15.11.3320 Goldberg et al. 1997]
-|1990-1995
-| style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[#FULV_.28L-Leucovorin.29|FULV]]; low-dose LV<br> 2. [[#FULV_3|FULV]]; oral LV
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV once per day on days 1 to 5
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5
-'''28-day cycle for 2 cycles, then 35-day cycles'''
-===Regimen variant #8, 2000/100 {{#subobject:d429aa|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1023/a:1008270916325 Borner et al. 1998]
-|1991-1995
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Fluorouracil_monotherapy|5-FU]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 5
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 5
-'''1-month cycles'''
-===Regimen variant #9, 2000/400 (LV5FU2 aka "de Gramont regimen") {{#subobject:66012|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.1997.15.2.808 de Gramont et al. 1997 (FFCD 9101)]
-|1991-1994
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#FULV_3|FULV]]; Mayo Clinic regimen
-| style="background-color:#1a9850" |Superior PFS
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)12388-4/fulltext Kerr et al. 2003]
-|1994-2000
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FULV_3|FULV]]; IHA LV5FU2
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://doi.org/10.1200/jco.2000.18.16.2938 de Gramont et al. 2000]
-|1995-1997
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFOX4_3|FOLFOX4]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08514-8/fulltext Maughan et al. 2002]
-|rowspan=2|1996-1998
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#Fluorouracil_monotherapy|Lokich regimen]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|2. Raltitrexed
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)12461-0/fulltext Maughan et al. 2003]
-|1996-2000
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FULV_3|FULV]]; intermittent LV5FU2
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext Douillard et al. 2000]
-|1997-1998
-| style="background-color:#1a9851" |Phase III (C)
-|1. [[#IFL|IFL]]<br> 2. [[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-| rowspan="2" |[https://www.karger.com/Article/Abstract/94357 Ducreux et al. 2006 (FFCD 9601)]
-|rowspan=2|1997-2001
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#FULV_3|FULV]]; ldLV5FU2<br> 2. [[#Fluorouracil_monotherapy|5-FU]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|2. Raltitrexed
-| style="background-color:#91cf60" |Seems to have superior PFS
-|-
-|[https://doi.org/10.1093/annonc/mdn638 Cunningham et al. 2008]
-|2000-NR
-| style="background-color:#1a9851" |Phase IIIb (C)
-|[[#FOLFOX4_3|FOLFOX4]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-| rowspan="2" |[https://doi.org/10.1093/annonc/mdv491 Aparicio et al. 2015 (FFCD 2001-02)]
-|rowspan=2|2003-2010
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#FOLFIRI_2|FOLFIRI]]; "classic"<br> 2. [[#FOLFIRI_2|FOLFIRI]]; "simplified"
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|3. [[#FULV_3|FULV]]; sLV5FU2
-| style="background-color:#ffffbf" |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/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first'''
-'''14-day cycles (see note)'''
-===Regimen variant #10, 2000/500 {{#subobject:d429aa|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.1997.15.3.908 Scheithauer et al. 1997]
-|1991-1994
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FULV_.28L-Leucovorin.29_2|FULV (L-leucovorin)]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS12
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 5
-*[[Folinic acid (Leucovorin)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
-'''28-day cycle for up to 6 cycles'''
-===Regimen variant #11, 2000/1000 {{#subobject:d539aa|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1093/oxfordjournals.annonc.a058047 Labianca et al. 1991]
-|1987-1989
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Fluorouracil_monotherapy|5-FU]]
-| style="background-color:#91cf60" |Seems to have superior ORR
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV over 15 minutes once per day on days 1 to 5
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5
-'''28-day cycles'''
-===Regimen variant #12, 2125/100 ("Mayo Clinic regimen") {{#subobject:ad7e77|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19890315)63:6%2B%3C1026::AID-CNCR2820631307%3E3.0.CO;2-R O'Connell 1989]
-|rowspan=2|NR
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#Fluorouracil_monotherapy|5-FU]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[[#FULV_3|FULV]]; HDLV
-| style="background-color:#ffffbf" |Did not meet primary efficacy endpoint
-|-
-|[https://doi.org/10.1200/JCO.1989.7.10.1407 Poon et al. 1989]
-|1984-1987
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#Fluorouracil_monotherapy|5-FU]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[https://doi.org/10.1200/JCO.1994.12.1.14 Buroker et al. 1994]
-|1988-1990
-| style="background-color:#1a9851" |Phase III (E-de-esc)
-|[[#FULV_3|FULV]]; Roswell Park regimen
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%
-|-
-|[https://doi.org/10.1200/JCO.1997.15.2.808 de Gramont et al. 1997 (FFCD 9101)]
-|1991-1994
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FULV_3|FULV]]; LV5FU2
-| style="background-color:#d73027" |Inferior PFS
-|-
-|[https://doi.org/10.1023/a:1008282824860 Aranda et al. 1998]
-|1994-1996
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Fluorouracil_monotherapy|5-FU]]; high-dose
-| style="background-color:#fc8d59" |Seems to have inferior ORR
-|-
-|[https://doi.org/10.1200/JCO.2002.04.123 Douillard et al. 2002]
-|1995-1997
-| style="background-color:#1a9851" |Phase III (C)
-|UFT & Leucovorin
-| style="background-color:#eeee01" |Seems to have equivalent OS
-|-
-|[https://doi.org/10.1200/JCO.2003.11.122 Köhne et al. 2003 (EORTC 40952)]
-|1995-1998
-| style="background-color:#1a9851" |Phase III (C)
-|1. FU24h<br> 2. FU24h + LV
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://doi.org/10.1200/JCO.2002.10.129 Carmichael et al. 2002]
-|1996-1997
-| style="background-color:#1a9851" |Phase III (C)
-|UFT & Leucovorin
-| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
-|-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 Saltz et al. 2000]
-|rowspan=2|1996-1998
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#IFL|IFL]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|2. [[#Irinotecan_monotherapy|Irinotecan]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|[https://doi.org/10.1200/jco.2001.19.8.2282 Hoff et al. 2001]
-|1996-1998
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Capecitabine_monotherapy_2|Capecitabine]]
-| style="background-color:#d73027" |Inferior ORR
-|-
-|[https://doi.org/10.1200/jco.2001.19.21.4097 Van Cutsem et al. 2001]
-|1996-1998
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Capecitabine_monotherapy_2|Capecitabine]]
-| style="background-color:#eeee01" |Equivalent ORR
-|-
-|[https://doi.org/10.1200/JCO.2002.20.6.1519 Schilsky et al. 2002 (FUMA3008)]
-|1997-1999
-| style="background-color:#1a9851" |Phase III (C)
-|Eniluracil & 5-FU
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS
-|-
-|[https://doi.org/10.1093/annonc/mdj090 Chong et al. 2005]
-|1998-2001
-| style="background-color:#1a9851" |Phase III (C)
-|FULV & 3H1
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://doi.org/10.1093/annonc/mdj104 Hospers et al. 2006]
-|1999-2002
-| style="background-color:#1a9851" |Phase III (C)
-|FOLFOX6
-| style="background-color:#fc8d59" |Seems to have inferior PFS
-|-
-|}
-''Note: not all manuscripts explicitly describe the timing described here; O'Connell 1989 is the clearest.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''
-'''28-day cycle for 3 cycles, then 35-day cycle for 3 cycles (see note)'''
-===Regimen variant #13, 2560/175 (reduced-dose sLV5FU2) {{#subobject:d246ce|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109515/ Seymour et al. 2011 (MRC FOCUS2)]
-| style="background-color:#1a9851" |Phase III (C)
-|1. [[#Capecitabine_monotherapy_2|Capecitabine]]<br> 2. [[#CapeOx_2|CapeOx]]<br> 3. OxFU
-| style="background-color:#fee08b" |Might have inferior PFS (see note)
-| style="background-color:#ffffbf" |Similar QoL (see note)
-|-
-|}
-''Note: efficacy comparison was to oxaliplatin-containing regimens; QoL comparison was to capecitabine-containing regimens.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 320 mg/m<sup>2</sup> IV bolus once on day 1, then 2240 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2560 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 175 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''14-day cycles'''
-===Regimen variant #14, 2600/500 {{#subobject:f4d2e9|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext Douillard et al. 2000]
-|1997-1998
-| style="background-color:#1a9851" |Phase III (C)
-|1. [[#IFL|IFL]]<br> 2. [[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
-*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV once on day 1
-'''7-day cycles'''
-===Regimen variant #15, 2800/350 ("modified de Gramont regimen") {{#subobject:a28e0a|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376131/ Cheeseman et al. 2002]
-| style="background-color:#91cf61" |Non-randomized
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61087-3/fulltext Seymour et al. 2007 (MRC FOCUS)]
-| style="background-color:#1a9851" |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/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>), '''given second'''
-*[[Folinic acid (Leucovorin)]] 350 mg IV over 2 hours once on day 1, '''given first'''
-====Supportive medications====
-*No routine prophylactic [[:Category:Emesis_prevention|antiemetics]] and [[:Category:Anti-diarrheals|antidiarrheal]] medications were used, but patients could use [[Metoclopramide (Reglan)]] prn nausea and [[Loperamide (Imodium)]] prn diarrhea.
-'''14-day cycles'''
-===Regimen variant #16, 2800/400 (sLV5FU2) {{#subobject:9bdfa8|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancetonc/article/PIIS1470204511701991/fulltext Ducreux et al. 2011 (FFCD 2000-05)]
-|2002-2006
-| style="background-color:#1a9851" |Phase III (C)
-|[[Complex_multipart_regimens#FFCD_2000-05|See link]]
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#FFCD_2000-05|See link]]
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''14-day cycles'''
-====Subsequent treatment====
-*Upon progression: [[#mFOLFOX6_4|mFOLFOX6]]
-===Regimen variant #17, other {{#subobject:8f03e1|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ejcancer.com/article/0959-8049(94)00360-H/pdf Heys et al. 1995]
-|NR
-| style="background-color:#1a9851" |Phase III (C)
-|FULV & rIL2
-| style="background-color:#fee08b" |Might have inferior OS
-|-
-|[https://www.ejcancer.com/article/S0959-8049(98)00397-9/fulltext Hausmaninger et al. 1999]
-|1991-1995
-| style="background-color:#1a9851" |Phase III (C)
-|FULV & IFN alfa-2c
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|[https://doi.org/10.1200/JCO.2000.18.1.136 Giacchetti et al. 2000]
-|1994-1996
-| style="background-color:#1a9851" |Phase III (C)
-|Chronomodulated FOLFOX
-| style="background-color:#fc8d59" |Seems to have inferior PFS
-|-
-|}
-''See papers for details.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]]
-*[[Folinic acid (Leucovorin)]]
-===References===
-#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. [https://doi.org/10.1200/JCO.1987.5.10.1559 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2443619 PubMed]
-#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. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19890315)63:6%2B%3C1026::AID-CNCR2820631307%3E3.0.CO;2-R link to original article] [https://pubmed.ncbi.nlm.nih.gov/2465076 PubMed]
-#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. [https://doi.org/10.1200/JCO.1989.7.10.1407 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2476530 PubMed]
-##'''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. [https://doi.org/10.1200/JCO.1991.9.11.1967 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1941055 PubMed]
-#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. [https://doi.org/10.1200/JCO.1989.7.10.1419 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/2674331 PubMed]
-#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. [https://doi.org/10.1093/oxfordjournals.annonc.a058047 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/1742223 PubMed]
-#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. [https://doi.org/10.1200/JCO.1994.12.1.14 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/7677801 PubMed]
-#'''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. [https://doi.org/10.1200/JCO.1995.13.4.921 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/7707120 PubMed]
-#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. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19951115)76:10%3C1709::AID-CNCR2820761006%3E3.0.CO;2-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8625038 PubMed]
-#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. [https://www.ejcancer.com/article/0959-8049(94)00360-H/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/7695972 PubMed]
-#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. [https://doi.org/10.1200/jco.1996.14.8.2274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8708717 PubMed]
