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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. link to PMC article 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in abstract have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 varying durations: 3 cycles (NSABP C-07); 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)	Not reported-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)	Not reported-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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in abstract have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in abstract have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in abstract have been reviewed by our editors 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 dosing details in abstract have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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: In ACTS-CC, this dosing was used for patients with BSA less than 1.17 m².

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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in abstract have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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:50%;"
+<span id="BackToTop"></span>
-!colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c"|'''Section 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">
-|-
+[[#top|Back to Top]]
-|style="background-color:#F0F0F0"|[[File:nkv.jpg|frameless|upright=0.3|center]]
+</div>
-|<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>Chicago, IL</big>
+{{#lst:Editorial board transclusions|gi}}
-|-
+''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>'''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.
-''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]]. If you still can't find it, please let us know so we can add it!''
+*See the [[Colon_cancer,_RAS_wild-type|'''RAS wild-type page''']] for biomarker-specific adjuvant regimens.
-<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.
-*See the [[Rectal_cancer|'''rectal cancer page''']] for regimens specific to rectal cancer.
-*See the [[Colon_cancer,_KRAS_wild-type|'''KRAS wild-type page''']] for biomarker-specific regimens.</big>
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
@@ Line 16: / Line 13: @@
 |}
 {{TOC limit|limit=3}}
 =Guidelines=
-==[http://www.esmo.org/ ESMO]==
+'''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.'''
-*'''2016:''' [http://annonc.oxfordjournals.org/content/27/8/1386.full.pdf+html ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.] [https://www.ncbi.nlm.nih.gov/pubmed/27380959 PubMed]
+==[https://www.asco.org/ ASCO]==
-*'''2013:''' [http://annonc.oxfordjournals.org/content/24/suppl_6/vi64.full.pdf+html Early Colon Cancer: ESMO Clinical Practice Guidelines] [https://www.ncbi.nlm.nih.gov/pubmed/24078664 PubMed]
+*'''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]
-*'''2013:''' [http://annonc.oxfordjournals.org/content/24/suppl_6/vi73.full.pdf+html Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines.] [https://www.ncbi.nlm.nih.gov/pubmed/23813931 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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/32702383 PubMed]
+**'''2013:''' Labianca et al. [https://doi.org/10.1093/annonc/mdt354 Early Colon Cancer: ESMO Clinical Practice Guidelines] [https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/31378807 PubMed]
-==[http://www.jsccr.jp/en/index.html Japanese Society for Cancer of the Colon and Rectum]==
+==NCCN==
-*'''2016:''' [https://link.springer.com/article/10.1007%2Fs10147-017-1101-6 Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer] [https://www.ncbi.nlm.nih.gov/pubmed/28349281 PubMed]
+*[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://www.ncbi.nlm.nih.gov/pmc/articles/PMC8613831/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19764149/ PubMed]
-==[https://www.nccn.org/ NCCN]==
+=Perioperative therapy=
-*[https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf NCCN Guidelines - Colon Cancer]
+==mFOLFOX6 (L-Leucovorin) {{#subobject:8uy6d7|Regimen=1}}==
+mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
+<div class="toccolours" style="background-color:#c8a2c8">
+{| 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC10022855/ Morton et al. 2023 (FOxTROT)]
+|2008-05-15 to 2016-12-23
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#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)
+|-
+|}
+''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">
+===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] '''dosing details in manuscript have been reviewed by our editors''' [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" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 20%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Dates of enrollment
-!style="width: 25%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://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)]
-|style="background-color:#1a9851"|Phase III (E)
+|1998-2001
-|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
-| style="background-color:#91cf60" |Seems to have superior OS (*)
+|[[#FULV|FULV]]
+| 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)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6461756/ Tomita et al. 2019 (JFMC37-0801)]
-|style="background-color:#1a9851"|Phase III (C)
+|2008-09 to 2009-12
-|Capecitabine & Bevacizumab
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#ffffbf"|Seems not superior
+|[[#Capecitabine_monotherapy|Capecitabine]] x 12 mo
+| style="background-color:#fee08b" |Might have inferior DFS
 |-
 |}
-''Note: efficacy for X-ACT is based on the 2011 update.''
+''<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
+*[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14
+*[[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. [http://www.nejm.org/doi/full/10.1056/NEJMoa043116 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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] '''dosing details in manuscript have been reviewed by our editors''' [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://academic.oup.com/annonc/article/23/5/1190/192299 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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]
-# '''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://www.ncbi.nlm.nih.gov/pubmed/27660192 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] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6461756/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30833647/ PubMed]
 ==CapeOx {{#subobject:cf9acc|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+CapeOx: '''<u>Cape</u>'''citabine & '''<u>Ox</u>'''aliplatin
-|-
-|[[#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">
-===Variant #1, 3 months {{#subobject:205ad6|Variant=1}}===
+===Regimen variant #1, 3 months {{#subobject:jgui19a|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 20%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Dates of enrollment
-!style="width: 25%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+!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)]
-|style="background-color:#1a9851"|Phase III (E)
+|2012-08-01 to 2014-06-30
-|CAPOX x 6 mo
+| style="background-color:#1a9851" |Phase 3 (E-de-esc)
-|style="background-color:#eeee01"|Seems to have non-inferior DFS
+|1a. [[#CapeOx|CapeOx]] x 6 mo<br>1b. [[#mFOLFOX6|mFOLFOX6]] x 6 mo
+| 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
+*[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO BID on days 1 to 14
+*[[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>
-===Variant #2, 6 months {{#subobject:1ef938|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Regimen variant #2, 6 months {{#subobject:1ef938|Variant=1}}===
-!style="width: 25%"|Study
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Study
-!style="width: 25%"|Comparator
+!style="width: 20%"|Dates of enrollment
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/25/1/102.long Schmoll et al. 2007 (XELOXA)]
+|[https://doi.org/10.1200/jco.2006.08.1075 Schmoll et al. 2007 (XELOXA)]
-|style="background-color:#1a9851"|Phase III (E)
+|2003-04 to 2004-10
-|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
-|style="background-color:#91cf60"|Seems to have superior OS (*)
+|[[#FULV|FULV]]
+| 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.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)]
-|style="background-color:#1a9851"|Phase III (C)
+|2012-08-01 to 2014-06-30
-|CAPOX x 3 mo
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#eeee01"|Seems to have non-inferior DFS
+|1a. [[#CapeOx|CapeOx]] x 3 mo<br>1b. [[#mFOLFOX6|mFOLFOX6]] x 3 mo
+| style="background-color:#eeee01" |Seems to have non-inferior DFS
 |-
 |}
-''Note: Efficacy for XELOXA is based on the 2015 update.''
+''<sup>1</sup>Reported efficacy for XELOXA is based on the 2015 update.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*Surgery
+*[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO BID on days 1 to 14
+*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-**Some references specify starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
+**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. [http://jco.ascopubs.org/content/25/1/102.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17194911 PubMed]
+#'''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] '''dosing details in manuscript have been reviewed by our editors''' [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. [http://jco.ascopubs.org/content/29/11/1465.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/33/32/3733.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1713709 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29590544 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]
-# '''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://www.ncbi.nlm.nih.gov/pubmed/29611518 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]
-==Fluorouracil & Folinic acid {{#subobject:a93a|Regimen=1}}==
+#'''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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/31513248/ PubMed] UMIN000008543
-{| class="wikitable" style="float:right; margin-left: 5px;"
+##'''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]
-|-
+#'''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]
-|[[#top|back to top]]
+#'''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]
-FULV: 5-'''<u>FU</u>''' & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid)
-===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]]
-===Variant #1, 5-FU & high-dose Leucovorin (Roswell Park regimen/HDLV) {{#subobject:489be0|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.1993.11.10.1879 Wolmark et al. 1993 (NSABP C-03)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[Colon_cancer_-_historical#MOF|MOF]]
-|style="background-color:#1a9850"|Superior OS
-|-
-|rowspan=3|[http://jco.ascopubs.org/content/23/34/8671.long Haller et al. 2005 (Intergroup 0089)]
-|rowspan=3 style="background-color:#1a9851"|Phase III (E)
-|[[#Fluorouracil_.26_Folinic_acid|Low-dose 5-FU & Folinic acid]]
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|LDLV & Levamisole
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|5-FU & Levamisole
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[http://jco.ascopubs.org/content/24/13/2059.long Lembersky et al. 2006 (NSABP C-06)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Tegafur.2C_Uracil.2C_Folinic_acid|Tegafur, Uracil, Folinic acid]]
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[http://jco.ascopubs.org/content/25/1/102.long Schmoll et al. 2007 (XELOXA)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#CapeOx.2C_XELOX|CapeOx]]
-|style="background-color:#fc8d59"|Seems to have inferior OS
-|-
-|[http://jco.ascopubs.org/content/25/16/2198.full Kuebler et al. 2007 (NSABP C-07)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#FLOX|FLOX]]
-|style="background-color:#d73027"|Inferior DFS
-|-
-|}
-====Preceding treatment====
-*Surgery
-====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, '''given first'''
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV push once per day on days 1, 8, 15, 22, 29, 36; '''1 hour after start of leucovorin'''
-'''8-week cycle for 3 to 6 cycles'''
-===Variant #2, 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV) {{#subobject:4bd336|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-||[http://www.nejm.org/doi/full/10.1056/NEJMoa043116 Twelves et al. 2005 (X-ACT)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Capecitabine_monotherapy|Capecitabine]]
-|style="background-color:#fc8d59"|Seems to have inferior OS (*)
-|-
-|[http://jco.ascopubs.org/content/25/1/102.long Schmoll et al. 2007 (XELOXA)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#CapeOx|XELOX]]
-|style="background-color:#fc8d59"|Seems to have inferior OS
-|-
-|}
-''Note: efficacy for X-ACT is based on the 2011 update.''
-====Preceding treatment====
-*Surgery
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV push once per day on days 1 to 5, '''given before before 5-FU'''
-*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV push once per day on days 1 to 5
-'''28-day cycle for 6 cycles'''
-===Variant #3, 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV) {{#subobject:e24014|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/15/1/246.long O'Connell et al. 1997]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Observation|Observation]]
-|style="background-color:#91cf60"|Seems to have superior OS
-|-
-|rowspan=3|[http://jco.ascopubs.org/content/23/34/8671.long Haller et al. 2005 (Intergroup 0089)]
-|rowspan=3 style="background-color:#1a9851"|Phase III (E)
-|[[#Fluorouracil_.26_Folinic_acid|High-dose 5-FU & Folinic acid]]
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|LDLV & Levamisole
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|5-FU & Levamisole
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|}
-====Preceding treatment====
-*Surgery
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV push once per day on days 1 to 5, '''given first'''
-*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV push once per day on days 1 to 5
-'''28-day cycle for 3 cycles, then 35-day cycle for 3 cycles'''
-===Variant #4, LV5FU2 {{#subobject:685f89|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa032709 André et al. 2004 (MOSAIC)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#FOLFOX4|FOLFOX4]]
-|style="background-color:#fc8d59"|Seems to have inferior OS (*)
-|-
-|}
-''Reported efficacy is based on 2009 updated results.''
-====Preceding treatment====
-*Surgery
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 600 mg/m<sup>2</sup>/day IV continuous infusion over 22 hours once per day on days 1 & 2 (both bolus and continuous infusion are given on days 1 & 2)
-'''14-day cycle for 12 cycles'''
-===References===
-# '''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. [http://ascopubs.org/doi/full/10.1200/JCO.1993.11.10.1879 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8410113 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. [http://jco.ascopubs.org/content/15/1/246.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8996149 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa032709 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15175436 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. [http://ascopubs.org/doi/full/10.1200/JCO.2008.20.6771 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://ascopubs.org/doi/full/10.1200/JCO.2015.63.4238 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://www.nejm.org/doi/full/10.1056/NEJMoa043116 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://academic.oup.com/annonc/article/23/5/1190/192299 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/23/34/8671.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16314627 PubMed]
-<!-- Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 13-17, 2004. -->
-# 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. [http://jco.ascopubs.org/content/24/13/2059.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16648506 PubMed]
-# Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A, Maroun J, Price T, Lim R, Van Cutsem E, Park YS, McKendrick J, Topham C, Soler-Gonzalez G, de Braud F, Hill M, Sirzén F, Haller DG. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007 Jan 1;25(1):102-9. [http://jco.ascopubs.org/content/25/1/102.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17194911 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. [http://jco.ascopubs.org/content/29/11/1465.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/33/32/3733.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/25/16/2198.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17470851 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. [http://ascopubs.org/doi/full/10.1200/JCO.2011.36.4539 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188282/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21859995 PubMed]
 ==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" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 20%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Dates of enrollment
-!style="width: 25%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/25/16/2198.full Kuebler et al. 2007 (NSABP C-07)]
+|[https://doi.org/10.1200/jco.2006.08.2974 Kuebler et al. 2007 (NSABP C-07)]
-|style="background-color:#1a9851"|Phase III (E)
+|2000-2002
-|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|style="background-color:#1a9850"|Superior DFS
+|[[#FULV|FULV]]
+| 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
+*[[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, '''to start 1 hour after start of leucovorin'''
+*[[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 before 5-FU'''
+*[[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. [http://jco.ascopubs.org/content/25/16/2198.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17470851 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] '''dosing details in manuscript have been reviewed by our editors''' [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. [http://ascopubs.org/doi/full/10.1200/JCO.2011.36.4539 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188282/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 20%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Dates of enrollment
-!style="width: 25%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa032709 André et al. 2004 (MOSAIC)]
+|[https://doi.org/10.1056/NEJMoa032709 André et al. 2004 (MOSAIC)]
-|style="background-color:#1a9851"|Phase III (E)
+|1998-2001
-|[[#Fluorouracil_.26_Folinic_acid|5-FU & Folinic acid]]
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|style="background-color:#91cf60"|Seems to have superior OS (*)
+|[[#FULV|FULV]]
+| 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 style="background-color:#1a9851"|Phase III (C)
+|rowspan=2|2004-2007
-|FOLFOX4 & Bevacizumab
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#ffffbf"|Seems not superior
+|1. [[#FOLFOX4_.26_Bevacizumab_999|FOLFOX4 & Bevacizumab]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|XELOX & Bevacizumab
+|2. [[#CapeOx_.26_Bevacizumab_999|XELOX & Bevacizumab]]
-|style="background-color:#ffffbf"|Seems not superior
+| 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)]
-|style="background-color:#1a9851"|Phase III (C)
+|2005-2009
-|FOLFOX4 & Cetuximab
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#ffffbf"|Seems not superior
+|[[#FOLFOX4_.26_Cetuximab_999|FOLFOX4 & Cetuximab]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|[http://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)]
-|style="background-color:#1a9851"|Phase III (C)
+|2007-2015
-|FOLFOX4 x 6
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#ffffbf"|Inconclusive whether non-inferior
+|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
 |-
 |}
-''Note: Reported efficacy for MOSAIC is based on the 2009 update. IDEA is a pooled analysis of six phase III RCTs.''