-#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. [https://doi.org/10.1200/JCO.1996.14.10.2682 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/8874327 PubMed]
-#'''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. [https://doi.org/10.1200/JCO.1997.15.2.808 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9053508 PubMed]
-#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. [https://doi.org/10.1200/JCO.1997.15.3.908 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/9060527 PubMed]
-#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. [https://doi.org/10.1200/JCO.1997.15.11.3320 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/9363861 PubMed]
-#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. [https://doi.org/10.1023/a:1008270916325 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/9653495 PubMed]
-#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. [https://doi.org/10.1023/a:1008282824860 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/9739438 PubMed]
-#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. [https://www.ejcancer.com/article/S0959-8049(98)00397-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/10448286 PubMed]
-#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. [https://doi.org/10.1200/JCO.2000.18.1.136 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10623704 PubMed]
-#Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10744089 PubMed]
-#de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. [https://doi.org/10.1200/jco.2000.18.16.2938 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10944126 PubMed]
-#Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. [https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11006366 PubMed]
-<!-- Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, Georgia, May 15-18, 1999. -->
-#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. [https://doi.org/10.1200/jco.2001.19.8.2282 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11304782 PubMed]
-##'''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. [https://www.nature.com/articles/6601676 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409640/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/15026800 PubMed]
-<!-- This study was presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999. -->
-#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. [https://doi.org/10.1200/jco.2001.19.21.4097 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11689577 PubMed]
-##'''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. [https://www.nature.com/articles/6601676 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409640/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/15026800 PubMed]
-#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. [https://doi.org/10.1093/annonc/mdf043 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11863117 PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2002.20.6.1519 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11896100 PubMed]
-#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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08514-8/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/12047964 PubMed]
-#Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12;87(4):393-9. [https://doi.org/10.1038/sj.bjc.6600467 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376131/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/12177775 PubMed]
-#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. [https://doi.org/10.1200/JCO.2002.04.123 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12202661 PubMed]
-#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. [https://doi.org/10.1200/JCO.2002.10.129 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12202662 PubMed]
-#'''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. [https://doi.org/10.1200/jco.2003.10.066 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12506171 PubMed]
-#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; [[Study_Groups#EORTC|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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)12388-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12573372 PubMed]
-#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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)12461-0/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/12583944 PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2003.11.122 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12963704 PubMed]
-#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. [https://doi.org/10.1200/JCO.2003.04.187 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14551293 PubMed]
-#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. [https://doi.org/10.1093/annonc/mdj090 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16311275 PubMed]
-#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. [https://doi.org/10.1093/annonc/mdj104 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16500914 PubMed]
-#'''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. [https://www.karger.com/Article/Abstract/94357 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16816536 PubMed]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61087-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/17630037 PubMed]
-#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. [https://doi.org/10.1200/JCO.2007.13.3934 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18445839 PubMed]
-#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. [https://doi.org/10.1093/annonc/mdn638 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18854549 PubMed]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60399-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109515/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21570111 PubMed] ISRCTN21221452
-#'''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. [https://www.thelancet.com/journals/lancetonc/article/PIIS1470204511701991/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/21903473 PubMed] NCT00126256
-#'''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. [https://doi.org/10.1093/annonc/mdv491 link to original article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/26487578 PubMed] NCT00303771
-==FULV (L-Leucovorin) {{#subobject:e9bgg2|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FULV (L-Leucovorin): 5-'''<u>FU</u>''' & Levo'''<u>L</u>'''euco'''<u>V</u>'''orin
-===Regimen variant #1, 1870/50 {{#subobject:138u06|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1023/a:1008200713533 Labianca et al. 1997]
-|1991-1994
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FULV_.28L-Leucovorin.29_2|FULV]]; HDLV
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV over 15 minutes once per day on days 1 to 5
-*[[Levoleucovorin (Fusilev)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
-'''28-day cycles'''
-===Regimen variant #2, 1875/500 {{#subobject:13cd06|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819990201%2985%3A3%3C535%3A%3AAID-CNCR4%3E3.0.CO%3B2-7 Colucci et al. 1999]
-|1991-1993
-| style="background-color:#1a9851" |Phase III (C)
-|FULV & IFN alfa-2b
-| style="background-color:#ffffbf" |Did not meet primary efficacy endpoints
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 375 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second'''
-*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given first'''
-'''21-day cycles'''
-===Regimen variant #3, 2800/350 ("modified de Gramont regimen") {{#subobject:a9juza|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376131/ Cheeseman et al. 2002]
-| style="background-color:#91cf61" |Non-randomized
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61087-3/fulltext Seymour et al. 2007 (MRC FOCUS)]
-| style="background-color:#1a9851" |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/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>), '''given second'''
-*[[Levoleucovorin (Fusilev)]] 175 mg IV over 2 hours once on day 1, '''given first'''
-====Supportive medications====
-*No routine prophylactic [[:Category:Emesis_prevention|antiemetics]] and [[:Category:Anti-diarrheals|antidiarrheal]] medications were used, but patients could use [[Metoclopramide (Reglan)]] prn nausea and [[Loperamide (Imodium)]] prn diarrhea.
-'''14-day cycles'''
-===References===
-#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. [https://doi.org/10.1023/a:1008200713533 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/9093726 PubMed]
-#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. [https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819990201%2985%3A3%3C535%3A%3AAID-CNCR4%3E3.0.CO%3B2-7 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10091727 PubMed]
-#Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12;87(4):393-9. [https://doi.org/10.1038/sj.bjc.6600467 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376131/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/12177775 PubMed]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61087-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/17630037 PubMed]
-==FUOX {{#subobject:b4j3b5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FUOX: 5-'''<u>FU</u>''' & '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:975a54|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.2006.09.8467 Díaz-Rubio et al. 2007]
-|2002-2004
-| style="background-color:#1a9851" |Phase III (C)
-|[[#CapeOx_2|CapeOx]]
-| style="background-color:#ffffbf" |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====
-*[[Fluorouracil (5-FU)]] 1125 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on days 1 & 8 (total dose per cycle: 4500 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''14-day cycle for 18 cycles'''
-===References===
-<!-- Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2005, Atlanta, GA; and the Annual Meeting of the European Society for Medical Oncology, Istanbul, Turkey, September 29-October 3, 2006. -->
-#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. [https://doi.org/10.1200/jco.2006.09.8467 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17548839 PubMed]
-==IFL {{#subobject:544878|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-IFL: '''<u>I</u>'''rinotecan, '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin (Folinic acid)
-<br>mIFL: '''<u>m</u>'''odified '''<u>I</u>'''rinotecan, '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin (Folinic acid)
-===Regimen variant #1, q3wk {{#subobject:2354b5|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.karger.com/Article/FullText/320520 Stathopoulos et al. 2010]
-|2004-2008
-| style="background-color:#1a9851" |Phase III (C)
-|[[#IFL_.26_Bevacizumab|IFL & Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS36
-|-
-|}
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 135 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycles'''
-===Regimen variant #2, 4 out of 6 weeks {{#subobject:1ec9e5|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 Saltz et al. 2000]
-|rowspan=2|1996-1998
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-esc)
-|1. [[#FULV_3|FULV]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|2. [[#Irinotecan_monotherapy|Irinotecan]]
-| style="background-color:#d9ef8b" |Might have superior OS
-|-
-| rowspan="2" |[https://doi.org/10.1200/JCO.2004.09.046 Goldberg et al. 2003 (NCCTG N9741)]
-|rowspan=2|1999-2001
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#FOLFOX4_3|FOLFOX4]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|2. [[#IROX|IROX]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa032691 Hurwitz et al. 2004 (AVF2107g)]
-|rowspan=2|2000-2002
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. FULV & Bevacizumab
-| style="background-color:#d3d3d3" |Not reported
-|-
-|2. [[#IFL_.26_Bevacizumab|IFL & Bevacizumab]]
-| style="background-color:#d73027" |Inferior OS
-|-
-| rowspan="2" |[https://doi.org/10.1200/jco.2007.11.3357 Fuchs et al. 2007 (BICC-C)]
-|rowspan=2|2003-2004
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. [[#CAPIRI|CapeIRI]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|2. [[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012268/ Guan et al. 2011 (ARTIST<sub>CRC</sub>)]
-|2007-2008
-| style="background-color:#1a9851" |Phase III (C)
-|[[#IFL_.26_Bevacizumab|mIFL & Bevacizumab]]
-| style="background-color:#fc8d59" |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====
-*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22, '''given first'''
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22
-'''42-day cycles'''
-===References===
-#Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. [https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11006366 PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2004.09.046 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14665611 PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa032691 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15175435 PubMed]
-##'''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. [https://doi.org/10.1200/JCO.2005.10.017 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15908660 PubMed]
-<!-- Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA. -->
-#'''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. [https://doi.org/10.1200/jco.2007.11.3357 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17947725 PubMed]
-##'''Update:''' Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. [https://doi.org/10.1200/jco.2007.15.5390 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18235136 PubMed]
-#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. [https://www.karger.com/Article/FullText/320520 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20798560 PubMed]
-#'''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. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012268/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21959045 PubMed] NCT00642577
-==IFL & Bevacizumab {{#subobject:1d3c2e|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-IFL & Bevacizumab: '''<u>I</u>'''rinotecan, '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin (Folinic acid), Bevacizumab
-<br>mIFL & Bevacizumab: '''<u>m</u>'''odified '''<u>I</u>'''rinotecan, '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin (Folinic acid), Bevacizumab
-===Regimen variant #1, IFL {{#subobject:772ed7|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa032691 Hurwitz et al. 2004 (AVF2107g)]
-|rowspan=2|2000-2002
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-esc)
-|1. FL & Bevacizumab
-| style="background-color:#d3d3d3" |Not reported
-|-
-|2. [[#IFL|IFL]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|[https://doi.org/10.1200/jco.2007.11.3357 Fuchs et al. 2007 (BICC-C)]
-|2003-2004
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI+Bev]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 8
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===Regimen variant #2, mIFL {{#subobject:e336a6|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012268/ Guan et al. 2011 (ARTIST<sub>CRC</sub>)]
-|2007-2008
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#IFL|mIFL]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-''Note: this trial should not be confused for the trial with the same name in gastric cancer.''
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22, '''given first'''
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV over 6 to 8 hours once per day on days 1, 8, 15, 22
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1, 15, 29
-'''42-day cycles'''
-===References===
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa032691 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15175435 PubMed]
-<!-- Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA. -->
-#'''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. [https://doi.org/10.1200/jco.2007.11.3357 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17947725 PubMed]
-##'''Update:''' Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. [https://doi.org/10.1200/jco.2007.15.5390 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18235136 PubMed]
-#'''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. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012268/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21959045 PubMed] NCT00642577
-==Irinotecan monotherapy {{#subobject:e5bfc5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Example orders===
-*[[Example orders for Irinotecan (Camptosar) in colon cancer]]
-===Regimen {{#subobject:7e0a89|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 Saltz et al. 2000]
-|rowspan=2|1996-1998
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-de-esc)
-|1. [[#FULV_3|FULV]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|2. [[#IFL|IFL]]
-| style="background-color:#fee08b" |Might have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22
-'''42-day cycles'''
-===References===
-#Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. [https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11006366 PubMed]
-==IRIS & Bevacizumab {{#subobject:923b54|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-IRIS & Bevacizumab: '''<u>IRI</u>'''notecan, '''<u>S</u>'''-1, Bevacizumab
-===Regimen variant #1, q3wk {{#subobject:e8b674|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889030/ Yamada et al. 2018 (TRICOLORE)]
-|2012-2014
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. [[#CapeOx_.26_Bevacizumab|CapeOx & Bevacizumab]]<br> 2. [[#mFOLFOX6-B_3|mFOLFOX6-B]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|}
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV once on day 1, '''given second'''
-*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 15, beginning in the evening (28 doses per cycle)
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1, '''given first'''
-'''21-day cycles'''
-===Regimen variant #2, q4wk {{#subobject:081d47|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889030/ Yamada et al. 2018 (TRICOLORE)]
-|2012-2014
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. [[#CapeOx_.26_Bevacizumab|CapeOx & Bevacizumab]]<br> 2. [[#mFOLFOX6-B_3|mFOLFOX6-B]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|}
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 15, '''given second'''
-*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 15, beginning in the evening (28 doses per cycle)
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1 & 15, '''given first'''
-'''28-day cycles'''
-===References===
-#'''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. [https://doi.org/10.1093/annonc/mdx816 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889030/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29293874 PubMed] UMIN000007834
-==IROX {{#subobject:e2032d|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-IROX: '''<u>IR</u>'''inotecan & '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:e75779|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://doi.org/10.1200/JCO.2004.09.046 Goldberg et al. 2003 (NCCTG N9741)]
-|rowspan=2|1999-2001
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
-|1. [[#FOLFOX4_3|FOLFOX4]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
-|-
-|2. [[#IFL|IFL]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV once on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycles'''
-===References===
-#'''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. [https://doi.org/10.1200/JCO.2004.09.046 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14665611 PubMed]
-==Nordic FLOX {{#subobject:68f8a9|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FLOX: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>OX</u>'''aliplatin
-===Example orders===
-*[[Example orders for FLOX in colon cancer]]
-===Regimen {{#subobject:8220b4|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2004.05.188 Sørbye et al. 2004]
-|2000-2001
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://doi.org/10.1200/JCO.2011.38.0915 Tveit et al. 2012 (NORDIC-VII)]
-|2005-2007
-| style="background-color:#1a9851" |Phase III (C)
-|Nordic FLOX & Cetuximab
-| style="background-color:#ffffbf" |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====
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, '''given second'''
-*[[Folinic acid (Leucovorin)]] 60 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, '''given third, 30 minutes after 5-FU'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first'''
-'''14-day cycle for 8 cycles (NORDIC-VII) or indefinitely (Sørbye et al. 2004)'''
-===References===
-#Sørbye H, Glimelius B, Berglund A, Fokstuen T, Tveit KM, Braendengen M, Øgreid D, Dahl O. Multicenter phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):31-8. [https://doi.org/10.1200/JCO.2004.05.188 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/14701765 PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2011.38.0915 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22473155 PubMed] NCT00145314
-##'''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. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482736/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28399112 PubMed]
-==OXAFAFU {{#subobject:a38b7e|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-OXAFAFU: '''<u>OXA</u>'''liplatin, '''<u>F</u>'''olinic '''<u>A</u>'''cid (Leucovorin), 5-'''<u>FU</u>''' (Fluorouracil)
-===Regimen {{#subobject:3dcd8b|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1093/annonc/mdi185 Comella et al. 2005]
-|2001-2003
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|IRIFAFU
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-====Chemotherapy====
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
-*[[Folinic acid (Leucovorin)]] 250 mg/m<sup>2</sup> IV once on day 2
-*[[Fluorouracil (5-FU)]] 850 mg/m<sup>2</sup> IV once on day 2
-'''14-day cycles'''
-===References===
-#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. [https://doi.org/10.1093/annonc/mdi185 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15837702 PubMed]
-==Pembrolizumab monotherapy {{#subobject:5aa59d|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:3af038|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#404040"
-|<small>'''FDA-recommended dose'''</small>
-|-
-|}
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1056/nejmoa2017699 André et al. 2020 (KEYNOTE-177)]
-|2016-2018
-| style="background-color:#1a9851" |Phase III (E-switch-ooc)
-|Investigator's choice of:<br> 1. [[#mFOLFOX6_3|mFOLFOX6]]<br> 2. [[#mFOLFOX6-B_3|mFOLFOX6-B]]<br> 3. [[Colon_cancer,_RAS_wild-type#mFOLFOX6_.26_Cetuximab_3|mFOLFOX6 & Cetuximab]]<br> 4. [[#FOLFIRI_2|FOLFIRI]]<br> 5. [[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]<br> 6. [[Colon_cancer,_RAS_wild-type#FOLFIRI_.26_Cetuximab_2|FOLFIRI & Cetuximab]]
-| style="background-color:#1a9850" | Superior PFS
-|-
-|}
-''Inclusion criteria: ECOG PS 0 or 1''
-====Biomarker eligibility criteria====
-*MSI-H/dMMR mCRC as determined locally
-====Immunotherapy====
-*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
-'''21-day cycle for up to 2 years'''
-===References===
-<!-- #'''Abstract:''' Andre T, Shiu KK, KIM TW, Jensen BV, Jensen LH, Punt CJA, Smith DM, Garcia-Carbonero R, Benavides M, Gibbs P, Fouchardiere CDL, Rivera F, Elez E, Bendell JC, Le DT, Yoshino T, Yang P, Farooqui MZH, Marinello P, Diaz LA. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study. J Clin Oncol 38: 2020 (suppl; abstr LBA4) [https://meetinglibrary.asco.org/record/186928/abstract Link to abstract] -->
-# '''KEYNOTE-177:''' André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. [https://doi.org/10.1056/nejmoa2017699 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33264544 33264544] NCT02563002
-==S-1 monotherapy {{#subobject:32c8c6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:b1642a|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 17%"|Study
-!style="width: 15%"|Years of enrollment
-!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 17%"|Comparator
-!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-|[https://doi.org/10.1093/annonc/mdx122 Kwakman et al. 2017 (SALTO)]
-|2014-2015
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Capecitabine_monotherapy_2|Capecitabine]]
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints<sup>1</sup>
-| style="background-color:#1a9850" |Lower incidence of hand-foot syndrome
-|-
-|}
-''<sup>1</sup>Reported efficacy is based on the 2019 update.''<br>
-''Note: this trial had a primary toxicity endpoint.''
-====Chemotherapy====
-*[[Tegafur, gimeracil, oteracil (S-1)]] 30 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-'''21-day cycles'''
-===References===
-#'''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. [https://doi.org/10.1093/annonc/mdx122 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/28383633 PubMed] NCT01918852
-##'''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. [https://www.clinical-colorectal-cancer.com/article/S1533-0028(18)30531-0/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/30782413 PubMed]
-==SOX {{#subobject:693823|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-SOX: '''<u>S</u>'''-1 & '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:c54d08|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext Hong et al. 2012 (SMC 2008-03-012)]
-|2008-2009
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#CapeOx_2|CapeOX]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|}
-====Chemotherapy====
-*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycle for up to 9 cycles'''
-====Subsequent treatment====
-*Patients were allowed to continue [[#S-1_monotherapy_2|S-1 maintenance]]
-===References===
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23062232 PubMed] NCT00677443
-##'''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. [https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-14-883 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289339/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25424120 PubMed]
-==SOX & Bevacizumab {{#subobject:6c92b3|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-SOX & Bevacizumab: '''<u>S</u>'''-1, '''<u>OX</u>'''aliplatin, Bevacizumab
-===Regimen {{#subobject:cjcn88|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70490-X/fulltext Yamada et al. 2013 (SOFT<sub>CRC</sub>)]
-|2009-2011
-| style="background-color:#1a9851" |Phase III (C)
-|[[#mFOLFOX6-B_3|mFOLFOX6-B]]
-| style="background-color:#eeee01" |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 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14 (see note)
-**BSA between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14 (see note)
-**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 14 (see note)
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1, '''given second'''
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1, '''given first'''