+''<sup>1</sup>Reported efficacy for MOSAIC is based on the 2015 update.''<br>
+''IDEA is a pooled analysis of six phase 3 RCTs.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*Surgery
+*[[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, then 600 mg/m<sup>2</sup>/day IV continuous infusion over 22 hours once per day on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)
+*[[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, '''before 5-FU'''
+*[[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, '''concurrent with leucovorin'''
+*[[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. [http://www.nejm.org/doi/full/10.1056/NEJMoa032709 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15175436 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://doi.org/10.1056/NEJMoa032709 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [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. [http://ascopubs.org/doi/full/10.1200/JCO.2008.20.6771 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://ascopubs.org/doi/full/10.1200/JCO.2015.63.4238 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70509-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23168362 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] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/23168362/ PubMed] [https://clinicaltrials.gov/study/NCT00112918 NCT00112918]
-# '''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://www.ncbi.nlm.nih.gov/pubmed/24928083 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]
-# '''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1713709 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29590544 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]
+#'''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]
+#'''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]]
-===Variant #1, 3 months {{#subobject:205ad6|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Regimen {{#subobject:30juz2|Variant=1}}===
-!style="width: 25%"|Study
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Study
-!style="width: 25%"|Comparator
+!style="width: 20%"|Dates of enrollment
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
+!style="width: 20%"|Comparator
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext Iveson et al. 2018 (SCOT)]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|style="background-color:#1a9851"|Phase III (E)
-|mFOLFOX6 x 12
-|style="background-color:#eeee01"|Seems to have non-inferior DFS
-|-
-|}
-====Preceding treatment====
-*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 last''' (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 with oxaliplatin'''
-**Alternatively, [[Levoleucovorin (Fusilev)]] 175 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given with oxaliplatin'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given with folinic acid'''
-'''14-day cycle for 6 cycles'''
-===Variant #2, 6 months {{#subobject:30b6e7|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717026/ Allegra et al. 2009 (NSABP C-08)]
-|style="background-color:#1a9851"|Phase III (C)
+|2004-2006
-|[[Colon_cancer_-_historical#mFOLFOX6_.26_Bevacizumab|mFOLFOX6 & Bevacizumab]]
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#ffffbf"|Seems not superior
+|[[Colon_cancer_-_historical#mFOLFOX6-B|mFOLFOX6-B]]
-|-
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-|[http://jama.jamanetwork.com/article.aspx?articleid=1148329 Alberts et al. 2012 (N0147)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[Colon_cancer,_KRAS_wild-type#mFOLFOX6_.26_Cetuximab|mFOLFOX6 & Cetuximab]]
-|style="background-color:#d9ef8b"|Might have superior DFS
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445286/ Pectasides et al. 2015]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6426127/ Grothey et al. 2018 (IDEA)]
-|style="background-color:#1a9851"|Phase III (C)
+|2007-2015
-|[[#CapeOx|CAPOX]]
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#ffffbf"|Seems not superior
+|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
 |-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa1713709 Grothey et al. 2018 (IDEA)]
+|[https://doi.org/10.1200/JCO.2017.76.0355 André et al. 2018 (IDEA France)]
-|style="background-color:#1a9851"|Phase III (C)
+|2009-2014
-|mFOLFOX6 x 6
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#ffffbf"|Inconclusive whether non-inferior
+|[[#mFOLFOX6_2|mFOLFOX6]] x 3 mo
+| style="background-color:#91cf60" |Seems to have superior DFS
 |-
-|[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/pmc8025124/ Meyerhardt et al. 2021 (CALGB 80702)]
-|style="background-color:#1a9851"|Phase III (C)
+|2010-2015
-|mFOLFOX6 x 6
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#eeee01"|Seems to have non-inferior DFS
+|[[#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, within 10 weeks
+*[[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 last''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[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)]] at one of the following doses, '''given with oxaliplatin:'''
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
-**Most trials: 400 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''
-**Pectasides et al. 2015: 200 mg/m<sup>2</sup> IV over 2 hours once on day 1
-**SCOT: 350 mg/m<sup>2</sup> IV over 2 hours once on day 1 or [[Levoleucovorin (Fusilev)]] 175 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given 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. [http://jco.ascopubs.org/content/27/20/3385.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717026/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19414665 PubMed]
+#'''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] '''dosing details in manuscript have been reviewed by our editors''' [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. [http://ascopubs.org/doi/full/10.1200/JCO.2010.30.0855 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055856/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20940184 PubMed]
+## '''Update:''' Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Colangelo LH, Atkins JN, Seay TE, Fehrenbacher L, Goldberg RM, O'Reilly S, Chu L, Azar CA, Lopa S, Wolmark N. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011 Jan 1;29(1):11-6. 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. [http://ascopubs.org/doi/full/10.1200/JCO.2012.44.4711 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732014/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23233715 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]
-# '''N0147:''' Alberts SR, Sargent DJ, Nair S, Mahoney MR, Mooney M, Thibodeau SN, Smyrk TC, Sinicrope FA, Chan E, Gill S, Kahlenberg MS, Shields AF, Quesenberry JT, Webb TA, Farr GH Jr, Pockaj BA, Grothey A, Goldberg RM. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA. 2012 Apr 4;307(13):1383-93. [http://jama.jamanetwork.com/article.aspx?articleid=1148329 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442260/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22474202 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://www.ncbi.nlm.nih.gov/pubmed/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]
-# '''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1713709 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29590544 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]
-# '''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://www.ncbi.nlm.nih.gov/pubmed/29611518 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] '''dosing details in manuscript have been reviewed by our editors''' [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]
-==Observation==
+==mFOLFOX6 (L-Leucovorin) {{#subobject:32d6d7|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+mFOLFOX6: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-|-
+===Example orders===
-|[[#top|back to top]]
+*[[Example orders for mFOLFOX 6 in colon cancer]]
-|}
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 3 months, 200 mg/m<sup>2</sup> L-LCV {{#subobject:38ig9a|Variant=1}}===
-===Regimen===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PII0140-6736(92)91708-G/fulltext Fielding et al. 1992 (AXIS-CRC)]
-|style="background-color:#1a9851"|Phase III (C)
-|Portal venous chemotherapy
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(94)92398-1/fulltext Riethmüller et al. 1994]
-|style="background-color:#1a9851"|Phase III (C)
-|Edrecolomab
-|style="background-color:#fc8d59"|Seems to have inferior OS
-|-
-|[http://jco.ascopubs.org/content/15/1/246.long O'Connell et al. 1997]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]
-|style="background-color:#fc8d59"|Seems to have inferior OS
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)08169-5/fulltext Rougier et al. 1998]
-|style="background-color:#1a9851"|Phase III (C)
-|Portal venous chemotherapy
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61866-2/fulltext Gray et al. 2007 (QUASAR)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]
-|style="background-color:#d73027"|Inferior OS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157980/ Niedzwiecki et al. 2011 (CALGB 9581)]
-|style="background-color:#1a9851"|Phase III (C)
-|Edrecolomab
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010179/ Hasegawa et al. 2016]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Tegafur.2C_Uracil.2C_Folinic_acid|Tegafur, Uracil, Leucovorin]]
-|style="background-color:#d73027"|Inferior RFS
-|-
-|}
-''No systemic treatment after surgery. Patients in QUASAR & CALGB 9581 had stage II disease. The AXIS trial is named "AXIS-CRC" here so as not to confuse it with the AXIS trial in renal cell carcinoma.''
-====Preceding treatment====
-*Surgery
-===References===
-# '''AXIS-CRC:''' Fielding LP, Hittinger R, Grace RH, Fry JS. Randomised controlled trial of adjuvant chemotherapy by portal-vein perfusion after curative resection for colorectal adenocarcinoma. Lancet. 1992 Aug 29;340(8818):502-6. [https://www.thelancet.com/journals/lancet/article/PII0140-6736(92)91708-G/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1354275 PubMed]
-# Riethmüller G, Schneider-Gädicke E, Schlimok G, Schmiegel W, Raab R, Höffken K, Gruber R, Pichlmaier H, Hirche H, Pichlmayr R, Buggisch P, Witte J; German Cancer Aid 17-1A Study Group. Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes' C colorectal carcinoma. Lancet. 1994 May 14;343(8907):1177-83. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(94)92398-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7909866 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. [http://jco.ascopubs.org/content/15/1/246.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8996149 PubMed]
-# Rougier P, Sahmoud T, Nitti D, Curran D, Doci R, De Waele B, Nakajima T, Rauschecker H, Labianca R, Pector JC, Marsoni S, Apolone G, Lasser P, Couvreur ML, Wils J; European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group and the Gruppo Interdisciplinare Valutazione Interventi in Oncologia and the Japanese Foundation for Cancer Research. Adjuvant portal-vein infusion of fluorouracil and heparin in colorectal cancer: a randomised trial. Lancet. 1998 Jun 6;351(9117):1677-81. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)08169-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9734883 PubMed]
-# '''QUASAR:''' 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://www.ncbi.nlm.nih.gov/pubmed/18083404 PubMed]
-# '''CALGB 9581:''' Niedzwiecki D, Bertagnolli MM, Warren RS, Compton CC, Kemeny NE, Benson AB 3rd, Eckhardt SG, Alberts S, Porjosh GN, Kerr DJ, Fields A, Rougier P, Pipas JM, Schwartz JH, Atkins J, O'Rourke M, Perry MC, Goldberg RM, Mayer RJ, Colacchio TA. Documenting the natural history of patients with resected stage II adenocarcinoma of the colon after random assignment to adjuvant treatment with edrecolomab or observation: results from CALGB 9581. J Clin Oncol. 2011 Aug 10;29(23):3146-52. Epub 2011 Jul 11. [http://ascopubs.org/doi/full/10.1200/JCO.2010.32.5357 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157980/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21747085 PubMed]
-# Hasegawa K, Saiura A, Takayama T, Miyagawa S, Yamamoto J, Ijichi M, Teruya M, Yoshimi F, Kawasaki S, Koyama H, Oba M, Takahashi M, Mizunuma N, Matsuyama Y, Watanabe T, Makuuchi M, Kokudo N. Adjuvant oral uracil-tegafur with leucovorin for colorectal cancer liver metastases: A randomized controlled trial. PLoS One. 2016 Sep 2;11(9):e0162400. eCollection 2016. [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://www.ncbi.nlm.nih.gov/pubmed/27588959 PubMed]
-==Tegafur, Uracil, Folinic acid {{#subobject:5ed2aa|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Variant #1, 300/75 {{#subobject:8cc7d8|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.sciencedirect.com/science/article/pii/S0959804914007242 Shimada et al. 2014 (JCOG0205)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]
-|style="background-color:#eeee01"|Non-inferior DFS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010179/ Hasegawa et al. 2016]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Observation|Observation]]
-|style="background-color:#1a9850"|Superior RFS
-|-
-|}
-====Preceding treatment====
-*JCOG0205: Surgery with D2/D3 lymph node dissection
-*Hasegawa et al. 2016: Surgical resection of colorectal cancer liver metastases, within 8 weeks
-====Chemotherapy====
-*[[Tegafur and uracil (UFT)]] 100 mg/m<sup>2</sup> PO q8h on days 1 to 28
-*[[Folinic acid (Leucovorin)]] 25 mg PO q8h on days 1 to 28
-'''35-day cycle for 5 cycles'''
-===Variant #2, 300/90 {{#subobject:643dbb|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/24/13/2059.long Lembersky et al. 2006 (NSABP C-06)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|}
-====Preceding treatment====
-*A potentially curative resection of stage II or stage III colon cancer
-====Chemotherapy====
-*[[Tegafur and uracil (UFT)]] 100 mg/m<sup>2</sup> PO Q8H on days 1 to 28
-*[[Folinic acid (Leucovorin)]] 30 mg PO Q8H on days 1 to 28
-*No food for 1 hour before and after each dose of medication.
-'''35-day cycle for 5 cycles'''
-===References===
-<!-- 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. [http://jco.ascopubs.org/content/24/13/2059.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16648506 PubMed]
-# '''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.sciencedirect.com/science/article/pii/S0959804914007242 link to SD article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24958736 PubMed]
-# Hasegawa K, Saiura A, Takayama T, Miyagawa S, Yamamoto J, Ijichi M, Teruya M, Yoshimi F, Kawasaki S, Koyama H, Oba M, Takahashi M, Mizunuma N, Matsuyama Y, Watanabe T, Makuuchi M, Kokudo N. Adjuvant oral uracil-tegafur with leucovorin for colorectal cancer liver metastases: A randomized controlled trial. PLoS One. 2016 Sep 2;11(9):e0162400. eCollection 2016. [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://www.ncbi.nlm.nih.gov/pubmed/27588959 PubMed]
-=Therapy for oligometastatic disease, including perioperative therapy and hyperthermic intra-peritoneal chemotherapy=
-==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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277487/ Nordlinger et al. 2008 (EORTC 40983)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Surgery_alone|Surgery alone]]
-|style="background-color:#1a9850"|Superior PFS
-|-
-|}
-''Note: this is the regimen as described by de Gramont et al. 2000; the manuscript refers to this protocol.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 600 mg/m<sup>2</sup>/day IV continuous infusion over 22 hours once per day on days 1 & 2 (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, '''before 5-FU'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''concurrent with leucovorin'''
-'''14-day cycle for 6 cycles before surgery, and 6 cycles after surgery (12 cycles total)'''
-===References===
-# '''EORTC 40983:''' Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008 Mar 22;371(9617):1007-16. [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://www.ncbi.nlm.nih.gov/pubmed/18358928 PubMed]
-## '''Update:''' Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Mauer M, Tanis E, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und–tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectalcancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1208-15. Epub 2013 Oct 11. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70447-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24120480 PubMed]
-==Hepatic arterial chemotherapy==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJM199912303412702 Kemeny et al. 1999]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Surgery_alone|Surgery alone]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-''Of historic interest; unlikely to be completed.''
-====Chemotherapy====
-*[[Floxuridine (FUDR)]]
-====Supportive medications====
-*[[Dexamethasone (Decadron)]]
-===References===
-# 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://www.ncbi.nlm.nih.gov/pubmed/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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.sciencedirect.com/science/article/pii/S0959804915008631 Cashin et al. 2016 (SPS-1)]
-|style="background-color:#1a9851"|Randomized (E)
-|[[#mFOLFOX6_2|mFOLFOX6]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-====Preceding treatment====
-*Cytoreductive surgery
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 550 mg/m<sup>2</sup>/d IP continuous infusion for 6 days (total dose per cycle: 3300 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 30 mg/m<sup>2</sup>/d IV once on day 1, '''given 60 minutes after start of IP infusion'''
-'''Monthly 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://www.sciencedirect.com/science/article/pii/S0959804915008631 link to SD article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26751236 PubMed]
-==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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2003.04.187 Verwaal et al. 2003]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Fluorouracil_.26_Folinic_acid_2|5-FU & LV (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: 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. [http://ascopubs.org/doi/full/10.1200/JCO.2003.04.187 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14551293 PubMed]
-==Surgery alone==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJM199912303412702 Kemeny et al. 1999]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Hepatic_arterial_chemotherapy|Hepatic arterial chemotherapy]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277487/ Nordlinger et al. 2008 (EORTC 40983)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFOX4_2|FOLFOX4]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|}
-''No treatment other than surgical resection of oligometastatic disease.''
-===References===
-# 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://www.ncbi.nlm.nih.gov/pubmed/10615075 PubMed]
-# '''EORTC 40983:''' Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008 Mar 22;371(9617):1007-16. [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://www.ncbi.nlm.nih.gov/pubmed/18358928 PubMed]
-## '''Update:''' Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Mauer M, Tanis E, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und–tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectalcancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1208-15. Epub 2013 Oct 11. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70447-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24120480 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
-===Variant #1, 2000 mg/m<sup>2</sup>/day {{#subobject:b1642a|Variant=1}}===
-{| class="wikitable" 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#Efficacy|Efficacy]]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 20%"|[[Levels_of_Evidence#Toxicity|Toxicity]]
 |-
-|[https://academic.oup.com/annonc/article-abstract/28/6/1288/3102942 Kwakman et al. 2017 (SALTO)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743062/ Yoshino et al. 2019 (ACHIEVE)]
-|style="background-color:#1a9851"|Phase III (C)
+|2012-08-01 to 2014-06-30
-|[[#S-1_monotherapy|S-1]]
+| style="background-color:#1a9851" |Phase 3 (E-de-esc)
-|
+|1a. [[#CapeOx|CapeOx]] x 6 mo<br>1b. [[#mFOLFOX6|mFOLFOX6]] x 6 mo
-|style="background-color:#d73027"|Higher incidence of hand-foot syndrome
+| 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)
 |-
 |}
-''Note: this trial had a primary toxicity endpoint; this dose was intended for patients at least 70 years old.''
+''<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 BID on days 1 to 14
+*[[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'''
-'''21-day cycles'''
+*[[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'''
-===Variant #2, 2500 mg/m<sup>2</sup>/day {{#subobject:303fab|Variant=1}}===
+</div></div><br>
-{| class="wikitable" style="width: 100%; text-align:center;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 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%"|Dates of enrollment
 !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 !style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 20%"|[[Levels_of_Evidence#Toxicity|Toxicity]]
-|-
-|[http://jco.ascopubs.org/content/19/8/2282.long Hoff et al. 2001]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Fluorouracil_.26_Folinic_acid_2|5-FU + Folinic acid]]
-|style="background-color:#1a9850"|Superior ORR
-|
-|-
-|[http://jco.ascopubs.org/content/19/21/4097.long Van Cutsem et al. 2001]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Fluorouracil_.26_Folinic_acid_2|5-FU + Folinic acid]]
-|style="background-color:#ffffbf"|Seems not superior
-|
-|-
-|rowspan=2|[http://ascopubs.org/doi/full/10.1200/JCO.2009.27.7723 Tebbutt et al. 2010 (AGITG MAX)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (C)
-|[[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]
-|style="background-color:#d73027"|Inferior PFS
-|
-|-
-|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)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]
-|style="background-color:#d73027"|Inferior PFS
-|
 |-
-|[https://academic.oup.com/annonc/article-abstract/28/6/1288/3102942 Kwakman et al. 2017 (SALTO)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743062/ Yoshino et al. 2019 (ACHIEVE)]
-|style="background-color:#1a9851"|Phase III (C)
+|2012-08-01 to 2014-06-30
-|[[#S-1_monotherapy|S-1]]
+| style="background-color:#1a9851" |Phase 3 (C)
-|
+|1a. [[#CapeOx|CapeOx]] x 3 mo<br>1b. [[#mFOLFOX6|mFOLFOX6]] x 3 mo
-|style="background-color:#d73027"|Higher incidence of hand-foot syndrome
+| style="background-color:#eeee01" |Seems to have non-inferior DFS
 |-
 |}
-''Note: SALTO had a primary toxicity endpoint; this dose was intended for patients less than 70 years old.''
+<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 BID on days 1 to 14
+*[[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'''
-'''21-day cycles'''
+*[[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 Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, Georgia, May 15-18, 1999. -->
+#'''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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/31513248/ PubMed] UMIN000008543
-# 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. [http://jco.ascopubs.org/content/19/8/2282.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11304782 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]
-## '''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://www.ncbi.nlm.nih.gov/pubmed/15026800 PubMed]
+==FULV {{#subobject:a93a|Regimen=1}}==
-<!-- 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. -->
+FULV: 5-'''<u>FU</u>''' & '''<u>L</u>'''euco'''<u>V</u>'''orin
-# 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. [http://jco.ascopubs.org/content/19/21/4097.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11689577 PubMed]
+<br>LV5FU2: '''<u>L</u>'''euco'''<u>V</u>'''orin & '''<u>5-FU</u>''' for '''<u>2</u>''' days
-## '''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://www.ncbi.nlm.nih.gov/pubmed/15026800 PubMed]
-# '''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. [http://ascopubs.org/doi/full/10.1200/JCO.2009.27.7723 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/24028813 PubMed]
-# '''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. 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://academic.oup.com/annonc/article-abstract/28/6/1288/3102942 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28383633 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
-===Variant #1, 1000/7.5 {{#subobject:f9f237|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70154-2/fulltext Cunningham et al. 2013 (AVEX)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Capecitabine_monotherapy_2|Capecitabine]]
-|style="background-color:#1a9850"|Superior PFS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO BID on days 1 to 14
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===Variant #2, 1250/7.5 {{#subobject:94ef02|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-||[http://ascopubs.org/doi/full/10.1200/JCO.2009.27.7723 Tebbutt et al. 2010 (AGITG MAX)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Capecitabine_monotherapy_2|Capecitabine]]
-|style="background-color:#1a9850"|Superior PFS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173448/ Giessen et al. 2011 (AIO KRK 0110)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#CAPIRI-Bev|CAPIRI-Bev]]
-|TBD
-|-
-|}
-''Note: there are no results for AIO KRK 0110 as of yet; the reference does describe the regimen, however.''
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO BID on days 1 to 14
-*[[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. [http://ascopubs.org/doi/full/10.1200/JCO.2009.27.7723 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20516443 PubMed]
-# '''AIO KRK 0110:''' Giessen C, von Weikersthal LF, Hinke A, Stintzing S, Kullmann F, Vehling-Kaiser U, Mayerle J, Bangerter M, Denzlinger C, Sieber M, Teschendorf C, Freiberg-Richter J, Schulz C, Modest DP, Moosmann N, Aubele P, Heinemann V. A randomized, phase III trial of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in first-line treatment of metastatic colorectal cancer: the AIO KRK 0110 trial/ML22011 trial. BMC Cancer. 2011 Aug 23;11:367. [https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-11-367 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173448/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21861888 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://www.ncbi.nlm.nih.gov/pubmed/24028813 PubMed]
-==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
 ===Example orders===
-*[[Example orders for CapeOx (XELOX) 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]]
-===Variant #1, 850/130 {{#subobject:d1897d|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Regimen variant #1, 500/200, 6 out of 8 weeks {{#subobject:2c3f1b|Variant=1}}===
-!style="width: 25%"|Study
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Study
-!style="width: 25%"|Comparator
+!style="width: 20%"|Dates of enrollment
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
+!style="width: 20%"|Comparator
-|rowspan=2|[http://jco.ascopubs.org/content/26/21/3523.full Hochster et al. 2008 (TREE-1)]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E)
-|bFOL
-|style="background-color:#ffffbf"|Seems not superior
 |-
-|[[#mFOLFOX6_2|mFOLFOX6]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038965/ Papadimitriou et al. 2011]
-|style="background-color:#ffffbf"|Seems not superior
+|1999-2004
-|-
+| style="background-color:#1a9851" |Phase 3 (C)
-|}
+|[[#IFL_999|IFL]]
-====Chemotherapy====
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
-*[[Capecitabine (Xeloda)]] 850 mg/m<sup>2</sup> PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
-**In TREE-2, based on safety data from TREE-1, the initial dose was decreased to 850 mg/m<sup>2</sup> PO BID. Patients with a CrCl of 30 to 50 mL/min/1.73m<sup>2</sup> received 650 mg/m<sup>2</sup> PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''21-day cycles'''
-===Variant #2, 1000/70 {{#subobject:b301d1|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/25/27/4217.long Porschen et al. 2007]
-|style="background-color:#1a9851"|Phase III (E)
-|FUFOX
-|style="background-color:#ffffbf"|Inconclusive whether non-inferior
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO BID 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'''
-===Variant #3, 1000/130 {{#subobject:162a54|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/25/27/4224.long Díaz-Rubio et al. 2007]
-|style="background-color:#1a9851"|Phase III (E)
-|FUOX
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|rowspan=2|[http://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 Cassidy et al. 2008 (NO16966)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (C)
-|[[#FOLFOX4_2|FOLFOX4]]<br> [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
-|style="background-color:#eeee01"|Non-inferior PFS
-|-
-|[[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]
-|style="background-color:#d3d3d3"|Not reported
-|-
-|rowspan=2|[http://jco.ascopubs.org/content/26/12/2013.long Saltz et al. 2008 (NO16966)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (C)
-|[[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]<br> [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]
-|style="background-color:#d73027"|Inferior PFS
-|-
-|[[#FOLFOX4_2|FOLFOX4]]
-|style="background-color:#d3d3d3"|Not reported
-|-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.25369 Ducreux et al. 2011]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#mFOLFOX6_2|mFOLFOX6]]
-|style="background-color:#eeee01"|Non-inferior OS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159415/ Maughan et al. 2011 (UK MRC COIN)]
-|style="background-color:#1a9851"|Phase III (C)
-|CapeOx & Cetuximab
-|style="background-color:#ffffbf"|Seems not superior (*)
-|-
-|[http://jco.ascopubs.org/content/30/29/3596.long Hoff et al. 2012 (HORIZON-II)]
-|style="background-color:#1a9851"|Phase III (C)
-|CAPOX & Cediranib<br> FOLFOX4 & Cediranib<br> 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]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#SOX|SOX]]
-|style="background-color:#eeee01"|Non-inferior PFS
-|-
-|}
-''Note: Ducreux et al. 2011 gave up to 8 cycles of treatment. NO16966 said that initial treatment could be given up to 16 cycles, but then could continue beyond that for patients who did not have progression of disease. Efficacy for UK MRC COIN is as reported for KRAS wild-type patients.''
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
-**Note: In '''Saltz et al. 2008''' and '''Hong et al. 2012''' capecitabine was described as being given 1000 mg/m<sup>2</sup> PO BID 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====
-*Hong et al. 2012: 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. [http://jco.ascopubs.org/content/25/27/4217.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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 Trial. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol. 2007 Sep 20;25(27):4224-30. Epub 2007 Jun 4. [http://jco.ascopubs.org/content/25/27/4224.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/26/12/2013.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/26/21/3523.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/21641636 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. [http://jco.ascopubs.org/content/30/29/3596.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22965965 PubMed]
-# Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23062232 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
-===Variant #1, 850/130/7.5 {{#subobject:618554|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|rowspan=2|[http://jco.ascopubs.org/content/26/21/3523.full Hochster et al. 2008 (TREE-2)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E)
-|bFOL & Bevacizumab
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[[#mFOLFOX6_.26_Bevacizumab|mFOLFOX6 & Bevacizumab]]
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 850 mg/m<sup>2</sup> PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
-**In TREE-2, patients with a CrCl of 30 to 50 mL/min/1.73m<sup>2</sup> received 650 mg/m<sup>2</sup> PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===Variant #2, 1000/130/7.5 x 6 {{#subobject:e7bd8e|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa0808268 Tol et al. 2009 (CAIRO2)]
-|style="background-color:#1a9851"|Phase III (C)
-|CapeOx, Bevacizumab, Cetuximab
-| style="background-color:#1a9850" |Superior PFS
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62004-3/fulltext Simkens et al. 2015 (CAIRO3)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
 |-
 |}
+<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 BID on days 1 to 14
+*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
+'''8-week cycle for 4 cycles'''
+</div></div><br>
-'''21-day cycle for 6 cycles'''
+<div class="toccolours" style="background-color:#eeeeee">
-====Subsequent treatment====
+===Regimen variant #2, 500/500, 6 out of 8 weeks {{#subobject:489be0|Variant=1}}===
-*CAIRO2: [[#Capecitabine_.26_Bevacizumab_2|Capecitabine & Bevacizumab maintenance]]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-*CAIRO3: [[#Capecitabine_.26_Bevacizumab_2|Capecitabine & Bevacizumab maintenance]] versus [[#Observation_2|Observation]]
-===Variant #3, 1000/130/7.5, indefinite {{#subobject:e7bd8e|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|rowspan=2|[http://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 Cassidy et al. 2008 (NO16966)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFOX4_2|FOLFOX4]]<br> [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
-|style="background-color:#eeee01"|Non-inferior PFS
-|-
-|[[#CapeOx|XELOX]]
-|style="background-color:#d3d3d3"|Not reported
-|-
-|rowspan=2|[http://jco.ascopubs.org/content/26/12/2013.long Saltz et al. 2008 (NO16966)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFOX4_2|FOLFOX4]]<br> [[#CapeOx|XELOX]]
-|style="background-color:#1a9850"|Superior PFS
-|-
-|[[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
-|style="background-color:#d3d3d3"|Not reported
-|-
-|[https://academic.oup.com/annonc/article/29/3/624/4779925 Yamada et al. 2018 (TRICOLORE)]
-|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)]
-|style="background-color:#1a9851"|Randomized Phase II (C)
-|[[#CAPIRI-Bev|CAPIRI & Bevacizumab]]
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|}
-''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 BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
-**Note: In Saltz et al. 2008--the same study as Cassidy et al. 2008--capecitabine was described as being given 1000 mg/m<sup>2</sup> PO BID on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
-*[[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. [http://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/26/12/2013.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/26/21/3523.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. 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://www.ncbi.nlm.nih.gov/pubmed/19196673 PubMed]
-# '''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. 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://www.ncbi.nlm.nih.gov/pubmed/25862517 PubMed]
-## '''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://academic.oup.com/annonc/article/28/9/2128/3884600 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://academic.oup.com/annonc/article/29/3/624/4779925 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29293874 PubMed]
-# '''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://www.ncbi.nlm.nih.gov/pubmed/30049885 PubMed]
-==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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|rowspan=2|[http://jco.ascopubs.org/content/25/30/4779.long Fuchs et al. 2007 (BICC-C)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFIRI|FOLFIRI]]
-|style="background-color:#fc8d59"|Seems to have inferior PFS
-|-
-|[[#IFL|mIFL]]
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366 Moehler et al. 2009]
-|style="background-color:#91cf61"|Phase II
-|style="background-color:#d3d3d3"|
-|style="background-color:#d3d3d3"|
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> BID on days 1 to 14
-*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-'''21-day cycles'''
-===References===
-<!-- Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA. -->
-# 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. [http://jco.ascopubs.org/content/25/30/4779.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/26/4/689.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18235136 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://www.ncbi.nlm.nih.gov/pubmed/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
-===Variant #1, 800/200/7.5 {{#subobject:f6bf78|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173448/ Giessen et al. 2011 (AIO KRK 0110)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Bevacizumab_.26_Capecitabine|Cape-Bev]]
-|TBD
-|-
-|}
-''Note: there are no results for this trial; the reference does describe the regimen, however.''
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO BID on days 1 to 14
-*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV once on day 1
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===Variant #2, 1000/200/7.5 {{#subobject:88c136|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 50%"|Study
-!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366 Moehler et al. 2009]
-|style="background-color:#91cf61"|Phase II
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO BID on days 1 to 14
-*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV once on day 1
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===Variant #3, 1000/240/7.5 {{#subobject:a19b6d|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466131/ Pectasides et al. 2012]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI-Bev]]
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO BID on days 1 to 14
-*[[Irinotecan (Camptosar)]] 240 mg/m<sup>2</sup> IV once on day 1
-*[[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://www.ncbi.nlm.nih.gov/pubmed/19152449 PubMed]
-# Giessen C, von Weikersthal LF, Hinke A, Stintzing S, Kullmann F, Vehling-Kaiser U, Mayerle J, Bangerter M, Denzlinger C, Sieber M, Teschendorf C, Freiberg-Richter J, Schulz C, Modest DP, Moosmann N, Aubele P, Heinemann V. A randomized, phase III trial of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in first-line treatment of metastatic colorectal cancer: the AIO KRK 0110 trial/ML22011 trial. BMC Cancer. 2011 Aug 23;11:367. [https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-11-367 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173448/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21861888 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. 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://www.ncbi.nlm.nih.gov/pubmed/22748098 PubMed]
-==Fluorouracil & Folinic acid {{#subobject:e9add2|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-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]]
-===Variant #1, "Roswell Park regimen" {{#subobject:3f90af|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/21/1/60.full Kabbinavar et al. 2003 (AVF0780)]
-|style="background-color:#1a9851"|Randomized Phase II (C)
-|5-FU, Folinic acid & Bevacizumab
-|style="background-color:#fee08b"|Might have inferior OS
-|-
-|}
-====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)]] 500 mg/m<sup>2</sup> IV push once per day on days 1, 8, 15, 22, 29, 36, '''1 hour after start of leucovorin'''
-'''8-week cycles'''
-===Variant #2, "Mayo Clinic regimen" {{#subobject:ad7e77|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.1997.15.2.808 de Gramont et al. 1997]
-|style="background-color:#1a9851"|Phase III (C)
-|LV5FU2
-|style="background-color:#d73027"|Inferior PFS
-|-
-|rowspan=2|[http://www.nejm.org/doi/full/10.1056/NEJM200009283431302 Saltz et al. 2000 (Irinotecan Study Group)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (C)
-|[[#IFL|IFL]]
-|style="background-color:#fc8d59"|Seems to have inferior OS
-|-
-|[[#Irinotecan_monotherapy|Irinotecan]]
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[http://jco.ascopubs.org/content/19/8/2282.long Hoff et al. 2001]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Capecitabine_monotherapy_2|Capecitabine]]
-|style="background-color:#d73027"|Inferior ORR
-|-
-|[http://jco.ascopubs.org/content/19/21/4097.long Van Cutsem et al. 2001]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Capecitabine_monotherapy_2|Capecitabine]]
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2002.20.6.1519 Schilsky et al. 2002 (FUMA3008)]
-|style="background-color:#1a9851"|Phase III (C)
-|Eniluracil & 5-FU
-|style="background-color:#ffffbf"|Inconclusive whether non-inferior
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2002.04.123 Douillard et al. 2002]
-|style="background-color:#1a9851"|Phase III (C)
-|UFT & Leucovorin
-|style="background-color:#eeee01"|Seems to have equivalent OS
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2002.10.129 Carmichael et al. 2002]
-|style="background-color:#1a9851"|Phase III (C)
-|UFT & Leucovorin
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV push once per day on days 1 to 5, '''before 5-FU'''
-*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV push once per day on days 1 to 5
-'''28- to 35-day cycles'''
-===Variant #3, LV5FU2 ("de Gramont regimen") {{#subobject:66012|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.1997.15.2.808 de Gramont et al. 1997]
-|style="background-color:#1a9851"|Phase III (E)
-|Mayo Clinic Regimen
-|style="background-color:#1a9850"|Superior PFS
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext Douillard et al. 2000]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#IFL|IFL]]<br> [[#FOLFIRI|FOLFIRI]]
-|style="background-color:#fc8d59"|Seems to have inferior OS
-|-
-|[http://jco.ascopubs.org/content/18/16/2938.long de Gramont et al. 2000]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#FOLFOX4_2|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 style="background-color:#1a9851"|Phase III (C)
-|Lokich regimen
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|Raltitrexed
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)12388-4/fulltext Kerr et al. 2003]
-|style="background-color:#1a9851"|Phase III (C)
-|IHA LV5FU2
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)12461-0/fulltext Maughan et al. 2003]
-|style="background-color:#1a9851"|Phase III (C)
-|Intermittent LV5FU2
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|}
-''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.''