-'''21-day cycles'''
-===References===
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70490-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/24225157 PubMed] JapicCTI-090699
-##'''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. [https://esmoopen.bmj.com/content/2/1/e000135 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519807/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28761727 PubMed]
-=Maintenance after first-line therapy=
-==Bevacizumab monotherapy {{#subobject:caff58|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:ab34c1|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1093/annonc/mdt236 Johnsson et al. 2013 (Nordic ACT)]
-|2007-2009
-| style="background-color:#1a9851" |Phase III (C)
-|Erlotinib & Bevacizumab
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00216-8/fulltext Tournigand et al. 2015 (OPTIMOX3)]
-|2007-2011
-| style="background-color:#1a9851" |Phase III (C)
-|Erlotinib & Bevacizumab
-| style="background-color:#fee08b" |Might have inferior PFS
-|-
-|[https://doi.org/10.1093/annonc/mdv011 Koeberle et al. 2015 (SAKK 41/06)]
-|2007-2012
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Colon_cancer_-_null_regimens#Observation_4|No further treatment]]
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior TTP
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00042-X/fulltext Hegewisch-Becker et al. 2015 (AIO KRK 0207)]
-|rowspan=2|2009-2013
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[Colon_cancer_-_null_regimens#Observation_4|No further treatment]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-|2. Fluoropyrimidine & Bevacizumab
-| style="background-color:#eeee01" |Non-inferior TTF
-|-
-|[https://doi.org/10.1200/JCO.2017.75.2931 Aparicio et al. 2018 (PRODIGE 9)]
-|2010-2013
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Colon_cancer_-_null_regimens#Observation_4|No further treatment]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of TCD
-|-
-|}
-====Preceding treatment====
-*Nordic ACT: [[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]] x 9 or [[#mFOLFOX6-B_2|mFOLFOX6-B]] x 9 or [[#CAPIRI-Bev|XELIRI & Bevacizumab]] x 6 or [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]] x 6
-*AIO KRK 0207 & OPTIMOX3: Bevacizumab-containing chemotherapy
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===References===
-#'''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. [https://doi.org/10.1093/annonc/mdt236 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23788755 PubMed] NCT00598156
-#'''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. [https://doi.org/10.1093/annonc/mdv011 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25605741 PubMed] NCT00544700
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00042-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/26361971 PubMed] NCT00973609
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00216-8/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/26474518 PubMed] NCT00265824
-#'''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. [https://doi.org/10.1200/JCO.2017.75.2931 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29346040 PubMed] NCT00952029
-==Capecitabine monotherapy {{#subobject:66ad1e|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:796f2e|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext Hong et al. 2012 (SMC 2008-03-012)]
-|2008-2009
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://doi.org/10.1093/annonc/mdw101 Luo et al. 2016]
-|2010-2013
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Colon_cancer_-_null_regimens#Observation_4|Observation]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|}
-====Preceding treatment====
-*SMC 2008-03-012: [[#CapeOx_2|CapeOX]] x 9
-*Luo et al. 2016: [[#mFOLFOX6_4|FOLFOX]] or [[#CapeOx_2|XELOX]]
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-'''21-day cycles'''
-===References===
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23062232 PubMed] NCT00677443
-#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. [https://doi.org/10.1093/annonc/mdw101 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26940686 PubMed] NCT02027363
-==Capecitabine & Bevacizumab {{#subobject:083f75|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CAP-B: '''<u>CAP</u>'''ecitabine & '''<u>B</u>'''evacizumab
-===Regimen {{#subobject:49256d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.karger.com/Article/FullText/355914 Yalcin et al. 2013 (Stop and Go)]
-|2008-2009
-| style="background-color:#1a9851" |Phase III (E-de-esc)
-|[[#CapeOx_.26_Bevacizumab|XELOX-B]]; continued
-| style="background-color:#1a9850" |Superior PFS
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62004-3/fulltext Simkens et al. 2015 (CAIRO3)]
-|2007-2012
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Colon_cancer_-_null_regimens#Observation_4|Observation]]
-| style="background-color:#1a9850" |Superior PFS-2
-|-
-|}
-====Preceding treatment====
-*[[#CapeOx_.26_Bevacizumab|CAPOX-B]] x 6
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===References===
-#'''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. [https://www.karger.com/Article/FullText/355914 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24247559 PubMed] NCT00623805
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62004-3/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25862517 PubMed] NCT00442637
-##'''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. [https://doi.org/10.1093/annonc/mdx322 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28911067 PubMed]
-==S-1 monotherapy {{#subobject:b5a1dd|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:608e8f|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext Hong et al. 2012 (SMC 2008-03-012)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Preceding treatment====
-*[[#SOX_2|SOX]] x 9
-====Chemotherapy====
-*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-'''21-day cycles'''
-===References===
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23062232 PubMed] NCT00677443
-=Advanced or metastatic disease, second-line therapy=
-==CapeOx {{#subobject:6b5972|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CapeOx: '''<u>Cape</u>'''citabine & '''<u>Ox</u>'''aliplatin
-<br>XELOX: '''<u>XEL</u>'''oda & '''<u>OX</u>'''aliplatin
-===Example orders===
-*[[Example orders for CapeOx (XELOX) in colon cancer]]
-===Regimen {{#subobject:df3e12|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext Koopman et al. 2007 (CAIRO)]
-|2003-2004
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[Complex_multipart_regimens#CAIRO|See link]]
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#CAIRO|See link]]
-|-
-|[https://doi.org/10.1093/annonc/mdn370 Rothenberg et al. 2008]
-|2003-2005
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FOLFOX4_4|FOLFOX4]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|}
-====Preceding treatment====
-*CAIRO: [[#CAPIRI|CAPIRI]], with progression
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''21-day cycles'''
-===References===
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17630036 PubMed] NCT00312000
-#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. [https://doi.org/10.1093/annonc/mdn370 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18550577 PubMed]
-==CapeOx & Erlotinib {{#subobject:6b52b2|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CapeOx & Erlotinib: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin, Erlotinib
-===Regimen {{#subobject:df3e14|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/jco.2005.05.3728 Meyerhardt et al. 2006]
-|2003-2004
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-====Targeted therapy====
-*[[Erlotinib (Tarceva)]] 150 mg PO once per day
-'''21-day cycles'''
-===References===
-# 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. [https://doi.org/10.1200/jco.2005.05.3728 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16622264 PubMed]
-==CAPIRI {{#subobject:26c557|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CapeIRI: '''<u>Cape</u>'''citabine and '''<u>IRI</u>'''notecan
-<br>CAPIRI: '''<u>CAP</u>'''ecitabine and '''<u>IRI</u>'''notecan
-<br>XELIRI: '''<u>XEL</u>'''ox (Capecitabine) and '''<u>IRI</u>'''notecan
-<br>mXELIRI: '''<u>m</u>'''odified '''<u>XEL</u>'''ox (Capecitabine) and '''<u>IRI</u>'''notecan
-===Regimen variant #1, "standard" {{#subobject:f1b041|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815882/ Lim et al. 2015 (SMC 2009-11-017)]
-|2010-2013
-| style="background-color:#1a9851" |Phase III (C)
-|XELIRI & Simvastatin
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-'''21-day cycles'''
-===Regimen variant #2, "modified" {{#subobject:b3be15|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]
-|2013-2015
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FOLFIRI_3|FOLFIRI]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-'''21-day cycles'''
-===References===
-#'''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. [https://doi.org/10.1038/bjc.2015.371 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815882/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26505681 PubMed] NCT01238094
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29555258 PubMed] NCT01996306
-==CAPIRI-Bev {{#subobject:7c6914|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CAPIRI-Bev: '''<u>CAP</u>'''ecitabine, '''<u>IRI</u>'''notecan, '''<u>Bev</u>'''acizumab
-<br>mXELIRI & Bevacizumab: '''<u>m</u>'''odified '''<u>XEL</u>'''ox (Capecitabine), '''<u>IRI</u>'''notecan, Bevacizumab
-===Regimen {{#subobject:b94028|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]
-|2013-2015
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FOLFIRI_.26_Bevacizumab_2|FOLFIRI & Bevacizumab]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV over 30 to 90 minutes once on day 1
-'''21-day cycles'''
-===References===
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29555258 PubMed] NCT01996306
-==Fluorouracil monotherapy {{#subobject:8ff0ed|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:a2b84b|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext Rougier et al. 1998 (V302)]
-|1995-1997
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Irinotecan_monotherapy_2|Irinotecan]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-''Note: this was one of three control regimens; see paper for details.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 250 to 300 mg/m<sup>2</sup>/day IV continuous infusion
-'''Continued indefinitely'''
-===References===
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9807986 PubMed]
-==FOLFIRI {{#subobject:7325e5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
-===Example orders===
-*[[Example orders for FOLFIRI in colon cancer]]
-===Regimen variant #1, lower-dose leucovorin {{#subobject:b1e6e2|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815882/ Lim et al. 2015 (SMC 2009-11-017)]
-|2010-2013
-| style="background-color:#1a9851" |Phase III (C)
-|FOLFIRI & Simvastatin
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given first'''
-'''14-day cycles'''
-===Regimen variant #2, higher-dose leucovorin {{#subobject:3cf53b|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2004.05.113 Tournigand et al. 2003]
-|1997-1999
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#mFOLFOX6_4|mFOLFOX6]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS15
-|-
-|[https://doi.org/10.1200/jco.2009.27.6055 Peeters et al. 2010 (20050181)]
-|2006-2008
-| style="background-color:#1a9851" |Phase III (C)
-|[[Colon_cancer,_RAS_wild-type#FOLFIRI_.26_Panitumumab|FOLFIRI & Panitumumab]]
-| style="background-color:#fc8d59" |Seems to have inferior PFS<sup>1</sup>
-|-
-|[https://doi.org/10.1200/JCO.2012.42.8201 Van Cutsem et al. 2012 (VELOUR)]
-|2007-2010
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFIRI_.26_Ziv-aflibercept|FOLFIRI & Ziv-aflibercept]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|[https://doi.org/10.1093/annonc/mdv012 Masi et al. 2015 (BEBYP)]
-|2008-2012
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFIRI_.26_Bevacizumab_2|FOLFIRI & Bevacizumab]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2815%2970127-0/fulltext Tabernero et al. 2015 (RAISE)]
-|2010-2013
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFIRI_.26_Ramucirumab|FOLFIRI & Ramucirumab]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]
-|2013-2015
-| style="background-color:#1a9851" |Phase III (C)
-|[[#CAPIRI_2|CAPIRI]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|}
-''<sup>1</sup>Reported efficacy for 20050181 is for wild-type KRAS, only, and is based on the 2014 update.''<br>
-''Note: BEBYP does not provide dosing details; this is the most commonly used variant of FOLFIRI.''
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-**In Tournigand et al. 2003, if no toxicity greater than grade 1 in cycles 1 & 2, increased to: 400 mg/m<sup>2</sup> IV bolus once on day 1, then 3000 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 3400 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> 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_4|mFOLFOX6]]
-===References===
-#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. [https://doi.org/10.1200/JCO.2004.05.113 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14657227 PubMed]
-#'''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. [https://doi.org/10.1200/jco.2009.27.6055 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20921462 PubMed] NCT00339183