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 600 mg/m<sup>2</sup>/day IV continuous infusion over 22 hours once per day on days 1 & 2 (both bolus and continuous infusion are given on days 1 & 2)
-'''14-day cycles (see note)'''
-===Variant #4, 500/2600 {{#subobject:f4d2e9|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext Douillard et al. 2000]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#IFL|IFL]]<br> [[#FOLFIRI|FOLFIRI]]
-|style="background-color:#fc8d59"|Seems to have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV over 24 hours once on day 1
-'''7-day cycles'''
-===Variant #5 {{#subobject:a1523|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/14/8/2274.long Jäger et al. 1996]
-|style="background-color:#1a9851"|Phase III (C)
-|5-FU & High-dose Folinic acid
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once on day 1, '''given 1 hour after start of leucovorin'''
-'''7-day cycles'''
-===Variant #6, "modified Laufman" {{#subobject:8f214e|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2003.04.187 Verwaal et al. 2003]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Intraperitoneal_hyperthermic_mitomycin|HIPEC]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 80 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
-'''7-day cycle for up to 26 weeks'''
-===Variant #7, "modified de Gramont" {{#subobject:a28e0a|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 50%"|Study
-!style="width: 50%"|[[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====
-*[[Folinic acid (Leucovorin)]] 350 mg IV over 2 hours once on day 1, '''given first'''
-**Alternatively, [[Levoleucovorin (Fusilev)]] 175 mg IV over 2 hours once on day 1, '''given first'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus over 5 minutes once on day 1 after leucovorin, then 1400 mg/m<sup>2</sup>/day IV continuous infusion over 46 hours on days 1 to 2 (total dose per cycle: 2800 mg/m<sup>2</sup>)
-====Supportive medications====
-*No routine prophylactic [[:Category:Emesis_prevention|antiemetics]] and [[:Category:Antidiarrheals|antidiarrheal]] medications were used, but patients could use [[Metoclopramide (Reglan)]] prn nausea and [[Loperamide (Imodium)]] prn diarrhea.
-'''14-day cycles'''
-===Variant #8 reduced-dose sLV5FU2 {{#subobject:d246ce|Variant=1}}===
-{| class="wikitable" 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#Efficacy|Efficacy]]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 20%"|[[Levels_of_Evidence#Toxicity|Toxicity]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109515/ Seymour et al. 2011 (MRC FOCUS2)]
+|[https://doi.org/10.1200/JCO.1993.11.10.1879 Wolmark et al. 1993 (NSABP C-03)]
-|style="background-color:#1a9851"|Phase III (C)
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-|[[#Capecitabine_monotherapy_2|Capecitabine]]<br> [[#CapeOx_2|CapeOx]]<br> OxFU
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-258-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
-| 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.''
+|1987-1989
-====Chemotherapy====
+| style="background-color:#1a9851" |Phase 3 (E-de-esc)
-*[[Folinic acid (Leucovorin)]] 175 mg/m<sup>2</sup> IV over 2 hours once on day 1
+|[[Colon_cancer_-_historical#MOF|MOF]]
-*[[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 on days 1 to 2 (total dose per cycle: 2560 mg/m<sup>2</sup>)
-'''14-day cycles'''
-===References===
-# 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 Study Protocol 1. 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. [http://jco.ascopubs.org/content/14/8/2274.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8708717 PubMed]
-# de Gramont A, Bosset JF, Milan C, Rougier P, Bouché O, Etienne PL, Morvan F, Louvet C, Guillot T, François E, Bedenne L. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol. 1997 Feb;15(2):808-15. [http://ascopubs.org/doi/full/10.1200/JCO.1997.15.2.808 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9053508 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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/18/16/2938.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10944126 PubMed]
-# '''Irinotecan Study Group:''' 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. [http://www.nejm.org/doi/full/10.1056/NEJM200009283431302 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/19/8/2282.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/19/21/4097.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/15026800 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. [http://ascopubs.org/doi/full/10.1200/JCO.2002.20.6.1519 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.nature.com/bjc/journal/v87/n4/full/6600467a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376131/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://ascopubs.org/doi/full/10.1200/JCO.2002.04.123 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://ascopubs.org/doi/full/10.1200/JCO.2002.10.129 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/21/1/60.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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; European Organisation for Research and Treatment of Cancer 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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/12583944 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. [http://ascopubs.org/doi/full/10.1200/JCO.2003.04.187 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14551293 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://www.ncbi.nlm.nih.gov/pubmed/17630037 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://www.ncbi.nlm.nih.gov/pubmed/21570111 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
-===Example orders===
-*[[Example orders for FOLFIRI in colon cancer]]
-===Variant #1, 400/2800/180, racemic leucovorin {{#subobject:abe1bd|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/25/13/1670.long Falcone et al. 2007]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#FOLFIRINOX|FOLFOXIRI]]
-|style="background-color:#fc8d59"|Seems to have inferior OS
-|-
-|rowspan=2|[http://jco.ascopubs.org/content/25/30/4779.long Fuchs et al. 2007 (BICC-C)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E)
-|[[#CAPIRI|CapeIRI]]
-|style="background-color:#91cf60"|Seems to have superior PFS
-|-
-|[[#IFL|mIFL]]
-|style="background-color:#1a9850"|Superior PFS
-|-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa0805019 Van Cutsem et al. 2009 (CRYSTAL)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[Colon_cancer,_KRAS_wild-type#FOLFIRI_.26_Cetuximab_2|FOLFIRI & Cetuximab]]
-|style="background-color:#d73027"|Inferior OS (*)
-|-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.31552 Sanoff et al. 2018]
-|style="background-color:#1a9851"|Randomized Phase II (C)
-|FOLFIRI & Regorafenib
-| style="background-color:#fee08b" |Might have inferior PFS
-|-
-|}
-''Reported efficacy for '''CRYSTAL''' is based on the 2012 pooled update and is only for KRAS wild-type tumors.''
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given during irinotecan infusion'''
-*[[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 on days 1 & 2, '''given last''' (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 together with leucovorin'''
-'''14-day cycles'''
-===Variant #2, 200/2800/180, L-leucovorin {{#subobject:a3c9bd|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa0805019 Van Cutsem et al. 2009 (CRYSTAL)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[Colon_cancer,_KRAS_wild-type#FOLFIRI_.26_Cetuximab_2|FOLFIRI & Cetuximab]]
-|style="background-color:#d73027"|Inferior OS (*)
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2012.45.1930 Carrato et al. 2013 (SUN 1122)]
-|style="background-color:#1a9851"|Phase III (C)
-|FOLFIRI & Sunitinib
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|}
-''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 during irinotecan infusion'''
-*[[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 on days 1 & 2, '''given last''' (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 together with levoleucovorin'''
-'''14-day cycles'''
-===Variant #3, 400/1000/180, bi-weekly {{#subobject:048237|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext Douillard et al. 2000]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Fluorouracil_.26_Folinic_acid_2|5-FU & LV]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 & 2
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on day 1
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1
-'''14-day cycles'''
-===Variant #4, 500/2300/80, weekly {{#subobject:355f88|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext Douillard et al. 2000]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Fluorouracil_.26_Folinic_acid_2|5-FU & LV]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-====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 on day 1
-*[[Irinotecan (Camptosar)]] 80 mg/m<sup>2</sup> IV once on day 1
-'''7-day cycles'''
-===Variant #5, 6 out of 7 weeks ("AIO regimen") {{#subobject:310a1a|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2005.05.546 Köhne et al. 2005 (EORTC 40986)]
-| style="background-color:#1a9851" |Phase III (E)
-|[[#Fluorouracil_.26_Folinic_acid_2|5-FU & LV]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup>/day IV continuous infusion over 24 hours 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
-*[[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'''
-===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://www.ncbi.nlm.nih.gov/pubmed/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; European Organisation for Research and Treatment of Cancer 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. [http://ascopubs.org/doi/full/10.1200/JCO.2005.05.546 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15939923 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. [http://jco.ascopubs.org/content/25/13/1670.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/25/30/4779.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/26/4/689.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18235136 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa0805019 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19339720 PubMed]
-## '''Update: Abstract:''' E. Van Cutsem, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D. Cunningham, I. Celik, C. Kohne. Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome. 2010 ASCO Annual Meeting abstract 3570. [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. [http://jco.ascopubs.org/content/29/15/2011.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21502544 PubMed]
-## '''Pooled Update:''' Bokemeyer C, Cutsem EV, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://www.ejcancer.com/article/S0959-8049(12)00209-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22446022 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. [http://ascopubs.org/doi/full/10.1200/JCO.2012.45.1930 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23358972 PubMed]
-# 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://www.ncbi.nlm.nih.gov/pubmed/29905927 PubMed]
-==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
-===Variant #1, indefinite {{#subobject:28b67a|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/25/30/4779.long Fuchs et al. 2007 (BICC-C)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#IFL_.26_Bevacizumab|mIFL & Bevacizumab]]
-|style="background-color:#91cf60"|Seems to have superior OS
-|-
-|[https://academic.oup.com/annonc/article/27/8/1539/2237296 Yamazaki et al. 2016 (WJOG4407G)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#mFOLFOX6_.26_Bevacizumab|mFOLFOX6 & Bevacizumab]]
-|style="background-color:#eeee01"|Non-inferior PFS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70330-4/fulltext Heinemann et al. 2014 (FIRE-3)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[Colon_cancer,_KRAS_wild-type#FOLFIRI_.26_Cetuximab_2|FOLFIRI & Cetuximab]]
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''started during irinotecan infusion'''
-*[[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 on days 1 to 2, '''given last''' (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'''
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1
-**In FIRE-3, initial infusion is over 90 minutes, next over 60 minutes, and subsequently over 30 minutes
-'''14-day cycles'''
-===Variant #2, limited duration {{#subobject:58ae38|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa1403108 Loupakis et al. 2014 (TRIBE)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#FOLFIRINOX_.26_Bevacizumab|FOLFOXIRI & Bevacizumab]]
-|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 on days 1 to 2 (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
-*[[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===
-<!-- 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. [http://jco.ascopubs.org/content/25/30/4779.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/26/4/689.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/23015662 PubMed]
-# '''FIRE-3:''' Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31.[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70330-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25088940 PubMed]
-<!-- # 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1403108 link to original article] [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1403108/suppl_file/nejmoa1403108_protocol.pdf link to protocol in supplementary material] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25337750 PubMed]
-## '''Update:''' Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, Mezi S, Tomasello G, Ronzoni M, Zaniboni A, Tonini G, Carlomagno C, Allegrini G, Chiara S, D'Amico M, Granetto C, Cazzaniga M, Boni L, Fontanini G, Falcone A. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015 Oct;16(13):1306-15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00122-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26338525 PubMed]
-# '''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://academic.oup.com/annonc/article/27/8/1539/2237296 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27177863 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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/25/13/1670.long Falcone et al. 2007]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFIRI|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====
-*[[Fluorouracil (5-FU)]] 1600 mg/m<sup>2</sup>/day (3200 mg/m<sup>2</sup> total dose) IV continuous infusion over 48 hours on days 1 to 2
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1
-*[[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===
-<!-- 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. [http://jco.ascopubs.org/content/25/13/1670.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17470860 PubMed]
-==FOLFIRINOX & Bevacizumab {{#subobject:9bf7|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRINOX & Bevacizumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin, Bevacizumab
-<br>FOLFOXIRI & Bevacizumab: '''<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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa1403108 Loupakis et al. 2014 (TRIBE)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]
-|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 on days 1 to 2, '''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, together with oxaliplatin'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given third, together with leucovorin'''
-*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given second'''
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV over 30 minutes once on day 1, '''given first'''
-'''14-day cycle for up to 12 cycles''', then followed by maintenance fluorouracil, leucovorin, and bevacizumab given until progression of disease or unacceptable adverse event. Loupakis et al. 2014 did not provide specific details about the maintenance therapy.
-===References===
-<!-- # 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1403108 link to original article] [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1403108/suppl_file/nejmoa1403108_protocol.pdf link to protocol in supplementary material] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25337750 PubMed]
-## '''Update:''' Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, Mezi S, Tomasello G, Ronzoni M, Zaniboni A, Tonini G, Carlomagno C, Allegrini G, Chiara S, D'Amico M, Granetto C, Cazzaniga M, Boni L, Fontanini G, Falcone A. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015 Oct;16(13):1306-15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00122-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26338525 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
-===Variant #1, racemic leucovorin {{#subobject:ab483a|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/18/16/2938.long de Gramont et al. 2000]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Fluorouracil_.26_Folinic_acid_2|5-FU & Folinic acid]]
-|style="background-color:#1a9850"|Superior PFS
-|-
-|rowspan=2|[http://ascopubs.org/doi/full/10.1200/JCO.2004.09.046 Goldberg et al. 2003]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E)
-|[[#IFL|IFL]]
 | style="background-color:#1a9850" |Superior OS
 |-
-|[[#IROX|IROX]]
+| rowspan="2" |[https://doi.org/10.1200/JCO.1999.17.11.3553 Wolmark et al. 1999 (NSABP C-04)]
-| style="background-color:#ffffbf" |Seems not superior
+|rowspan=2|1989-07 to 1990-12
+| 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 (co-primary endpoint)
 |-
-|[http://jco.ascopubs.org/content/24/3/394.long Tournigand et al. 2006 (OPTIMOX1)]
+|2. [[Colon_cancer_-_historical#FULV_.26_Levamisole|FULV & Levamisole]]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of DFS/OS
-|[[#FOLFOX_7_.26_sLV5FU2|FOLFOX7/LV5FU2]]
-|style="background-color:#ffffbf"|Seems not superior
 |-
-|rowspan=2|[http://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 Cassidy et al. 2008 (NO16966)]
+| rowspan="3" |[https://doi.org/10.1200/jco.2004.00.5686 Haller et al. 2005 (Intergroup 0089)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (C)
+|rowspan=3|1988-1992
-|[[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
+| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-esc)
-|style="background-color:#d3d3d3"|Not reported
+|1. [[#FULV|FULV]]; low-dose
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[[#CapeOx|XELOX]]<br> [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]
+|2. [[Colon_cancer_-_historical#FULV_.26_Levamisole|FULV & Levamisole]]; LDLV
-|style="background-color:#eeee01"|Non-inferior PFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|rowspan=2|[http://jco.ascopubs.org/content/26/12/2013.long Saltz et al. 2008 (NO16966)]
+|3. [[Colon_cancer_-_historical#Fluorouracil_.26_Levamisole|5-FU & Levamisole]]
-|rowspan=2 style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|[[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]<br> [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]
-|style="background-color:#d73027"|Inferior PFS
 |-
-|[[#CapeOx|XELOX]]
+|[https://doi.org/10.1200/jco.2005.04.7498 Lembersky et al. 2006 (NSABP C-06)]
-|style="background-color:#d3d3d3"|Not reported
+|1997-1999
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Tegafur.2C_Uracil.2C_Folinic_acid|Tegafur, Uracil, Folinic acid]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of DFS/OS
 |-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2008.20.8397 Bokemeyer et al. 2008 (OPUS)]
+|[https://doi.org/10.1200/JCO.2007.11.2144 Saltz et al. 2007 (CALGB 89803)]
-|style="background-color:#1a9851"|Phase III (C)
+|1999-2001
-|[[Colon_cancer,_KRAS_wild-type#FOLFOX4_.26_Cetuximab|FOLFOX4 & Cetuximab]]
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#d73027"|Inferior OS (*)
+|[[#IFL_999|IFL]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of DFS/OS
 |-
-|[http://jco.ascopubs.org/content/28/31/4697.long Douillard et al. 2010 (PRIME)]
+|[https://doi.org/10.1200/jco.2006.08.2974 Kuebler et al. 2007 (NSABP C-07)]
-|style="background-color:#1a9851"|Phase III (C)
+|2000-2002
-|[[Colon_cancer,_KRAS_wild-type#FOLFOX4_.26_Panitumumab|FOLFOX4 & Panitumumab]]
+| style="background-color:#1a9851" |Phase 3 (C)
-|See note
+|[[#FLOX|FLOX]]
-|-
+| style="background-color:#d73027" |Inferior DFS
-|[http://ascopubs.org/doi/full/10.1200/JCO.2010.29.4496 Hecht et al. 2011]
-|style="background-color:#1a9851"|Phase III (C)
-|FOLFOX4 & Vatalanib
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[http://jco.ascopubs.org/content/30/29/3596.long Hoff et al. 2012 (HORIZON II)]
-|style="background-color:#1a9851"|Phase III (C)
-|CAPOX & Cediranib<br> FOLFOX4 & Cediranib<br> mFOLFOX6 & Cediranib
-|style="background-color:#fc8d59"|Seems to have inferior PFS
-|-
-|}
-''Note: in '''PRIME''', KRAS wild-type patients receiving this regimen seem to have inferior PFS. Conversely, in KRAS mutants, this regimen seems to have superior PFS. Reported efficacy for '''OPUS''' is based on the 2012 pooled update and is only for KRAS wild-type tumors.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 600 mg/m<sup>2</sup>/day IV continuous infusion over 22 hours once per day on days 1 & 2 (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, '''before 5-FU'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''before 5-FU'''
-'''14-day cycles'''
-===Variant #2, L-leucovorin {{#subobject:0af678|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2010.29.4496 Hecht et al. 2011]
-|style="background-color:#1a9851"|Phase III (C)
-|FOLFOX4 & Vatalanib
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 600 mg/m<sup>2</sup>/day IV continuous infusion over 22 hours once per day on days 1 & 2 (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, '''before 5-FU'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''before 5-FU'''
-'''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. [http://jco.ascopubs.org/content/18/16/2938.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10944126 PubMed]
-# 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. [http://ascopubs.org/doi/full/10.1200/JCO.2004.09.046 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/24/3/394.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/24/25/4085.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/26/12/2013.long link to original article] '''refers to de Gramont et al. 2000 for protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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. [http://ascopubs.org/doi/full/10.1200/JCO.2008.20.8397 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19114683 PubMed]
-## '''Pooled Update:''' Bokemeyer C, Cutsem EV, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://www.ejcancer.com/article/S0959-8049(12)00209-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/28/31/4697.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20921465 PubMed]
-# 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. [http://ascopubs.org/doi/full/10.1200/JCO.2010.29.4496 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21464406 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. [http://jco.ascopubs.org/content/30/29/3596.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22965965 PubMed]
-==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]]
-===Variant #1, LCV 200 mg/m<sup>2</sup> {{#subobject:792d00|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext Wasan et al. 2017 (SIRFLOX; FOXFIRE-Global)]
-|style="background-color:#1a9851"|Phase III (C)
-|mFOLFOX6 plus SIRT
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|}
-''Note: '''Wasan et al. 2017''' describes the folinic acid as a flat 200 mg dose, but an [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289171/ earlier description of the SIRFLOX protocol] uses 200 mg/m<sup>2</sup>; the authors were contacted for clarification.''
-====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 on days 1 to 2 (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 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'''
-===Variant #2, LCV 350 mg/m<sup>2</sup> {{#subobject:90f8fc|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376131/ Cheeseman et al. 2002]
-|style="background-color:#91cf61"|Non-randomized
-|style="background-color:#d3d3d3"|
-|style="background-color:#d3d3d3"|
-|-
-|rowspan=2|[http://ascopubs.org/doi/abs/10.1200/JCO.2007.15.4138 Hochster et al. 2008 (TREE-1)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E)
-|bFOL
-|style="background-color:#ffffbf"|Seems not superior
 |-
+|[https://doi.org/10.1200/jco.2006.08.1075 Schmoll et al. 2007 (XELOXA)]
+|2003-04 to 2004-10
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#CapeOx|CapeOx]]
-|style="background-color:#ffffbf"|Seems not superior
+| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159415/ Maughan et al. 2011 (UK MRC COIN)]
-|style="background-color:#1a9851"|Phase III (C)
-|mFOLFOX6 & Cetuximab
-|style="background-color:#ffffbf"|Seems not superior (*)
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext Wasan et al. 2017 (FOXFIRE)]
-|style="background-color:#1a9851"|Phase III (C)
-|OxMdG plus SIRT
-|style="background-color:#ffffbf"|Seems not superior
 |-
 |}
-''Note: Efficacy for UK MRC COIN is as reported for KRAS wild-type patients.''
+''<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)]] 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 on days 1 to 2 (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[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)]] 350 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[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'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
+'''8-week cycle for varying durations: 3 cycles (NSABP C-07); 3 to 6 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-'''14-day cycles'''
+===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;"
-===Variant #3, LCV 400 mg/m<sup>2</sup> {{#subobject:db877a|Variant=1}}===
+!style="width: 20%"|Study
-{| class="wikitable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Dates of enrollment
-!style="width: 25%"|Study
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
-!style="width: 25%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/30/29/3596.long Hoff et al. 2012 (HORIZON II)]
+|[https://doi.org/10.1159/000012105 Fountzilas et al. 2000]
-|style="background-color:#1a9851"|Phase III (C)
+|1989-1997
-|CAPOX & Cediranib<br> FOLFOX4 & Cediranib<br> mFOLFOX6 & Cediranib
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#fc8d59"|Seems to have inferior PFS
+|[[#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)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 on days 1 to 2 (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[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)]] 400 mg/m<sup>2</sup> IV once on day 1
+*[[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'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
+'''8-week cycle for 4 cycles'''
+</div></div><br>
-'''14-day cycles'''
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, 1850/100 ("Mayo Clinic regimen") {{#subobject:4bnc36|Variant=1}}===
-===Variant #4, levoleucovorin {{#subobject:8c4386|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-{| class="wikitable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
-!style="width: 25%"|Study
+!style="width: 20%"|Dates of enrollment
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+!style="width: 20%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+!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)]
-|style="background-color:#1a9851"|Phase III (C)
-|mFOLFOX6 & Cetuximab
-|style="background-color:#ffffbf"|Seems not superior (*)
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext Wasan et al. 2017 (FOXFIRE)]
+|[https://doi.org/10.1016/j.ejca.2008.07.002 Popov et al. 2008 (PETACC-1)]
-|style="background-color:#1a9851"|Phase III (C)
+|Not reported-1999
-|OxMdG plus SIRT
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#ffffbf"|Seems not superior
+|[[#Raltitrexed_monotherapy_999|Raltitrexed]]
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior RFS/OS
 |-
 |}
-''Note: Efficacy for UK MRC COIN is as reported for KRAS wild-type patients.''
+''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)]] 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 on days 1 to 2 (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''
-*[[Levoleucovorin (Fusilev)]] 175 mg IV over 2 hours once on day 1
+*[[Leucovorin (Folinic acid)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
+'''28-day cycle for 6 cycles'''
+</div></div><br>
-'''14-day cycles'''
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #5, 1850/2500 ("NCI schedule") {{#subobject:7cc2b9|Variant=1}}===
-===References===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-# 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://www.nature.com/bjc/journal/v87/n4/full/6600467a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376131/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/12177775 PubMed]
+!style="width: 20%"|Study
-# '''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. [http://ascopubs.org/doi/abs/10.1200/JCO.2007.15.4138 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18640933 PubMed]
+!style="width: 20%"|Dates of enrollment
-# '''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://www.ncbi.nlm.nih.gov/pubmed/21641636 PubMed]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-# '''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. [http://jco.ascopubs.org/content/30/29/3596.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22965965 PubMed]
+!style="width: 20%"|Comparator
-# '''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. [http://ascopubs.org/doi/full/10.1200/JCO.2015.66.1181 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26903575 PubMed]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-## '''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://www.ncbi.nlm.nih.gov/pubmed/28781171 PubMed]
-==FOLFOX 7 & sLV5FU2 {{#subobject:5513db|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1093/jnci/90.23.1810 Wolmark et al. 1998 (NSABP C-05)]
-|}
+|1991-1994
-FOLFOX 7 & sLV5FU2: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin and '''<u>s</u>'''implified '''<u>L</u>'''euco'''<u>V</u>'''orin, '''<u>5-FU</u>''', '''<u>2</u>'''-weekly (every 2 weeks)
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#FULV_.26_Interferon_alfa_999|FULV & Interferon alfa]]
-===Regimen {{#subobject:b39a65|Variant=1}}===
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of DFS/OS
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/24/3/394.long Tournigand et al. 2006 (OPTIMOX1)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFOX4_2|FOLFOX4]]
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|}
-====Chemotherapy, FOLFOX 7 portion====
-*[[Fluorouracil (5-FU)]] 1200 mg/m<sup>2</sup>/day IV continuous infusion over 46 hours on days 1 to 2 (total dose per cycle: 2400 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-**Alternatively, [[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
-'''14-day cycle for 6 cycles, until progression of disease or unacceptable toxicity''', then proceed to sLV5FU2
-====Chemotherapy, sLV5FU2 portion====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, '''given second'''; then [[Fluorouracil (5-FU)]] 1500 mg/m<sup>2</sup>/day IV continuous infusion over 46 hours on days 1 to 2 (total dose per cycle: 3000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-**Alternatively, [[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''14-day cycle for 12 cycles, until progression of disease or unacceptable toxicity''', then resume FOLFOX 7 for 6 additional cycles as described above
-===References===
-# Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, Mineur L, Carola E, Etienne PL, Rivera F, Chirivella I, Perez-Staub N, Louvet C, André T, Tabah-Fisch I, de Gramont A. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006 Jan 20;24(3):394-400. [http://jco.ascopubs.org/content/24/3/394.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16421419 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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894803/ Emmanouilides et al. 2007]
-|style="background-color:#91cf61"|Phase II
-|style="background-color:#d3d3d3"|
-|style="background-color:#d3d3d3"|
-|-
-|rowspan=2|[http://jco.ascopubs.org/content/26/12/2013.long Saltz et al. 2008 (NO16966)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFOX4_2|FOLFOX4]]<br> [[#CapeOx|XELOX]]
-|style="background-color:#1a9850"|Superior PFS
-|-
-|[[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]
-|style="background-color:#d3d3d3"|Not reported
 |-
 |}
+<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, then 600 mg/m<sup>2</sup>/day IV continuous infusion over 22 hours on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)
+*[[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)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2
+*[[Leucovorin (Folinic acid)]] 500 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
+'''28-day cycle for 6 cycles'''
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given first'''
+</div></div><br>
-**Infusion times are 2 hours for cycle 1, 1 hour for cycle 2, then 30 minutes for cycles 3 and later
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #6, 2000/400 ("de Gramont regimen"/LV5FU2) {{#subobject:685f89|Variant=1}}===
-'''14-day cycles'''
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-===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://www.ncbi.nlm.nih.gov/pubmed/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. -->
-# 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. [http://jco.ascopubs.org/content/26/12/2013.long link to original article] '''refers to de Gramont et al. 2000 for protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18421054 PubMed]
-==mFOLFOX6 & Bevacizumab {{#subobject:b74416|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX-B: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-===Example orders===
-*[[Example orders for mFOLFOX 6 & Bevacizumab (Avastin) in colon cancer]]
-===Variant #1, standard leucovorin {{#subobject:eeb338|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|rowspan=2|[http://jco.ascopubs.org/content/26/21/3523.full Hochster et al. 2008 (TREE-2)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E)
-|bFOL & Bevacizumab
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[[#CapeOx_.26_Bevacizumab|CapeOx & Bevacizumab]]
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[http://ascopubs.org/doi/10.1200/JCO.2008.19.8135 Hecht et al. 2008 (PACCE)]
-|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]
-|style="background-color:#1a9851"|Phase III (C)
-|FOLF-CB
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[http://jco.ascopubs.org/content/30/29/3588.long Schmoll et al. 2012 (HORIZON III)]
-|style="background-color:#1a9851"|Phase III (C)
-|mFOLFOX6 & Cediranib
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70490-X/fulltext Yamada et al. 2013 (SOFT)]
-|style="background-color:#1a9851"|Phase III (C)
-|SOX & Bevacizumab
-|style="background-color:#eeee01"|Seems to have non-inferior PFS
-|-
-|[https://academic.oup.com/annonc/article/27/8/1539/2237296 Yamazaki et al. 2016 (WJOG4407G)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]
-|style="background-color:#eeee01"|Non-inferior PFS
-|-
-|}
-''This was the most common oxaliplatin-based reigimen used in PACCE.''
-====Chemotherapy====
-*[[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 46 to 48 hours on days 1 to 2 (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
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1
-'''14-day cycles'''
-===Variant #2, racemic L-leucovorin {{#subobject:1d15de|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/29/3/624/4779925 Yamada et al. 2018 (TRICOLORE)]
-|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 1200 mg/m<sup>2</sup>/day IV continuous infusion over 46 to 48 hours on days 1 to 2 (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
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, given first
-'''14-day cycles'''
-===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. [http://jco.ascopubs.org/content/26/21/3523.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://ascopubs.org/doi/10.1200/JCO.2008.19.8135 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/30/29/3588.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22965961 PubMed]
-# '''Observational cohort:''' Bendell JC, Bekaii-Saab TS, Cohn AL, Hurwitz HI, Kozloff M, Tezcan H, Roach N, Mun Y, Fish S, Flick ED, Dalal D, Grothey A. Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-bevacizumab or FOLFIRI-bevacizumab: results from ARIES, a bevacizumab observational cohort study. Oncologist. 2012;17(12):1486-95. Epub 2012 Sep 26. [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://www.ncbi.nlm.nih.gov/pubmed/23015662 PubMed]
-# '''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://www.ncbi.nlm.nih.gov/pubmed/24225157 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. [http://ascopubs.org/doi/full/10.1200/JCO.2015.66.1181 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26903575 PubMed]
-# '''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://academic.oup.com/annonc/article/27/8/1539/2237296 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27177863 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://academic.oup.com/annonc/article/29/3/624/4779925 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29293874 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 {{#subobject:1ec9e5|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|rowspan=2|[http://www.nejm.org/doi/full/10.1056/NEJM200009283431302 Saltz et al. 2000 (Irinotecan Study Group)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E)
-|[[#Fluorouracil_.26_Folinic_acid_2|5-FU & Folinic acid]]
-|style="background-color:#91cf60"|Seems to have superior OS
-|-
-|[[#Irinotecan_monotherapy|Irinotecan]]
-|style="background-color:#d9ef8b"|Might have superior OS
-|-
-|rowspan=2|[http://ascopubs.org/doi/full/10.1200/JCO.2004.09.046 Goldberg et al. 2003]
-|rowspan=2 style="background-color:#1a9851"|Phase III (C)
-|[[#FOLFOX4_3|FOLFOX4]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|[[#IROX|IROX]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|rowspan=2|[http://www.nejm.org/doi/full/10.1056/NEJMoa032691 Hurwitz et al. 2004 (AVF2107)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (C)
-|FL & Bevacizumab
-|style="background-color:#d3d3d3"|Not reported
-|-
-|[[#IFL_.26_Bevacizumab|IFL & Bevacizumab]]
-|style="background-color:#d73027"|Inferior OS
-|-
-|rowspan=2|[http://jco.ascopubs.org/content/25/30/4779.long Fuchs et al. 2007 (BICC-C)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E)
-|[[#CAPIRI|CapeIRI]]
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[[#FOLFIRI|FOLFIRI]]
-|style="background-color:#d73027"|Inferior PFS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012268/ Guan et al. 2011 (ARTIST)]
-|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.''