-##'''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. [https://doi.org/10.1093/annonc/mdt523 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24356622 PubMed]
-#'''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. [https://www.thelancet.com/journals/lancetonc/article/PIIS1470204511701991/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/21903473 PubMed] NCT00126256
-<!-- Presented in part at the European Society for Medical Oncology 13th World Congress on Gastrointestinal Cancer, June 22-25, 2011, Barcelona, Spain; and the 2011 European Multidisciplinary Cancer Congress, September 24-27, 2011, Stockholm, Sweden. -->
-#'''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. [https://doi.org/10.1200/JCO.2012.42.8201 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22949147 PubMed] NCT00561470
-##'''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. [https://www.ejcancer.com/article/S0959-8049%2813%2900853-8/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/24140268 PubMed]
-##'''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. [https://www.geriatriconcology.net/article/S1879-4068(17)30140-6/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28807738 PubMed]
-#'''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. [https://doi.org/10.1093/annonc/mdv012 link to original article] '''does not contain protocol''' [https://pubmed.ncbi.nlm.nih.gov/25600568 PubMed] NCT00720512
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2815%2970127-0/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25877855 PubMed] NCT01183780
-##'''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. [https://doi.org/10.1093/annonc/mdw402 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091322/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27573561 PubMed]
-#'''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. [https://doi.org/10.1038/bjc.2015.371 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815882/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26505681 PubMed] NCT01238094
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29555258 PubMed] NCT01996306
-==FOLFIRI (L-Leucovorin) {{#subobject:7477e5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
-===Regimen {{#subobject:db9c30|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2004.05.113 Tournigand et al. 2003]
-|1997-1999
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#mFOLFOX6_4|mFOLFOX6]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS15
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]
-|2013-2015
-| style="background-color:#1a9851" |Phase III (C)
-|[[#CAPIRI_2|CAPIRI]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-**In Tournigand et al. 2003, if no toxicity greater than grade 1 in cycles 1 & 2, increased to: 400 mg/m<sup>2</sup> IV bolus once on day 1, then 3000 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 3400 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given first, with levoleucovorin'''
-'''14-day cycles'''
-====Subsequent treatment====
-*Tournigand et al. 2003, upon progression: [[#mFOLFOX6_4|mFOLFOX6]]
-===References===
-#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. [https://doi.org/10.1200/JCO.2004.05.113 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14657227 PubMed]
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29555258 PubMed] NCT01996306
-==FOLFIRI & Bevacizumab {{#subobject:bcdb7d|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI & Bevacizumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Bevacizumab
-===Regimen {{#subobject:548cd8a|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70477-1/fulltext Bennouna et al. 2012 (ML18147)]
-|2006-2010
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#FOLFIRI_3|FOLFIRI]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|[https://doi.org/10.1093/annonc/mdv012 Masi et al. 2015 (BEBYP)]
-|2008-2012
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#FOLFIRI_3|FOLFIRI]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]
-|2013-2015
-| style="background-color:#1a9851" |Phase III (C)
-|[[#CAPIRI-Bev_2|mXELIRI & Bevacizumab]]
-| style="background-color:#eeee01" |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/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given first, with leucovorin'''
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given second'''
-'''14-day cycles'''
-===References===
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70477-1/fulltext link to original article]  [https://pubmed.ncbi.nlm.nih.gov/23168366 PubMed]
-#'''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. [https://doi.org/10.1093/annonc/mdv012 link to original article] '''does not contain protocol''' [https://pubmed.ncbi.nlm.nih.gov/25600568 PubMed] NCT00720512
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29555258 PubMed] NCT01996306
-==FOLFIRI & Bevacizumab (L-Leucovorin) {{#subobject:bedg7d|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI & Bevacizumab: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Bevacizumab
-===Regimen variant #1, 200/2800/150/5 {{#subobject:5b2542|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478977/ Iwamoto et al. 2015 (EAGLE<sub>CRC</sub>)]
-|2009-2012
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFIRI_.26_Bevacizumab_.28L-Leucovorin.29_2|FOLFIRI & Bevacizumab]]; lower-dose bevacizumab (10 mg/kg)
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-''Note: this study should not be confused by the one of the same name for head & neck cancer.''
-====Chemotherapy====
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given second, with levoleucovorin'''
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV over 30 minutes once on day 1, '''given first'''
-'''14-day cycles'''
-===Regimen variant #2, 200/2800/180/5 {{#subobject:2c0ba3|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]
-|2013-2015
-| style="background-color:#1a9851" |Phase III (C)
-|[[#CAPIRI-Bev_2|mXELIRI & Bevacizumab]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given first, with levoleucovorin'''
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given second'''
-'''14-day cycles'''
-===References===
-#'''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. [https://doi.org/10.1093/annonc/mdv197 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478977/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25908603 PubMed] UMIN000002557
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29555258 PubMed] NCT01996306
-==FOLFIRI & Ramucirumab {{#subobject:pyr1|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI & Ramucirumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan & Ramucirumab
-===Regimen {{#subobject:pyv1|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#404040"
-|<small>'''FDA-recommended dose'''</small>
-|-
-|}
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2815%2970127-0/fulltext Tabernero et al. 2015 (RAISE)]
-|2010-2013
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#FOLFIRI_3|FOLFIRI]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''either given third or concurrently with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given second'''
-*[[Ramucirumab (Cyramza)]] 8 mg/kg IV over 60 minutes once on day 1, '''given first'''
-'''14-day cycles'''
-===References===
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2815%2970127-0/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25877855 PubMed] NCT01183780
-##'''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. [https://doi.org/10.1093/annonc/mdw402 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091322/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27573561 PubMed]
-==FOLFIRI & Ziv-aflibercept {{#subobject:615d3f|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI & Ziv-aflibercept: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Ziv-aflibercept
-===Regimen {{#subobject:29895|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2012.42.8201 Van Cutsem et al. 2012 (VELOUR)]
-|2007-2010
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#FOLFIRI_3|FOLFIRI]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|[https://www.futuremedicine.com/doi/10.2217/fon-2017-0669 Li et al. 2018 (AFLAME)]
-|2012-2014
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#FOLFIRI_3|FOLFIRI]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given second'''
-====Targeted therapy====
-*[[Ziv-aflibercept (Zaltrap)]] 4 mg/kg IV over 60 minutes once on day 1, '''given first'''
-====Supportive medications====
-*"Premedication with [[Atropine (Atropen)]] and [[:Category:Emesis_prevention|anti-emetics]] was permitted. [[:Category:Granulocyte_colony-stimulating_factors|Granulocyte-colony stimulating factor (G-CSF)]] was used according to the [https://doi.org/10.1200/jco.2006.06.4451 American Society of Clinical Oncology guidelines (2006)]."
-'''14-day cycles'''
-===References===
-<!-- Presented in part at the European Society for Medical Oncology 13th World Congress on Gastrointestinal Cancer, June 22-25, 2011, Barcelona, Spain; and the 2011 European Multidisciplinary Cancer Congress, September 24-27, 2011, Stockholm, Sweden. -->
-#'''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. [https://doi.org/10.1200/JCO.2012.42.8201 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22949147 PubMed] NCT00561470
-##'''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. [https://www.ejcancer.com/article/S0959-8049%2813%2900853-8/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24140268 PubMed]
-##'''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. [https://www.geriatriconcology.net/article/S1879-4068(17)30140-6/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28807738 PubMed]
-#'''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. [https://www.futuremedicine.com/doi/10.2217/fon-2017-0669 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30117334 PubMed] NCT01661270
-==FOLFOX4 {{#subobject:9034b5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:78b107|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2003.11.126 Rothenberg et al. 2003]
-|2000-2001
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|1. LV5FU2<br> 2. Oxaliplatin
-| style="background-color:#1a9850" |Superior TTP
-|-
-|[https://doi.org/10.1093/annonc/mdn370 Rothenberg et al. 2008]
-|2003-2005
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#CapeOx_3|XELOX]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''14-day cycles'''
-===References===
-#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. [https://doi.org/10.1200/JCO.2003.11.126 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12775730 PubMed]
-#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. [https://doi.org/10.1093/annonc/mdn370 link to original article] '''refers to de Gramont et al. 2000 protocol''' [https://pubmed.ncbi.nlm.nih.gov/18550577 PubMed]
-==mFOLFOX6 {{#subobject:9a3dc9|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Example orders===
-*[[Example orders for mFOLFOX 6 in colon cancer]]
-===Regimen {{#subobject:f71fa5|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1093/annonc/mdv012 Masi et al. 2015 (BEBYP)]
-|2008-2012
-| style="background-color:#1a9851" |Phase III (C)
-|[[#mFOLFOX6-B_3|mFOLFOX6-B]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-''Note: BEBYP does not provide dosing details; this is the most commonly used variant of mFOLFOX6.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''14-day cycles'''
-===References===
-#'''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. [https://doi.org/10.1093/annonc/mdv012 link to original article] '''does not contain protocol''' [https://pubmed.ncbi.nlm.nih.gov/25600568 PubMed] NCT00720512
-==mFOLFOX6-B {{#subobject:46965e|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6-B: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-===Regimen {{#subobject:61186f|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1093/annonc/mdv012 Masi et al. 2015 (BEBYP)]
-|2008-2012
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#mFOLFOX6_4|mFOLFOX6]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-''Note: BEBYP does not provide dosing details; this is the most commonly used variant of mFOLFOX6.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1
-'''14-day cycles'''
-===References===
-#'''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. [https://doi.org/10.1093/annonc/mdv012 link to original article] '''does not contain protocol''' [https://pubmed.ncbi.nlm.nih.gov/25600568 PubMed] NCT00720512
-==Irinotecan monotherapy {{#subobject:d4d4f9|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Example orders===
-*[[Example orders for Irinotecan (Camptosar) in colon cancer]]
-===Regimen variant #1, 100 mg/m<sup>2</sup>, 4 weeks out of 6 {{#subobject:77bz17|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819990215%2985%3A4%3C786%3A%3AAID-CNCR5%3E3.0.CO%3B2-9 Rothenberg et al. 1999]
-|1994
-| style="background-color:#91cf61" |Phase II (RT)
-|-
-|}
-''Note: this was a mid-protocol dose amendment for excess toxicity.''
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-'''42-day cycles'''
-===Regimen variant #2, 125 mg/m<sup>2</sup>, 4 weeks out of 6 {{#subobject:73a017|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.1996.14.4.1128 Rothenberg et al. 1996]
-|NR
-| style="background-color:#91cf61" |Phase II (RT)
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://doi.org/10.1200/JCO.1997.15.8.2910 Pitot et al. 1997]