-====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===
-# '''Irinotecan Study Group:''' 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. [http://www.nejm.org/doi/full/10.1056/NEJM200009283431302 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11006366 PubMed]
-# 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. [http://ascopubs.org/doi/full/10.1200/JCO.2004.09.046 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14665611 PubMed]
-# '''AVF2107:''' 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa032691 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/25/30/4779.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/26/4/689.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/21959045 PubMed]
-==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
-===Variant #1, IFL {{#subobject:772ed7|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|rowspan=2|[http://www.nejm.org/doi/full/10.1056/NEJMoa032691 Hurwitz et al. 2004 (AVF2107)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E)
-|FL & Bevacizumab
-|style="background-color:#d3d3d3"|Not reported
-|-
-|[[#IFL|IFL]]
-|style="background-color:#1a9850"|Superior OS
-|-
-|[http://jco.ascopubs.org/content/25/30/4779.long Fuchs et al. 2007 (BICC-C)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#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
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===Variant #2, mIFL {{#subobject:e336a6|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012268/ Guan et al. 2011 (ARTIST)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#IFL|mIFL]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-====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
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1, 15, 29
-'''42-day cycles'''
-===References===
-# '''AVF2107:''' 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa032691 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/25/30/4779.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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. [http://jco.ascopubs.org/content/26/4/689.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/21959045 PubMed]
-==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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|rowspan=2|[http://www.nejm.org/doi/full/10.1056/NEJM200009283431302 Saltz et al. 2000 (Irinotecan Study Group)]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E)
-|[[#Fluorouracil_.26_Folinic_acid_2|5-FU & Folinic acid]]
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[[#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===
-# '''Irinotecan Study Group:''' 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. [http://www.nejm.org/doi/full/10.1056/NEJM200009283431302 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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
-===Variant #1, q3wk {{#subobject:e8b674|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/29/3/624/4779925 Yamada et al. 2018 (TRICOLORE)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#CapeOx_.26_Bevacizumab|CapeOx & Bevacizumab]]<br> [[#mFOLFOX6_.26_Bevacizumab_2|mFOLFOX6 & Bevacizumab]]
-|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> BID on days 1 to 15, beginning in the evening (28 doses per cycle)
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1, '''given first'''
-'''21-day cycles'''
-===Variant #2, q4wk {{#subobject:081d47|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/29/3/624/4779925 Yamada et al. 2018 (TRICOLORE)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#CapeOx_.26_Bevacizumab|CapeOx & Bevacizumab]]<br> [[#mFOLFOX6_.26_Bevacizumab_2|mFOLFOX6 & Bevacizumab]]
-|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> BID on days 1 to 15, beginning in the evening (28 doses per cycle)
-*[[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://academic.oup.com/annonc/article/29/3/624/4779925 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29293874 PubMed]
-==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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|rowspan=2|[http://ascopubs.org/doi/full/10.1200/JCO.2004.09.046 Goldberg et al. 2003]
-|rowspan=2 style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFOX4_3|FOLFOX4]]
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|[[#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===
-# 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. [http://ascopubs.org/doi/full/10.1200/JCO.2004.09.046 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2004.05.188 Sørbye et al. 2004]
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2011.38.0915 Tveit et al. 2012 (NORDIC-VII)]
-|style="background-color:#1a9851"|Phase III (C)
-|Nordic FLOX & Cetuximab
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2
-*[[Folinic acid (Leucovorin)]] 60 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, '''given 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. [http://ascopubs.org/doi/full/10.1200/JCO.2004.05.188 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14701765 PubMed]
-# Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, Sigurdsson F, Kure E, Ikdahl T, Skovlund E, Fokstuen T, Hansen F, Hofsli E, Birkemeyer E, Johnsson A, Starkhammar H, Yilmaz MK, Keldsen N, Erdal AB, Dajani O, Dahl O, Christoffersen T. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012 May 20;30(15):1755-62. Epub 2012 Apr 2. [http://ascopubs.org/doi/full/10.1200/JCO.2011.38.0915 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22473155 PubMed]
-## '''Update:''' Guren TK, Thomsen M, Kure EH, Sorbye H, Glimelius B, Pfeiffer P, Österlund P, Sigurdsson F, Lothe IMB, Dalsgaard AM, Skovlund E, Christoffersen T, Tveit KM. Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study. Br J Cancer. 2017 May 9;116(10):1271-1278. Epub 2017 Apr 11. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482736/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28399112 PubMed]
-==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" 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#Efficacy|Efficacy]]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 20%"|[[Levels_of_Evidence#Toxicity|Toxicity]]
 |-
-|[https://academic.oup.com/annonc/article-abstract/28/6/1288/3102942 Kwakman et al. 2017 (SALTO)]
+|[https://doi.org/10.1200/JCO.2003.10.065 André et al. 2003 (GERCOR C96.1)]
-|style="background-color:#1a9851"|Phase III (E)
+|1996-1999
-|[[#Capecitabine_monotherapy_2|Capecitabine]]
+| style="background-color:#1a9851" |Phase 3 (C)
-|
+|[[#FULV|FULV]]; monthly
-|style="background-color:#1a9850"|Lower incidence of hand-foot syndrome
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|}
+|[https://doi.org/10.1056/NEJMoa032709 André et al. 2004 (MOSAIC)]
-''Note: this trial had a primary toxicity endpoint.''
+|1998-2001
-====Chemotherapy====
+| style="background-color:#1a9851" |Phase 3 (C)
-*[[Tegafur, gimeracil, oteracil (S-1)]] 30 mg/m<sup>2</sup> PO BID on days 1 to 14
+|[[#FOLFOX4|FOLFOX4]]
+| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
-'''21-day cycles'''
-===References===
-# 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. 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://academic.oup.com/annonc/article-abstract/28/6/1288/3102942 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28383633 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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext Hong et al. 2012]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#CapeOx_2|CapeOX]]
-|style="background-color:#eeee01"|Non-inferior PFS
-|-
-|}
-====Chemotherapy====
-*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO BID 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===
-# 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://www.ncbi.nlm.nih.gov/pubmed/23062232 PubMed]
-=Maintenance after first-line therapy=
-==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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext Hong et al. 2012]
+|[https://doi.org/10.1093/annonc/mdn680 Ychou et al. 2009 (FFCD 9802)]
-|style="background-color:#91cf61"|Non-randomized portion of RCT
+|1998-2002
-|style="background-color:#d3d3d3"|
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#d3d3d3"|
+|[[#IFL_999|IFL]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|[https://academic.oup.com/annonc/article/27/6/1074/1741605 Luo et al. 2016]
+|[https://doi.org/10.1200/JCO.2008.21.6663 Van Cutsem et al. 2009 (PETACC-3)]
-|style="background-color:#1a9851"|Phase III (E)
+|2000-2002
-|[[#Observation_2|Observation]]
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#1a9850"|Superior PFS
+|[[#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 2015 update.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*Hong et al. 2012: [[#CapeOx_2|CapeOX]] x 9
+*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-*Luo et al. 2016: [[#mFOLFOX6_2|FOLFOX]] or [[#CapeOx_2|XELOX]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO BID on days 1 to 14
+*[[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>)
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first'''
-'''21-day cycles'''
+'''14-day cycle for 12 cycles'''
+</div></div><br>
-===References===
+<div class="toccolours" style="background-color:#eeeeee">
-# 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://www.ncbi.nlm.nih.gov/pubmed/23062232 PubMed]
+===Regimen variant #7, 2000/1000 {{#subobject:6igjc9|Variant=1}}===
-# 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://academic.oup.com/annonc/article/27/6/1074/1741605 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26940686 PubMed]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
-==Capecitabine & Bevacizumab {{#subobject:083f75|Regimen=1}}==
+!style="width: 20%"|Dates of enrollment
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1016/0016-5085(94)90748-x Francini et al. 1994]
-|}
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-CAP-B: '''<u>CAP</u>'''ecitabine & '''<u>B</u>'''evacizumab
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-259-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
-===Regimen {{#subobject:49256d|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62004-3/fulltext Simkens et al. 2015 (CAIRO3)]
+|} -->
-|style="background-color:#1a9851"|Phase III (E)
+|1985-1990
-|[[#Observation_2|Observation]]
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|style="background-color:#1a9850"|Superior PFS2
+|[[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====
-*[[#CapeOx_.26_Bevacizumab|CAPOX-B]] x 6
+*[[Surgery#Colorectal_cancer_surgery|Surgery]], within 3 weeks
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO BID
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 5
-*[[Bevacizumab (Avastin)]] 7.5 mg IV once on day 1
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5
+'''28-day cycle for 12 cycles'''
-'''21-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-===References===
+===Regimen variant #8, 2125/100 ("Mayo Clinic regimen") {{#subobject:4bd336|Variant=1}}===
-# '''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. 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://www.ncbi.nlm.nih.gov/pubmed/25862517 PubMed]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-## '''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://academic.oup.com/annonc/article/28/9/2128/3884600 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28911067 PubMed]
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
-==Observation==
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 20%"|Comparator
-|-
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|[[#top|back to top]]
-|}
-===Regimen===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62004-3/fulltext Simkens et al. 2015 (CAIRO3)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Capecitabine_.26_Bevacizumab_2|CAP-B]]
-|style="background-color:#d73027"|Inferior PFS2
 |-
-|[https://academic.oup.com/annonc/article/27/6/1074/1741605 Luo et al. 2016]
+||[https://doi.org/10.1056/NEJMoa043116 Twelves et al. 2005 (X-ACT)]
-|style="background-color:#1a9851"|Phase III (C)
+|1998-2001
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#Capecitabine_monotherapy|Capecitabine]]
-|style="background-color:#d73027"|Inferior PFS
+| style="background-color:#fee08b" |Might have inferior OS<sup>1</sup>
 |-
-|}
+|[https://doi.org/10.1016/j.ejca.2008.07.002 Popov et al. 2008 (PETACC-1)]
-''No further treatment after first-line induction.''
+|Not reported-1999
-====Preceding treatment====
+| style="background-color:#1a9851" |Phase 3 (C)
-*CAIRO3: [[#CapeOx_.26_Bevacizumab|CAPOX-B]] x 6
+|[[#Raltitrexed_monotherapy_999|Raltitrexed]]
-*Luo et al. 2016: [[#mFOLFOX6_2|FOLFOX]] or [[#CapeOx_2|XELOX]]
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior RFS/OS
-===References===
-# '''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. 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://www.ncbi.nlm.nih.gov/pubmed/25862517 PubMed]
-## '''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://academic.oup.com/annonc/article/28/9/2128/3884600 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28911067 PubMed]
-# Luo HY, Li YH, Wang W, Wang ZQ, Yuan X, Ma D, Wang FH, Zhang DS, Lin DR, Lin YC, Jia J, Hu XH, Peng JW, Xu RH. Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety. Ann Oncol. 2016 Jun;27(6):1074-81. Epub 2016 Mar 2. [https://academic.oup.com/annonc/article/27/6/1074/1741605 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26940686 PubMed]
-==S-1 monotherapy {{#subobject:b5a1dd|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1016/j.ejca.2013.01.030 Köhne et al. 2013 (PETACC-2)]
-|}
+|1999-2004
-===Regimen {{#subobject:608e8f|Variant=1}}===
+| style="background-color:#1a9851" |Phase 3 (C)
-{| class="wikitable" style="width: 100%; text-align:center;"
+|1. [[#FULV|FULV]]; LV5FU2<br>2. [[#FULV|FULV]]; AIO regimen<br> 3. [[#FULV|FULV]]; TTD regimen
-!style="width: 50%"|Study
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS60
-!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext Hong et al. 2012]
+|[https://doi.org/10.1200/jco.2006.08.1075 Schmoll et al. 2007 (XELOXA)]
-|style="background-color:#91cf61"|Non-randomized portion of RCT
+|2003-04 to 2004-10
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#CapeOx|XELOX]]
+| style="background-color:#fc8d59" |Seems to have inferior OS<sup>2</sup>
 |-
 |}
+''<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>
+''Note: This was the upper bound of 5-FU dosing in PETACC-1.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#SOX|SOX]] x 9
+*[[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 BID on days 1 to 14
+*[[Fluorouracil (5-FU)]] 425 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">
-'''21-day cycles'''
+===Regimen variant #9, 2125/100, with cycle elongation ("Mayo Clinic regimen") {{#subobject:e24014|Variant=1}}===
-===References===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-# 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://www.ncbi.nlm.nih.gov/pubmed/23062232 PubMed]
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
-=Advanced or metastatic disease, second-line therapy=
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-==CapeOx {{#subobject:6b5972|Regimen=1}}==
+!style="width: 20%"|Comparator
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[[#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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://academic.oup.com/annonc/article/19/10/1720/240463 Rothenberg et al. 2008]
+|[https://doi.org/10.1200/jco.1997.15.1.246 O'Connell et al. 1997 (CALGB 8896)]
-|style="background-color:#1a9851"|Phase III (E)
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-|[[#FOLFOX4_4|FOLFOX4]]
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-260-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
-|style="background-color:#eeee01"|Non-inferior PFS
 |-
-|}
+|} -->
-====Chemotherapy====
+|1988-02 to 1989-08
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
+|[[Colon_cancer_-_null_regimens#Observation|Observation]]
-'''21-day cycles'''
-===References===
-# 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://academic.oup.com/annonc/article/19/10/1720/240463 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18550577 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
-===Variant #1, "standard" {{#subobject:f1b041|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815882/ Lim et al. 2015]
-|style="background-color:#1a9851"|Phase III (C)
-|XELIRI & Simvastatin
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> BID on days 1 to 14
-*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-'''21-day cycles'''
-===Variant #2, "modified" {{#subobject:b3be15|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFIRI_2|FOLFIRI]]
-|style="background-color:#eeee01"|Non-inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> BID 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===
-# 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://www.nature.com/bjc/journal/v113/n10/full/bjc2015371a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815882/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26505681 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://www.ncbi.nlm.nih.gov/pubmed/29555258 PubMed]
-==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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFIRI_.26_Bevacizumab_2|FOLFIRI & Bevacizumab]]
-|style="background-color:#eeee01"|Non-inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO BID on days 1 to 14
-*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-*[[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://www.ncbi.nlm.nih.gov/pubmed/29555258 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]]
-===Variant #1, lower-dose leucovorin {{#subobject:b1e6e2|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815882/ Lim et al. 2015]
-|style="background-color:#1a9851"|Phase III (C)
-|FOLFIRI & Simvastatin
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given after irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup>/day IV continuous infusion over 46 hours on days 1 & 2, '''given last''' (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'''
-===Variant #2, higher-dose leucovorin {{#subobject:3cf53b|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/28/31/4706.long Peeters et al. 2010]
-|style="background-color:#1a9851"|Phase III (C)
-|[[Colon_cancer,_KRAS_wild-type#FOLFIRI_.26_Panitumumab|FOLFIRI & Panitumumab]]
-|style="background-color:#d73027"|Inferior PFS (*)
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2012.42.8201 Van Cutsem et al. 2012 (VELOUR)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#FOLFIRI_.26_Ziv-aflibercept|FOLFIRI & Ziv-aflibercept]]
-|style="background-color:#d73027"|Inferior OS
-|-
-|[https://academic.oup.com/annonc/article/26/4/724/204710 Masi et al. 2015 (BEBYP)]
-|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)]
-|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)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#CAPIRI_2|CAPIRI]]
-|style="background-color:#eeee01"|Non-inferior OS
-|-
-|}
-''Note: BEBYP does not provide dosing details; this is the most commonly used variant of FOLFIRI. Efficacy reported for Peeters et al. 2010 is for wild-type KRAS, only.''
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given during irinotecan infusion'''
-*[[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 on days 1 & 2, '''given last''' (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 together with leucovorin'''
-'''14-day cycles'''
-===Variant #3, levo-leucovorin {{#subobject:db9c30|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]
-|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 during irinotecan infusion'''
-*[[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 on days 1 & 2, '''given last''' (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 together with levo-leucovorin'''
-'''14-day cycles'''
-===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. [http://ascopubs.org/doi/full/10.1200/JCO.2004.05.113 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14657227 PubMed]
-# Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010 Nov 1;28(31):4706-13. Epub 2010 Oct 4. [http://jco.ascopubs.org/content/28/31/4706.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20921462 PubMed]
-<!-- 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. [http://ascopubs.org/doi/full/10.1200/JCO.2012.42.8201 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22949147 PubMed]
-## '''Subgroup analysis:''' Tabernero J, Van Cutsem E, Lakomý R, Prausová J, Ruff P, van Hazel GA, Moiseyenko VM, Ferry DR, McKendrick JJ, Soussan-Lazard K, Chevalier S, Allegra CJ. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014 Jan;50(2):320-31. [https://www.ejcancer.com/article/S0959-8049%2813%2900853-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24140268 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://academic.oup.com/annonc/article/26/4/724/204710 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25600568 PubMed]
-# '''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://www.ncbi.nlm.nih.gov/pubmed/25877855 PubMed]
-# Lim SH, Kim TW, Hong YS, Han SW, Lee KH, Kang HJ, Hwang IG, Lee JY, Kim HS, Kim ST, Lee J, Park JO, Park SH, Park YS, Lim HY, Jung SH, Kang WK. A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer. Br J Cancer. 2015 Nov 17;113(10):1421-6. Epub 2015 Oct 27. [https://www.nature.com/bjc/journal/v113/n10/full/bjc2015371a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815882/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26505681 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://www.ncbi.nlm.nih.gov/pubmed/29555258 PubMed]
-==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
-===Variant #1 {{#subobject:548cd8a|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70477-1/fulltext Bennouna et al. 2012 (ML18147)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|[https://academic.oup.com/annonc/article/26/4/724/204710 Masi et al. 2015 (BEBYP)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFIRI_2|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)]
-|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 during irinotecan infusion'''
-*[[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 on days 1 & 2, '''given last''' (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 together with leucovorin'''
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1
-'''14-day cycles'''
-===Variant #2, levo-leucovorin {{#subobject:2c0ba3|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]
-|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 during irinotecan infusion'''
-*[[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 on days 1 & 2, '''given last''' (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 together with levo-leucovorin'''
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1
-'''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://www.ncbi.nlm.nih.gov/pubmed/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://academic.oup.com/annonc/article/26/4/724/204710 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25600568 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://www.ncbi.nlm.nih.gov/pubmed/29555258 PubMed]
-==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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2815%2970127-0/fulltext Tabernero et al. 2015 (RAISE)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFIRI_2|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 over 2 to 4 minutes once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 48 hours on days 1 to 2, '''given last''' (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://www.ncbi.nlm.nih.gov/pubmed/25877855 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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2012.42.8201 Van Cutsem et al. 2012 (VELOUR)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFIRI_2|FOLFIRI]]
-|style="background-color:#1a9850"|Superior OS
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given after ziv-aflibercept'''
-*[[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 on days 1 to 2, '''given last''' (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 after ziv-aflibercept'''
-*[[Ziv-aflibercept (Zaltrap)]] 4 mg/kg IV over 60 minutes once on day 1, '''given first'''
-====Supportive medications====
-*"Premedication with [[Atropine (Atropen)]] and [[:Category:Emesis_prevention|anti-emetics]] was permitted. [[:Category:Granulocyte_colony-stimulating_factors|Granulocyte-colony stimulating factor (G-CSF)]] was used according to the [http://jop.ascopubs.org/content/2/4/196.full 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. [http://ascopubs.org/doi/full/10.1200/JCO.2012.42.8201 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22949147 PubMed]
-## '''Subgroup analysis:''' Tabernero J, Van Cutsem E, Lakomý R, Prausová J, Ruff P, van Hazel GA, Moiseyenko VM, Ferry DR, McKendrick JJ, Soussan-Lazard K, Chevalier S, Allegra CJ. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014 Jan;50(2):320-31. [https://www.ejcancer.com/article/S0959-8049%2813%2900853-8/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24140268 PubMed]
-==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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/19/10/1720/240463 Rothenberg et al. 2008]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#CapeOx_3|XELOX]]
-|style="background-color:#eeee01"|Non-inferior PFS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 600 mg/m<sup>2</sup>/day IV continuous infusion over 22 hours once per day on days 1 & 2 (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, '''before 5-FU'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''before 5-FU'''
-'''14-day cycles'''
-===References===
-# 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://academic.oup.com/annonc/article/19/10/1720/240463 link to original article] '''refers to de Gramont et al. 2000 protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/26/4/724/204710 Masi et al. 2015 (BEBYP)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#mFOLFOX6_.26_Bevacizumab_2|mFOLFOX6 & Bevacizumab]]
-|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 on days 1 to 2 (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://academic.oup.com/annonc/article/26/4/724/204710 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25600568 PubMed]
-==mFOLFOX6 & Bevacizumab {{#subobject:46965e|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6 & Bevacizumab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Bevacizumab
-===Regimen {{#subobject:61186f|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/26/4/724/204710 Masi et al. 2015 (BEBYP)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#mFOLFOX6_.26_3|mFOLFOX6]]
 | style="background-color:#91cf60" |Seems to have superior OS
 |-
-|}
+| rowspan="3" |[https://doi.org/10.1200/jco.2004.00.5686 Haller et al. 2005 (Intergroup 0089)]
-''Note: BEBYP does not provide dosing details; this is the most commonly used variant of mFOLFOX6.''
+|rowspan=3|1988-1992
-====Chemotherapy====
+| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-de-esc)
-*[[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 on days 1 to 2 (total dose per cycle: 2800 mg/m<sup>2</sup>)
+|1. [[#FULV|FULV]]; high-dose
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[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://academic.oup.com/annonc/article/26/4/724/204710 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25600568 PubMed]
-==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]]
-===Variant #1, 125 mg/m<sup>2</sup>, 4 weeks out of 6 {{#subobject:73a017|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/21/5/807.long Fuchs et al. 2003]
-|style="background-color:#1a9851"|Phase III (E)
-|Irinotecan every 3 weeks
-|style="background-color:#ffffbf"|Seems not superior
 |-
-|}
+|2. [[Colon_cancer_-_historical#FULV_.26_Levamisole|FULV & Levamisole]]; LDLV
-''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.''
+| style="background-color:#ffffbf" |Did not meet primary endpoint of 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'''
-===Variant #2, 250 mg/m<sup>2</sup> q3wk {{#subobject:7c1d8f|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/26/28/4544.long Haller et al. 2008]
+|3. [[Colon_cancer_-_historical#Fluorouracil_.26_Levamisole|5-FU & Levamisole]]
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|[[#IROX_2|IROX]]
-|style="background-color:#d73027"|Inferior OS
 |-
-|}
+| rowspan="2" |[https://doi.org/10.1016/s0140-6736(02)09836-7 Punt et al. 2002 (Study 157-002)]
-''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.''
+|rowspan=2|1995-1999
-====Chemotherapy====
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
-*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 90 minutes once on day 1
+|1. [[#FULV_.26_Edrecolomab_999|FULV & Edrecolomab]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-'''21-day cycles'''
-===Variant #3, 300 mg/m<sup>2</sup> q3wk {{#subobject:190e25|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext Rougier et al. 1998]
+|2. [[Colon_cancer_-_historical#Edrecolomab_monotherapy|Edrecolomab]]
-|style="background-color:#1a9851"|Phase III (E)
-|Continuous 5-FU
 | style="background-color:#91cf60" |Seems to have superior OS
 |-
-|[http://jco.ascopubs.org/content/21/5/807.long Fuchs et al. 2003]
+|[https://doi.org/10.1200/JCO.2008.18.5710 Fields et al. 2009 (Study 157-001)]
-|style="background-color:#1a9851"|Phase III (E)
+|1995-1999
-|Irinotecan 4 weeks out of 6
+| style="background-color:#1a9851" |Phase 3 (C)
-|style="background-color:#ffffbf"|Seems not superior
+|[[#FULV_.26_Edrecolomab_999|FULV & Edrecolomab]]
-|-
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|[http://jco.ascopubs.org/content/26/14/2311.long Sobrero et al. 2008 (EPIC)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[Colon_cancer,_KRAS_wild-type#Irinotecan_.26_Cetuximab|Irinotecan & Cetuximab]]
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698019/ Kim et al. 2009 (N9841)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#FOLFOX4_4|FOLFOX4]]
-|style="background-color:#eeee01"|Non-inferior OS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70163-3/fulltext Seymour et al. 2013 (PICCOLO)]
-|style="background-color:#1a9851"|Phase III (C)
-|Irinotecan & Panitumumab
-|style="background-color:#ffffbf"|Seems not superior
 |-
 |}
-''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.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 300 mg/m<sup>2</sup> IV over 90 minutes once on day 1
+*[[Fluorouracil (5-FU)]] 425 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'''
-'''21-day cycles'''
+'''28-day cycle for 3 cycles, then 35-day cycle for 3 cycles'''
+</div></div>
-===Variant #4, 350 mg/m<sup>2</sup> q3wk {{#subobject:627110|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext Rougier et al. 1998]
-|style="background-color:#1a9851"|Phase III (E)
-|Continuous 5-FU
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[http://jco.ascopubs.org/content/21/5/807.long Fuchs et al. 2003]
-|style="background-color:#1a9851"|Phase III (E)
-|Irinotecan 4 weeks out of 6
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[http://jco.ascopubs.org/content/26/14/2311.long Sobrero et al. 2008 (EPIC)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Irinotecan_.26_Cetuximab|Irinotecan & Cetuximab]]
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|[http://jco.ascopubs.org/content/26/28/4544.long Haller et al. 2008]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#IROX_2|IROX]]
-|style="background-color:#d73027"|Inferior OS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698019/ Kim et al. 2009 (N9841)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#FOLFOX4_4|FOLFOX4]]
-|style="background-color:#eeee01"|Non-inferior OS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70163-3/fulltext Seymour et al. 2013 (PICCOLO)]
-|style="background-color:#1a9851"|Phase III (C)
-|Irinotecan & Cyclosporine<br> Irinotecan & Panitumumab
-|style="background-color:#ffffbf"|Seems not superior
-|-
-|}
-''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.''
-====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===
-# 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://www.ncbi.nlm.nih.gov/pubmed/9807986 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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/8410113/ 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. [http://jco.ascopubs.org/content/21/5/807.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12610178 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]
-<!-- 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. -->
+#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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/8143995/ PubMed]
-# '''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. [http://jco.ascopubs.org/content/26/14/2311.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18390971 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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/8996149/ 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. [http://jco.ascopubs.org/content/26/28/4544.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18824706 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]
-# '''N9841:''' Kim GP, Sargent DJ, Mahoney MR, Rowland KM Jr, Philip PA, Mitchell E, Mathews AP, Fitch TR, Goldberg RM, Alberts SR, Pitot HC. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol. 2009 Jun 10;27(17):2848-54. Epub 2009 Apr 20. [http://ascopubs.org/doi/full/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://www.ncbi.nlm.nih.gov/pubmed/19380443 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]
-# '''PICCOLO:''' Seymour MT, Brown SR, Middleton G, Maughan T, Richman S, Gwyther S, Lowe C, Seligmann JF, Wadsley J, Maisey N, Chau I, Hill M, Dawson L, Falk S, O'Callaghan A, Benstead K, Chambers P, Oliver A, Marshall H, Napp V, Quirke P. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013 Jul;14(8):749-59. Epub 2013 May 29. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70163-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699713/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23725851 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] '''dosing details in manuscript have been reviewed by our editors''' [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://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://doi.org/10.1159/000012105 link to original article] '''dosing details in abstract have been reviewed by our editors''' [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://doi.org/10.1016/s0140-6736(02)09836-7 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [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]
+##'''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://doi.org/10.1056/NEJMoa032709 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [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, 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://doi.org/10.1056/NEJMoa043116 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [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]
+<!-- 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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [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]
+#'''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] '''dosing details in manuscript have been reviewed by our editors''' [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]
+#'''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] '''dosing details in manuscript have been reviewed by our editors''' [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://doi.org/10.1016/j.ejca.2008.07.002 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in abstract have been reviewed by our editors''' [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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/19451425/ PubMed] [https://clinicaltrials.gov/study/NCT00026273 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. [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] '''dosing details in abstract have been reviewed by our editors''' [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]
-==IRIS {{#subobject:7f7223|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}}===
+{| 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]]
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143094/ Yoshida et al. 2014 (ACTS-CC)]
-|}
+|2008-04 to 2009-06
-IRIS '''<u>IRI</u>'''notecan & '''<u>S</u>'''-1
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-===Regimen {{#subobject:dd01b1|Variant=1}}===
+|[[#Tegafur.2C_Uracil.2C_Folinic_acid|UFT + LV]]
-{| class="wikitable" style="width: 100%; text-align:center;"
+| 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)
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.sciencedirect.com/science/article/pii/S1470204510701819 Muro et al. 2010 (FIRIS)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFIRI_2|FOLFIRI]]
-|style="background-color:#eeee01"|Non-inferior PFS
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV once per day on days 1 & 15
+*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
-*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:
+**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 28
-**BSA less than 1.25 m<sup>2</sup>: 40 mg PO BID on days 1 to 14
+**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 between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO BID on days 1 to 14
+**BSA greater than 1.50 m<sup>2</sup>: 60 mg PO twice per day on days 1 to 28
-**BSA at least 1.5 m<sup>2</sup>: 60 mg PO BID on days 1 to 14
+'''42-day cycle for 4 cycles'''
+</div></div>
-'''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://www.sciencedirect.com/science/article/pii/S1470204510701819 link to SD article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20708966 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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/24942277/ PubMed] [https://clinicaltrials.gov/study/NCT00660894 NCT00660894]
+==SOX {{#subobject:617cc1|Regimen=1}}==
-==IROX {{#subobject:2c150d|Regimen=1}}==
+SOX: '''<u>S</u>'''-1, '''<u>OX</u>'''aliplatin
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
+===Regimen {{#subobject:c80e20|Variant=1}}===
-|[[#top|back to top]]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-|}
+!style="width: 20%"|Study
-IROX: '''<u>IR</u>'''inotecan & '''<u>OX</u>'''aliplatin
+!style="width: 20%"|Dates of enrollment
-===Regimen {{#subobject:78e355|Variant=1}}===
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-{| class="wikitable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Comparator
-!style="width: 25%"|Study
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/26/28/4544.long Haller et al. 2008]
+|[https://doi.org/10.1016/j.clcc.2019.10.002 Sunami et al. 2019 (ACTS-CC 02)]
-|style="background-color:#1a9851"|Phase III (E)
+|2010-2014
-|[[#Irinotecan_monotherapy_2|Irinotecan]]
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|style="background-color:#1a9850"|Superior OS
+|[[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====
-*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV over 30 to 90 minutes 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 14
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
+*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV once on day 1
+'''21-day cycle for 8 cycles'''
-'''21-day cycles'''
+</div></div>
 ===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. [http://jco.ascopubs.org/content/26/28/4544.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18824706 PubMed]
+#'''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] '''dosing details in manuscript have been reviewed by our editors''' [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]
-=Advanced or metastatic disease, third-line therapy=
+==Tegafur, Uracil, Folinic acid {{#subobject:5ed2aa|Regimen=1}}==
-==FOLFIRI {{#subobject:f7001b|Regimen=1}}==
+UFT + LV: '''<u>UFT</u>''' (Tegafur and uracil) & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid)
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<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%"|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]]
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621030/ Sadahiro et al. 2015 (JFMC33-0502)]
-|}
+|2005-2007
-FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
+| style="background-color:#1a9851" |Phase 3 (C)
-===Example orders===
+|[[#Tegafur.2C_Uracil.2C_Folinic_acid|UFT + LV]]; weekly x 18 mo
-*[[Example orders for FOLFIRI in colon cancer]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-===Regimen {{#subobject:31fcbe|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 50%"|Study
-!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ejcancer.com/article/S0959-8049(99)00150-1/fulltext André et al. 1999]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143094/ Yoshida et al. 2014 (ACTS-CC)]
-|style="background-color:#91cf61"|Non-randomized
+|2008-04 to 2009-06
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#S-1_monotherapy|S-1]]
+| style="background-color:#eeee01" |Non-inferior DFS36
 |-
-|}
+|[https://doi.org/10.1016/j.clcc.2019.10.002 Sunami et al. 2019 (ACTS-CC 02)]
-====Chemotherapy====
+|2010-2014
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given during irinotecan infusion'''
+| style="background-color:#1a9851" |Phase 3 (C)
-*[[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 on days 1 & 2, '''given last''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
+|[[#SOX|SOX]]
-**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
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first together with leucovorin'''
-'''14-day cycles'''
-===References===
-# André T, Louvet C, Maindrault-Goebel F, Couteau C, Mabro M, Lotz JP, Gilles-Amar V, Krulik M, Carola E, Izrael V, de Gramont A. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer; GERCOR. Eur J Cancer. 1999 Sep;35(9):1343-7. [https://www.ejcancer.com/article/S0959-8049(99)00150-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10658525 PubMed]
-=Advanced or metastatic disease, subsequent lines of therapy=
-''Note: these are trials that are for lines other than first-line; trials restricted to second-line or third-line therapy are to be found in the sections above.''