-|1993-1994
-| style="background-color:#91cf61" |Phase II (RT)
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://doi.org/10.1200/jco.2003.08.058 Fuchs et al. 2003]
-|1998-2001
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Irinotecan_monotherapy_2|Irinotecan]]; every 3 weeks
-| style="background-color:#ffffbf" |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====
-*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22
-'''42-day cycles'''
-===Regimen variant #3, 250 mg/m<sup>2</sup> q3wk {{#subobject:7c1d8f|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.2008.17.1249 Haller et al. 2008]
-|2001-2004
-| style="background-color:#1a9851" |Phase III (C)
-|[[#IROX_2|IROX]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|}
-''This starting dose was intended for patients who were at least 65 years old, had prior abdomen/pelvic radiation, or had elevated bilirubin. Dose escalations in the absence of grade 2 or higher toxicities were allowed.''
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-'''21-day cycles'''
-===Regimen variant #4, 300 mg/m<sup>2</sup> q3wk {{#subobject:190e25|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext Rougier et al. 1998 (V302)]
-|1995-1997
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
-|[[#Fluorouracil_monotherapy_2|CI 5-FU]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[https://doi.org/10.1200/jco.2003.08.058 Fuchs et al. 2003]
-|1998-2001
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Irinotecan_monotherapy_2|Irinotecan]]; 4 weeks out of 6
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS12
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698019/ Kim et al. 2009 (N9841)]
-|1999-2003
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFOX4_4|FOLFOX4]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|[https://doi.org/10.1200/jco.2007.13.1193 Sobrero et al. 2008 (EPIC)]
-|2003-2006
-| style="background-color:#1a9851" |Phase III (C)
-|[[Colon_cancer,_RAS_wild-type#Irinotecan_.26_Cetuximab|Irinotecan & Cetuximab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of 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 [[Performance status|ECOG performance status]] 2 or more, or had prior pelvic radiation. Patients in N9841 had not previously received irinotecan or oxaliplatin.''
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 300 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-'''21-day cycles'''
-===Regimen variant #5, 350 mg/m<sup>2</sup> q3wk {{#subobject:627110|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.1997.15.1.251 Rougier et al. 1997]
-|1992-1993
-| style="background-color:#91cf61" |Phase II (RT)
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext Rougier et al. 1998 (V302)]
-|1995-1997
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
-|[[#Fluorouracil_monotherapy_2|CI 5-FU]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[https://doi.org/10.1200/JCO.2004.01.005 Lal et al. 2004]
-|1997-2002
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Irinotecan_monotherapy_2|Irinotecan]] x 8
-| style="background-color:#ffffbf" |Did not meet primary endpoint of FFS
-|-
-|[https://doi.org/10.1200/jco.2003.08.058 Fuchs et al. 2003]
-|1998-2001
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Irinotecan_monotherapy_2|Irinotecan]]; 4 weeks out of 6
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS12
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698019/ Kim et al. 2009 (N9841)]
-|1999-2003
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFOX4_4|FOLFOX4]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|[https://doi.org/10.1200/jco.2008.17.1249 Haller et al. 2008]
-|2001-2004
-| style="background-color:#1a9851" |Phase III (C)
-|[[#IROX_2|IROX]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext Koopman et al. 2007 (CAIRO)]
-|2003-2004
-| style="background-color:#1a9851" |Phase III (C)
-|[[Complex_multipart_regimens#CAIRO|See link]]
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#CAIRO|See link]]
-|-
-|[https://doi.org/10.1200/jco.2007.13.1193 Sobrero et al. 2008 (EPIC)]
-|2003-2006
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Irinotecan_.26_Cetuximab|Irinotecan & Cetuximab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of 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====
-*CAIRO: [[#Capecitabine_monotherapy_2|Capecitabine]], with progression
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 350 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-====Supportive medications====
-*(varied depending on reference):
-*"Standard regimens of [[:Category:Emesis_prevention|antiemetics]], [[Atropine (Atropen)]], and intensive [[Loperamide (Imodium)]]," but no prophylactic [[Atropine (Atropen)]] allowed on cycle 1 day 1
-'''21-day cycles'''
-====Subsequent treatment====
-*CAIRO, with progression: [[#CapeOx_4|CapeOx]]
-===References===
-#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. [https://doi.org/10.1200/JCO.1996.14.4.1128 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/8648367 PubMed]
-#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. [https://doi.org/10.1200/JCO.1997.15.1.251 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8996150 PubMed]
-#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. [https://doi.org/10.1200/JCO.1997.15.8.2910 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/9256135 PubMed]
-#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. [https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819990215%2985%3A4%3C786%3A%3AAID-CNCR5%3E3.0.CO%3B2-9 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10091755 PubMed]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/9807986 PubMed]
-#Fuchs CS, Moore MR, Harker G, Villa L, Rinaldi D, Hecht JR. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003 Mar 1;21(5):807-14. [https://doi.org/10.1200/jco.2003.08.058 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12610178 PubMed]
-#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. [https://doi.org/10.1200/JCO.2004.01.005 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15284252 PubMed]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17630036 PubMed] NCT00312000
-<!-- Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, June 2005; the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2006; safety and efficacy results from this study were presented at the Annual Meeting of the American Association for Cancer Research, April 14-18, 2007, Los Angeles, CA; and the quality of life results from this study were presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 2007. -->
-#'''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. [https://doi.org/10.1200/jco.2007.13.1193 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18390971 PubMed]
-#Haller DG, Rothenberg ML, Wong AO, Koralewski PM, Miller WH Jr, Bodoky G, Habboubi N, Garay C, Olivatto LO. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008 Oct 1;26(28):4544-50. [https://doi.org/10.1200/jco.2008.17.1249 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18824706 PubMed]
-#'''N9841:''' Kim GP, Sargent DJ, Mahoney MR, Rowland KM Jr, Philip PA, Mitchell E, Mathews AP, Fitch TR, Goldberg RM, Alberts SR, Pitot HC; NCCTG. 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. [https://doi.org/10.1200/JCO.2008.20.4552 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698019/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19380443 PubMed] NCT00005036
-==IRIS {{#subobject:7f7223|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-IRIS: '''<u>IRI</u>'''notecan & '''<u>S</u>'''-1
-===Regimen {{#subobject:dd01b1|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1016/s1470-2045(10)70181-9 Muro et al. 2010 (FIRIS)]
-|2006-2008
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FOLFIRI_3|FOLFIRI]]
-| style="background-color:#eeee01" |Non-inferior OS<sup>1</sup>
-|-
-|}
-''<sup>1</sup>Reported efficacy is based on the 2014 update.''
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV once per day on days 1 & 15
-*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:
-**BSA less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14
-**BSA between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14
-**BSA at least 1.5 m<sup>2</sup>: 60 mg PO twice per day on days 1 to 14
-'''28-day cycles'''
-===References===
-#'''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. [https://doi.org/10.1016/s1470-2045(10)70181-9 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20708966 PubMed] NCT00284258
-##'''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. [https://link.springer.com/article/10.1007%2Fs00432-014-1783-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25106731 PubMed]
-==IROX {{#subobject:2c150d|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-IROX: '''<u>IR</u>'''inotecan & '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:78e355|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/jco.2008.17.1249 Haller et al. 2008]
-|2001-2004
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Irinotecan_monotherapy_2|Irinotecan]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|}
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given second'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''21-day cycles'''
-===References===
-#Haller DG, Rothenberg ML, Wong AO, Koralewski PM, Miller WH Jr, Bodoky G, Habboubi N, Garay C, Olivatto LO. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008 Oct 1;26(28):4544-50. [https://doi.org/10.1200/jco.2008.17.1249 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18824706 PubMed]
-=Advanced or metastatic disease, third-line therapy=
-==CapeOx {{#subobject:fed770|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin
-===Example orders===
-*[[Example orders for CapeOx (XELOX) in colon cancer]]
-===Regimen {{#subobject:09dff5|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext Koopman et al. 2007 (CAIRO)]
-|2003-2004
-| style="background-color:#1a9851" |Phase III (C)
-|[[Complex_multipart_regimens#CAIRO|See link]]
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#CAIRO|See link]]
-|-
-|}
-====Preceding treatment====
-*[[#Irinotecan_monotherapy_2|Irinotecan]], with progression
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycles'''
-===References===
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17630036 PubMed] NCT00312000
-==FOLFIRI {{#subobject:f7001b|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
-===Example orders===
-*[[Example orders for FOLFIRI in colon cancer]]
-===Regimen {{#subobject:31fcbe|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ejcancer.com/article/S0959-8049(99)00150-1/fulltext André et al. 1999]
-| style="background-color:#91cf61" |Non-randomized
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-**In André et al. 1999, the continuous infusion dose could be increased from 1200 mg/m<sup>2</sup>/day to 1500 mg/m<sup>2</sup>/day if there were no toxicities higher than grade 1
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first, with leucovorin'''
-'''14-day cycles'''
-===References===
-#André T, Louvet C, Maindrault-Goebel F, Couteau C, Mabro M, Lotz JP, Gilles-Amar V, Krulik M, Carola E, Izrael V, de Gramont A. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer; GERCOR. Eur J Cancer. 1999 Sep;35(9):1343-7. [https://www.ejcancer.com/article/S0959-8049(99)00150-1/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10658525 PubMed]
-==Regorafenib monotherapy {{#subobject:b6f523|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:7ab205|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30027-0/fulltext Eng et al. 2019 (IMblaze370)]
-|2016-2017
-| style="background-color:#1a9851" |Phase III (C)
-|1. Atezolizumab<br> 2. Atezolizumab & Cobimetinib
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Targeted therapy====
-*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21
-'''28-day cycles'''
-===References===
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30027-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/31003911 PubMed] NCT02788279
-=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.''
-==Capecitabine monotherapy {{#subobject:6jgu1e|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:b164ia|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|(X-PECT)
-|2010-NR
-| style="background-color:#1a9851" |Phase III (C)
-| Capecitabine & Perifosine
-| style="background-color:#d3d3d3" |Not reported
-|-
-|}
-''Note: this trial has not yet been published; dosing details are from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-'''21-day cycles'''
-===References===
-#'''X-PECT:''' NCT01097018
-==Durvalumab & Tremelimumab {{#subobject:8bb0ed|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:c0f84b|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7206536/ Chen et al. 2020 (NCIC CTG CO.26)]
-|2016-2017
-| style="background-color:#1a9851" |Randomized Phase II (E-esc)
-| Best supportive care
-| style="background-color:#d9ef8b" |Might have superior OS
-|-
-|}
-''Eligibility criteria: advanced CRC progressed on all available standard systemic therapies, ECOG PS 0-1. PD-L1, TMB, MSI status were NOT used as inclusion criteria''
-====Immunotherapy====
-*[[Durvalumab (Imfinzi)]] 1500 mg IV once on day 1
-*[[Tremelimumab (ticilimumab)]] as follows:
-**Cycles 1 to 4: 75 mg IV once on day 1
-'''28-day cycles'''
-===References===
-#'''NCIC CTG CO.26:''' Chen EX, Jonker DJ, Loree JM, Kennecke HF, Berry SR, Couture F, Ahmad CE, Goffin JR, Kavan P, Harb M, Colwell B, Samimi S, Samson B, Abbas T, Aucoin N, AUbin F, Koski S, Wei AC, Magoski NM, Tu D, O'Callaghan CJ. Effect of Combined Immune Checkpoint Inhibition vs Best Supportive Care Alone in Patients With Advanced Colorectal Cancer: The Canadian Cancer Trials Group CO.26 Study. JAMA Oncol. 2020;6(6):831–838. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2765332 link to article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7206536/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32379280/ PubMed] NCT02870920
-==Fluorouracil monotherapy {{#subobject:8bb0ed|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:c0f84b|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2010.28.5643 Hendlisz et al. 2010 (Sir-Spheres1)]
-|2004-2007
-| style="background-color:#1a9851" |Phase III (C)
-|5-FU & Radioembolization
-| style="background-color:#fc8d59" |Seems to have inferior TTP
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion over 14 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
-'''21-day cycles'''
-===References===
-#'''Sir-Spheres1:''' 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. [https://doi.org/10.1200/JCO.2010.28.5643 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20567019 PubMed] NCT00199173
-==FOLFOX4 {{#subobject:be6f3b|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:ecdc32|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://doi.org/10.1200/JCO.2006.09.6305 Giantonio et al. 2007 (ECOG E3200)]
-|rowspan=2|2001-2003
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|2. Bevacizumab
-| style="background-color:#d3d3d3" |Not reported
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698019/ Kim et al. 2009 (N9841)]
-|1999-2003
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Irinotecan_monotherapy_2|Irinotecan]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|[https://doi.org/10.1200/JCO.2010.29.5436 Van Cutsem et al. 2011 (CONFIRM 2)]
-|2003-2004
-| style="background-color:#1a9851" |Phase III (C)
-|FOLFOX4 & Vatalanib
-| style="background-color:#ffffbf" |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/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''14-day cycles'''
-===References===
-#'''ECOG E3200:''' Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd; [[Study_Groups#ECOG|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. [https://doi.org/10.1200/JCO.2006.09.6305 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17442997 PubMed]
-#'''N9841:''' Kim GP, Sargent DJ, Mahoney MR, Rowland KM Jr, Philip PA, Mitchell E, Mathews AP, Fitch TR, Goldberg RM, Alberts SR, Pitot HC; NCCTG. 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. [https://doi.org/10.1200/JCO.2008.20.4552 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698019/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19380443 PubMed] NCT00005036
-#'''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. [https://doi.org/10.1200/JCO.2010.29.5436 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21464401 PubMed] NCT00056446
-==FOLFOX4 (L-Leucovorin) {{#subobject:be17hb|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX4: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:16c59a|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2010.29.5436 Van Cutsem et al. 2011 (CONFIRM 2)]
-|2003-2004
-| style="background-color:#1a9851" |Phase III (C)
-|FOLFOX4 & Vatalanib
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-''Note: these patients had not previously received oxaliplatin.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''14-day cycles'''
-===References===
-#'''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. [https://doi.org/10.1200/JCO.2010.29.5436 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21464401 PubMed] NCT00056446
-==FOLFOX4 & Bevacizumab {{#subobject:8228ca|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX4 & Bevacizumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-===Regimen {{#subobject:2d2be1|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://doi.org/10.1200/JCO.2006.09.6305 Giantonio et al. 2007 (ECOG E3200)]
-| rowspan="2"|2001-2003
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-esc)
-|1. [[#FOLFOX4_5|FOLFOX4]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|2. Bevacizumab
-| style="background-color:#d3d3d3" |Not reported
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV over 30 to 90 minutes once on day 1
-'''14-day cycles'''
-===References===
-#'''ECOG E3200:''' Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd; [[Study_Groups#ECOG|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. [https://doi.org/10.1200/JCO.2006.09.6305 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17442997 PubMed]
-==FULV & Bevacizumab {{#subobject:83ygca|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FULV & Bevacizumab: 5-'''<u>FU</u>''', '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid), Bevacizumab
-===Regimen variant #1, Roswell Park backbone {{#subobject:2d7yqg|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/JCO.2005.05.1573 Chen et al. 2006 (TRC-301)]
-|2003
-| style="background-color:#91cf61" |Phase II (RT)
-|-
-|}
-''Note: this is based on the Roswell Park regimen backbone.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
-*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1, 15, 29, 43
-'''56-day cycles'''
-===Regimen variant #2, de Gramont backbone {{#subobject:2d79ug|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/JCO.2005.05.1573 Chen et al. 2006 (TRC-301)]
-|2003
-| style="background-color:#91cf61" |Phase II (RT)
-|-
-|}
-''Note: this is based on the de Gramont regimen backbone.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once per day on days 1 & 2
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1 & 15
-'''14-day cycles'''
-===References===
-#'''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. [https://doi.org/10.1200/JCO.2005.05.1573 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16849749 PubMed]
-==Ipilimumab & Nivolumab {{#subobject:517ff0|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:3a481c|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/JCO.2017.76.9901 Overman et al. 2018 (CheckMate 142)]
-|2015-2016
-| style="background-color:#91cf61" |Phase II (RT)
-|-
-|}
-====Immunotherapy====
-*[[Ipilimumab (Yervoy)]] as follows:
-**Cycles 1 to 4: 1 mg/kg IV once on day 1
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
-'''21-day cycle for 4 cycles, then 14-day cycles'''
-===References===
-# '''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. [https://doi.org/10.1200/JCO.2017.76.9901 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29355075 PubMed] NCT02060188
-==Irinotecan monotherapy {{#subobject:ea8bb0|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Example orders===
-*[[Example orders for Irinotecan (Camptosar) in colon cancer]]
-===Regimen {{#subobject:37d8df|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2898%2902309-5/fulltext Cunningham et al. 1998 (V301)]
-|1995-NR
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[Colon_cancer_-_null_regimens#Best_supportive_care_2|Supportive care]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|}
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 350 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-====Supportive medications====
-*(varied depending on reference):
-*"Standard regimens of [[:Category:Emesis_prevention|antiemetics]], [[Atropine (Atropen)]], and intensive [[Loperamide (Imodium)]]," but no prophylactic [[Atropine (Atropen)]] allowed on cycle 1 day 1
-'''21-day cycles'''
-===References===
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2898%2902309-5/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9807987 PubMed]
-==Nivolumab monotherapy {{#subobject:ac98g4|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:91abt2|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207072/ Overman et al. 2017 (CheckMate 142)]
-|2014-2016
-| style="background-color:#91cf61" |Phase II (RT)
-|-
-|}
-====Biomarker eligibility criteria====
-*dMMR or MSI-H colorectal cancer.
-====Immunotherapy====
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
-'''14-day cycles'''
-===References===
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30422-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207072/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/28734759 PubMed] NCT02060188
-==Pembrolizumab monotherapy {{#subobject:ac2c94|Regimen=1}}==
-{{#subobject:fe5344|Variant=1}}
-{{#subobject:B34AD4|Variant=1}}
-{{:Pembrolizumab (Keytruda) for unresectable or metastatic colon cancer}}
-==Regorafenib monotherapy {{#subobject:b6f696|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen variant #1, Standard Dosing {{#subobject:77bz17|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961900-X/fulltext Grothey et al. 2012 (CORRECT)]
-|2010-2011
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[Colon_cancer_-_null_regimens#Placebo_3|Placebo]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70156-7/fulltext Li et al. 2015 (CONCUR)]
-|2012-2013
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Colon_cancer_-_null_regimens#Placebo_3|Placebo]]
-| style="background-color:#1a9850" |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 {{#subobject:55bz17|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30272-4/fulltext Bekaii-Saab et al. 2019 (ReDOS)]
-| style="background-color:#1a9851" |Randomized Phase II (E-esc)
-|[[#Regorafenib_monotherapy_2|Regorafenib]]; standard dosing
-| style="background-color:#91cf60" |Seems to have superior OS
-| style="background-color:#1a9850" |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===
-<!-- # '''Abstract:''' Axel Grothey, Alberto F. Sobrero, Salvatore Siena, Alfredo Falcone, Marc Ychou, Heinz-Josef Lenz, Takayuki Yoshino, Frank Cihon, Andrea Wagner, Eric Van Cutsem, on behalf of the CORRECT Study Team. Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. 2012 ASCO Gastrointestinal Cancers Symposium abstract LBA385 [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=115&abstractID=87795 link to abstract] '''contains verified protocol''' -->
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961900-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23177514 PubMed] NCT01103323
-##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/273 Project Data Sphere]
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70156-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/25981818 PubMed] NCT01584830
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30272-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/25981818 PubMed] NCT02368886
-==Trifluridine and tipiracil monotherapy {{#subobject:pyr2|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:pyv2|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70345-5/fulltext Yoshino et al. 2012]
-|2009-2010
-| style="background-color:#1a9851" |Randomized Phase II (E-esc)
-|[[Colon_cancer_-_null_regimens#Placebo_3|Placebo]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1414325 Mayer et al. 2015 (RECOURSE)]
-|2012-2013
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[Colon_cancer_-_null_regimens#Placebo_3|Placebo]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|[https://doi.org/10.1200/JCO.2017.74.3245 Xu et al. 2017 (TERRA)]
-|2013-2015
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Colon_cancer_-_null_regimens#Placebo_3|Placebo]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-====Chemotherapy====
-*[[Trifluridine and tipiracil (Lonsurf)]] 35 mg/m<sup>2</sup> PO twice per day, used within 1 hour after the morning and evening meals on days 1 to 5, 8 to 12
-'''28-day cycles'''
-===References===
-#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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70345-5/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22951287 PubMed] JapicCTI-090880
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1414325 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25970050 PubMed] NCT01607957
-##'''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. [https://doi.org/10.1016/j.ejca.2017.10.009 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29274618 PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2017.74.3245 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29215955 PubMed] NCT01955837
-==Trifluridine and tipiracil & Bevacizumab {{#subobject:86sdfg|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:9nvcks|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1016/s1470-2045(19)30827-7 Pfeiffer et al. 2020]
-|2017-2018
-| style="background-color:#1a9851" |Randomized Phase II (E-esc)
-|[[#Trifluridine_and_tipiracil_monotherapy|Trifluridine and tipiracil]]
-| style="background-color:#1a9850" |Superior PFS
-|}
-====Chemotherapy====
-*[[Trifluridine and tipiracil (Lonsurf)]] 35 mg/m<sup>2</sup> PO twice per day, used within 1 hour after the morning and evening meals on days 1 to 5, 8 to 12
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1, 15, 29, 43
-'''28-day cycles'''
-===References===
-# 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://doi.org/10.1016/s1470-2045(19)30827-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31999946/ PubMed] EudraCT 2016-005241-23
 [[Category:Colon cancer regimens]]
 [[Category:Disease-specific pages]]
 [[Category:Colorectal cancers]]