-==Best supportive care==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2898%2902309-5/fulltext Cunningham et al. 1998]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Irinotecan_monotherapy_3|Irinotecan]]
-|style="background-color:#d73027"|Inferior OS
-|-
-|[http://jco.ascopubs.org/content/25/13/1658.long Van Cutsem et al. 2007]
-|style="background-color:#1a9851"|Phase III (C)
-|[[Colon_cancer,_KRAS_wild-type#Panitumumab_monotherapy|Panitumumab]]
-|style="background-color:#d73027"|Inferior PFS
-|-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa071834 Jonker et al. 2007 (NCIC CTG CO.17)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[Colon_cancer,_KRAS_wild-type#Cetuximab_monotherapy|Cetuximab]]
-|style="background-color:#d73027"|Inferior OS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104888/ Kim et al. 2016 (20100007)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[Colon_cancer,_KRAS_wild-type#Panitumumab_monotherapy|Panitumumab]]
-|style="background-color:#d73027"|Inferior OS
-|-
-|}
-''No treatment except for supportive care.''
-===References===
-# Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1413-8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2898%2902309-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9807987 PubMed]
-<!-- Presented at the 97th Annual Meeting of the American Association for Cancer Research, April 1-5, 2006, Washington, DC; 2nd Annual Conference of the Hematology/Oncology Pharmacy Association, June 15-18, 2006, Orlando, FL; 8th Annual Conference of the World Congress on Gastrointestinal Cancer, June 28-July 1, 2006, Barcelona, Spain; and at the 31st European Society of Medical Oncology Congress, September 29-October 3, 2006, Istanbul, Turkey. -->
-# Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1;25(13):1658-64. [http://jco.ascopubs.org/content/25/13/1658.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17470858 PubMed]
-<!-- # Bristol-Myers Squibb and ImClone. A Phase III Randomized Study of Cetuximab (Erbitux, C225) and Best Supportive Care Versus Best Supportive Care in Patients with Pretreated Metastatic Epidermal Growth Factor Receptor (EGFR)-Positive Colorectal Carcinoma. Final Clinical Study Report for CA225025. 2007 Mar 5. [http://ctr.bms.com/pdf//CA225025.pdf link to original report] '''contains verified protocol''' -->
-# Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007 Nov 15;357(20):2040-8. [http://www.nejm.org/doi/full/10.1056/NEJMoa071834 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18003960 PubMed]
-## '''Subgroup analysis:''' Asmis TR, Powell E, Karapetis CS, Jonker DJ, Tu D, Jeffery M, Pavlakis N, Gibbs P, Zhu L, Dueck DA, Whittom R, Langer C, O'Callaghan CJ. Comorbidity, age and overall survival in cetuximab-treated patients with advanced colorectal cancer (ACRC)--results from NCIC CTG CO.17: a phase III trial of cetuximab versus best supportive care. Ann Oncol. 2011 Jan;22(1):118-26. Epub 2010 Jul 5. [http://annonc.oxfordjournals.org/content/22/1/118.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20603436 PubMed]
-# '''20100007:''' Kim TW, Elme A, Kusic Z, Park JO, Udrea AA, Kim SY, Ahn JB, Valencia RV, Krishnan S, Bilic A, Manojlovic N, Dong J, Guan X, Lofton-Day C, Jung AS, Vrdoljak E. A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer. Br J Cancer. 2016 Nov 8;115(10):1206-1214. Epub 2016 Oct 13. [https://www.nature.com/bjc/journal/v115/n10/full/bjc2016309a.html link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104888/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27736842 PubMed]
-==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
-===Variant #1, racemic leucovorin {{#subobject:ecdc32|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|rowspan=2|[http://ascopubs.org/doi/full/10.1200/JCO.2006.09.6305 Giantonio et al. 2007 (ECOG E3200)]
-|rowspan = 2 style="background-color:#1a9851"|Phase III (C)
-|[[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|Bevacizumab
-|style="background-color:#d3d3d3"|Not reported
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698019/ Kim et al. 2009 (N9841)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Irinotecan_monotherapy_2|Irinotecan]]
-|style="background-color:#eeee01"|Non-inferior OS
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2010.29.5436 Van Cutsem et al. 2011]
-|style="background-color:#1a9851"|Phase III (C)
-|FOLFOX4 & Vatalanib
-|style="background-color:#ffffbf"|Seems not superior
 |-
 |}
-''Note: patients in N9841 had not previously received irinotecan or oxaliplatin; patients in Van Cutsem et al. 2011 had not previously received oxaliplatin.''
+''Note: In ACTS-CC, this dosing was used for patients with BSA less than 1.17 m<sup>2</sup>.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours once per day on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)
+*[[Tegafur and uracil (UFT)]] 100 mg/m<sup>2</sup> PO every 8 hours on days 1 to 28
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''before 5-FU'''
+*[[Leucovorin (Folinic acid)]] 25 mg PO every 8 hours on days 1 to 28
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''before 5-FU'''
+'''35-day cycle for 5 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-'''14-day cycles'''
+===Regimen variant #2, 300/90 {{#subobject:643dbb|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-===Variant #2, L-leucovorin {{#subobject:16c59a|Variant=1}}===
+!style="width: 20%"|Study
-{| class="wikitable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Dates of enrollment
-!style="width: 25%"|Study
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
-!style="width: 25%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2010.29.5436 Van Cutsem et al. 2011]
+|[https://doi.org/10.1200/jco.2005.04.7498 Lembersky et al. 2006 (NSABP C-06)]
-|style="background-color:#1a9851"|Phase III (C)
+|1997-1999
-|FOLFOX4 & Vatalanib
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|style="background-color:#ffffbf"|Seems not superior
+|[[#FULV|FULV]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of DFS/OS
 |-
 |}
-''Note: these patients had not previously received oxaliplatin.''
+<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====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours once per day on days 1 & 2 (total dose per cycle: 2000 mg/m<sup>2</sup>)
+*[[Tegafur and uracil (UFT)]] 100 mg/m<sup>2</sup> PO every 8 hours on days 1 to 28
-*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''before 5-FU'''
+*[[Leucovorin (Folinic acid)]] 30 mg PO every 8 hours on days 1 to 28
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''before 5-FU'''
+*No food for 1 hour before and after each dose of medication.
+'''35-day cycle for 5 cycles'''
-'''14-day cycles'''
+</div></div>
 ===References===
-# '''ECOG E3200:''' Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd; Eastern Cooperative Oncology Group Study E3200. 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. [http://ascopubs.org/doi/full/10.1200/JCO.2006.09.6305 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17442997 PubMed]
+<!-- Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 13-17, 2004. -->
-# '''N9841:''' Kim GP, Sargent DJ, Mahoney MR, Rowland KM Jr, Philip PA, Mitchell E, Mathews AP, Fitch TR, Goldberg RM, Alberts SR, Pitot HC. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol. 2009 Jun 10;27(17):2848-54. Epub 2009 Apr 20. [http://ascopubs.org/doi/full/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://www.ncbi.nlm.nih.gov/pubmed/19380443 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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/16648506/ PubMed] [https://clinicaltrials.gov/study/NCT00378716 NCT00378716]
-# 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. [http://ascopubs.org/doi/full/10.1200/JCO.2010.29.5436 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21464401 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] '''dosing details in manuscript have been reviewed by our editors''' [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] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/26347106/ PubMed] UMIN C000000245
-==FOLFOX4 & Bevacizumab {{#subobject:8228ca|Regimen=1}}==
+#'''ACTS-CC 02:''' Sunami E, Kusumoto T, Ota M, SakamotoY, Yoshida K, Tomita N, Maeda A, Teshima J, Okabe M, Tanaka C, Yamauchi J, Itabashi M, Kotake K, Takahashi K, Baba H, Boku N, Aiba K, Ishiguro M, Morita S, Takenaka N, Okude R, Sugihara K. S-1 and oxaliplatin versus tegafur-uracil and leucovorin as postoperative adjuvant chemotherapy in patients with high-risk stage III colon cancer (ACTS-CC 02): a randomized, open-label, multicenter, phase 3, superiority trial. 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] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/31917122/ PubMed] JapicCTI-101073
-{| class="wikitable" style="float:right; margin-left: 5px;"
+##'''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]
-|-
-|[[#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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|rowspan=2|[http://ascopubs.org/doi/full/10.1200/JCO.2006.09.6305 Giantonio et al. 2007 (ECOG E3200)]
-|rowspan = 2 style="background-color:#1a9851"|Phase III (E)
-|[[#FOLFOX4_5|FOLFOX4]]
-|style="background-color:#1a9850"|Superior OS
-|-
-|Bevacizumab
-|style="background-color:#d3d3d3"|Not reported
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours on days 1 & 2 (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
-*[[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; Eastern Cooperative Oncology Group Study E3200. 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. [http://ascopubs.org/doi/full/10.1200/JCO.2006.09.6305 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17442997 PubMed]
-==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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2898%2902309-5/fulltext Cunningham et al. 1998]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Best_supportive_care|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===
-# 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://www.ncbi.nlm.nih.gov/pubmed/9807987 PubMed]
-==Pembrolizumab monotherapy {{#subobject:ac2c94|Regimen=1}}==
-{{#subobject:fe5344|Variant=1}}
-{{#subobject:B34AD4|Variant=1}}
-{{:Pembrolizumab (Keytruda) for unresectable or metastatic colon cancer}}
-==Placebo==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70345-5/fulltext Yoshino et al. 2012]
-|style="background-color:#1a9851"|Randomized Phase II (C)
-|[[#Trifluridine_and_tipiracil_monotherapy|Trifluridine and tipiracil]]
-|style="background-color:#d73027"|Inferior OS
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961900-X/fulltext Grothey et al. 2013 (CORRECT)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Regorafenib_monotherapy|Regorafenib]]
-|style="background-color:#d73027"|Inferior OS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70156-7/fulltext Li et al. 2015 (CONCUR)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Regorafenib_monotherapy|Regorafenib]]
-|style="background-color:#d73027"|Inferior OS
-|-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa1414325 Mayer et al. 2015 (RECOURSE)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Trifluridine_and_tipiracil_monotherapy|Trifluridine and tipiracil]]
-|style="background-color:#d73027"|Inferior OS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30006-2/fulltext Hickish et al. 2017]
-|style="background-color:#1a9851"|Phase III (C)
-|MABp1
-|style="background-color:#d73027"|Inferior primary endpoint
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2017.74.3245 Xu et al. 2017 (TERRA)]
-|style="background-color:#1a9851"|Phase III (C)
-|[[#Trifluridine_and_tipiracil_monotherapy|Trifluridine and tipiracil]]
-|style="background-color:#fc8d59"|Seems to have inferior OS
-|-
-|[https://www.thelancet.com/journals/langas/article/PIIS2468-1253(18)30009-8/fulltext Jonker et al. 2018 (NCIC CTG CO.23)]
-|style="background-color:#1a9851"|Phase III (C)
-|Napabucasin
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|[https://jamanetwork.com/journals/jama/fullarticle/2685988 Li et al. 2018 (FRESCO)]
-|style="background-color:#1a9851"|Phase III (C)
-|Fruquintinib
-|style="background-color:#d73027"|Inferior OS
-|-
-|}
-''No active antineoplastic treatment.''
-===References===
-# Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, Tsuji A, Yamaguchi K, Muro K, Sugimoto N, Tsuji Y, Moriwaki T, Esaki T, Hamada C, Tanase T, Ohtsu A. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2012 Oct;13(10):993-1001. Epub 2012 Aug 28. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70345-5/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22951287 PubMed]
-<!-- # '''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961900-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23177514 PubMed]
-# '''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://www.ncbi.nlm.nih.gov/pubmed/25981818 PubMed]
-# '''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1414325 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25970050 PubMed]
-# Hickish T, Andre T, Wyrwicz L, Saunders M, Sarosiek T, Kocsis J, Nemecek R, Rogowski W, Lesniewski-Kmak K, Petruzelka L, Apte RN, Mohanty P, Stecher M, Simard J, de Gramont A. MABp1 as a novel antibody treatment for advanced colorectal cancer: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2017 Feb;18(2):192-201. Epub 2017 Jan 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30006-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28094194 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. [http://ascopubs.org/doi/full/10.1200/JCO.2017.74.3245 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29215955 PubMed]
-# '''NCIC CTC CO.23:''' Jonker DJ, Nott L, Yoshino T, Gill S, Shapiro J, Ohtsu A, Zalcberg J, Vickers MM, Wei AC, Gao Y, Tebbutt NC, Markman B, Price T, Esaki T, Koski S, Hitron M, Li W, Li Y, Magoski NM, Li CJ, Simes J, Tu D, O'Callaghan CJ. Napabucasin versus placebo in refractory advanced colorectal cancer: a randomised phase 3 trial. Lancet Gastroenterol Hepatol. 2018 Apr;3(4):263-270. Epub 2018 Feb 1. [https://www.thelancet.com/journals/langas/article/PIIS2468-1253(18)30009-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29397354 PubMed]
-# '''FRESCO:''' Li J, Qin S, Xu RH, Shen L, Xu J, Bai Y, Yang L, Deng Y, Chen ZD, Zhong H, Pan H, Guo W, Shu Y, Yuan Y, Zhou J, Xu N, Liu T, Ma D, Wu C, Cheng Y, Chen D, Li W, Sun S, Yu Z, Cao P, Chen H, Wang J, Wang S, Wang H, Fan S, Hua Y, Su W. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018 Jun 26;319(24):2486-2496. [https://jamanetwork.com/journals/jama/fullarticle/2685988 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29946728 PubMed]
-==Regorafenib monotherapy {{#subobject:b6f696|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:79bc05|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961900-X/fulltext Grothey et al. 2013 (CORRECT)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Best_supportive_care|Best supportive care]]
-|style="background-color:#1a9850"|Superior OS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70156-7/fulltext Li et al. 2015 (CONCUR)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Best_supportive_care|Best supportive care]]
-|style="background-color:#1a9850"|Superior OS
-|-
-|}
-====Chemotherapy====
-*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21, taken with a low-fat (less than 30% fat) breakfast
-'''28-day cycles'''
-===References===
-<!-- # '''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2961900-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23177514 PubMed]
-# '''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://www.ncbi.nlm.nih.gov/pubmed/25981818 PubMed]
-==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" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70345-5/fulltext Yoshino et al. 2012]
-|style="background-color:#1a9851"|Randomized Phase II (E)
-|[[#Placebo|Placebo]]
-|style="background-color:#1a9850"|Superior OS
-|-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa1414325 Mayer et al. 2015 (RECOURSE)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Placebo|Placebo]]
-|style="background-color:#1a9850"|Superior OS
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2017.74.3245 Xu et al. 2017 (TERRA)]
-|style="background-color:#1a9851"|Phase III (E)
-|[[#Placebo|Placebo]]
-|style="background-color:#91cf60"|Seems to have superior OS
-|-
-|}
-====Chemotherapy====
-*[[Trifluridine and tipiracil (Lonsurf)]] 35 mg/m<sup>2</sup> PO BID, 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://www.ncbi.nlm.nih.gov/pubmed/22951287 PubMed]
-# '''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1414325 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25970050 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. [http://ascopubs.org/doi/full/10.1200/JCO.2017.74.3245 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29215955 PubMed]
+=Advanced or metastatic disease=
+''See the [[Colorectal cancer|colorectal cancer page]] for colorectal cancer regimens.''
 [[Category:Colon cancer regimens]]
 [[Category:Disease-specific pages]]
-[[Category:Gastrointestinal cancers]]
+[[Category:Colorectal cancers]]

Difference between revisions of "Colon cancer"

Latest revision as of 18:17, 21 July 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