Difference between revisions of "Colon cancer"

Latest revision as of 01:00, 29 June 2024

Guidelines

ASCO

ESMO

NCCN

Perioperative therapy

mFOLFOX6 (L-Leucovorin)

Neoadjuvant

Chemotherapy

Definitive

Local therapy

Adjuvant

Chemotherapy

References

Adjuvant therapy

Capecitabine monotherapy

Regimen

Preceding treatment

Chemotherapy

References

CapeOx

Example orders

Regimen variant #1, 3 months

Preceding treatment

Chemotherapy

Regimen variant #2, 6 months

Preceding treatment

Chemotherapy

References

FLOX

Example orders

Regimen

Preceding treatment

Chemotherapy

References

FOLFOX4

Regimen

Preceding treatment

Chemotherapy

References

mFOLFOX6

Example orders

Regimen

Preceding treatment

Chemotherapy

References

mFOLFOX6 (L-Leucovorin)

Example orders

Regimen variant #1, 3 months, 200 mg/m2 L-LCV

Preceding treatment

Chemotherapy

Regimen variant #2, 6 months, 200 mg/m2 L-LCV

Preceding treatment

Chemotherapy

References

FULV

Example orders

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

Preceding treatment

Chemotherapy

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

Preceding treatment

Chemotherapy

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

Preceding treatment

Chemotherapy

Regimen variant #4, 1850/100 ("Mayo Clinic regimen")

Preceding treatment

Chemotherapy

Regimen variant #5, 1850/2500 ("NCI schedule")

Preceding treatment

Chemotherapy

Regimen variant #6, 2000/400 ("de Gramont regimen"/LV5FU2)

Preceding treatment

Chemotherapy

Regimen variant #7, 2000/1000

Preceding treatment

Chemotherapy

Regimen variant #8, 2125/100 ("Mayo Clinic regimen")

Regimen variant #1, 3 months, 200 mg/m² L-LCV

Regimen variant #2, 6 months, 200 mg/m² L-LCV