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

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

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

10 regimens on this page 20 variants on this page

Guidelines

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

ASCO

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

ESMO

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

NCCN

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

Perioperative therapy

mFOLFOX6 (L-Leucovorin)

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

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

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

Neoadjuvant

Chemotherapy

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

14-day cycle for 3 cycles, followed by:

Definitive

Local therapy

Surgery

Adjuvant

Chemotherapy

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

14-day cycle for 9 cycles

References

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

Adjuvant therapy

Capecitabine monotherapy

Regimen

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

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

Preceding treatment

Surgery

Chemotherapy

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

21-day cycle for 8 cycles

References

X-ACT: Twelves C, Wong A, Nowacki MP, Abt M, Burris HA 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005 Jun 30;352(26):2696-704. link to original article contains dosing details in manuscript PubMed NCT00009737
1. Update: Twelves C, Scheithauer W, McKendrick J, Seitz JF, Van Hazel G, Wong A, Díaz-Rubio E, Gilberg F, Cassidy J. Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy. Ann Oncol. 2012 May;23(5):1190-7. Epub 2011 Sep 6. link to original article PubMed
JFMC37-0801: Tomita N, Kunieda K, Maeda A, Hamada C, Yamanaka T, Sato T, Yoshida K, Boku N, Nezu R, Yamaguchi S, Mishima H, Sadahiro S, Muro K, Ishiguro M, Sakamoto J, Saji S, Maehara Y. Phase III randomised trial comparing 6 vs 12-month of capecitabine as adjuvant chemotherapy for patients with stage III colon cancer: final results of the JFMC37-0801 study. Br J Cancer. 2019 Apr;120(7):689-696. Epub 2019 Mar 5. link to original article contains dosing details in manuscript link to PMC article PubMed

CapeOx

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

Example orders

Example orders for CapeOx (XELOX) in colon cancer

Regimen variant #1, 3 months

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

¹Reported efficacy is based on the 2022 update.

Preceding treatment

Surgery

Chemotherapy

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

21-day cycle for 4 cycles

Regimen variant #2, 6 months

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

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

Preceding treatment

Surgery

Chemotherapy

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

21-day cycle for 8 cycles

References

XELOXA: Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A, Maroun J, Price T, Lim R, Van Cutsem E, Park YS, McKendrick J, Topham C, Soler-Gonzalez G, de Braud F, Hill M, Sirzén F, Haller DG. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007 Jan 1;25(1):102-9. link to original article contains dosing details in manuscript PubMed NCT00069121
1. Update: Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011 Apr 10;29(11):1465-71. Epub 2011 Mar 7. link to original article PubMed
2. Update: Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: Final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015 Nov 10;33(32):3733-40. Epub 2015 Aug 31. link to original article PubMed
IDEA: Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018 Mar 29;378(13):1177-1188. link to original article does not contain dosing details link to PMC article PubMed NCT01308086
1. Subgroup analysis: Souglakos J, Boukovinas I, Kakolyris S, Xynogalos S, Ziras N, Athanasiadis A, Androulakis N, Christopoulou A, Vaslamatzis M, Ardavanis A, Emmanouilides C, Bompolaki I, Kourousis C, Makrantonakis P, Christofyllakis C, Athanasiadis E, Kentepozidis N, Karampeazis A, Katopodi U, Anagnosopoulos A, Papadopoulos G, Prinarakis E, Kalisperi A, Mavroudis D, Georgoulias V; Hellenic Oncology Research Group. Three versus six months adjuvant FOLFOX or CAPOX for high risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project. Ann Oncol. 2019 Aug 1;30(8):1304-1310. Epub 2019 Jun 22. link to original article PubMed
2. Update: André T, Meyerhardt J, Iveson T, Sobrero A, Yoshino T, Souglakos I, Grothey A, Niedzwiecki D, Saunders M, Labianca R, Yamanaka T, Boukovinas I, Vernerey D, Meyers J, Harkin A, Torri V, Oki E, Georgoulias V, Taieb J, Shields A, Shi Q. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020 Dec;21(12):1620-1629. link to original article link to PMC article PubMed
ACHIEVE: Yoshino T, Yamanaka T, Oki E, Kotaka M, Manaka D, Eto T, Hasegawa J, Takagane A, Nakamura M, Kato T, Munemoto Y, Takeuchi S, Bando H, Taniguchi H, Gamoh M, Shiozawa M, Mizushima T, Saji S, Maehara Y, Ohtsu A, Mori M. Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer: The ACHIEVE Phase 3 Randomized Clinical Trial. JAMA Oncol. 2019 Nov 1;5(11):1574-1581. Erratum in: JAMA Oncol. 2019 Nov 1;5(11):1643. Epub 2019 Sep 12. Erratum in: JAMA Oncol. 2019 Dec 19. link to original article link to PMC article contains dosing details in manuscript PubMed UMIN000008543
1. Update: Yoshino T, Oki E, Misumi T, Kotaka M, Manaka D, Eto T, Hasegawa J, Takagane A, Nakamura M, Kato T, Munemoto Y, Nakamura F, Bando H, Taniguchi H, Sakamoto Y, Shiozawa M, Nishi M, Horiuchi T, Yamagishi H, Sakamoto J, Mizushima T, Ohtsu A, Mori M. Final Analysis of 3 Versus 6 Months of Adjuvant Oxaliplatin and Fluoropyrimidine-Based Therapy in Patients With Stage III Colon Cancer: The Randomized Phase III ACHIEVE Trial. J Clin Oncol. 2022 Oct 10;40(29):3419-3429. Epub 2022 May 5. link to original article PubMed
TOSCA: Petrelli F, Rulli E, Labianca R, Lonardi S, Rosati G, Dotti K, Ronzoni M, Pella N, Pusceddu V, Banzi M, Zampino MG, Yasmina M, Marchetti P, Cantore M, Zaniboni A, Rimassa L, Ciuffreda L, Ferrari D, Zagonel V, Maiello E, Sobrero A; TOSCA Investigators. Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial. Ann Oncol. 2021 Jan;32(1):66-76. Epub 2020 Oct 21. link to original article PubMed NCT00646607
KCSG CO09-07: Kim ST, Kim SY, Lee J, Yun SH, Kim HC, Lee WY, Kim TW, Hong YS, Lim SB, Baek JY, Oh JH, Ahn JB, Shin SJ, Han SW, Kim SG, Kang SY, Sym SJ, Zang DY, Kim YH, Choi IS, Kang JH, Kim MJ, Park YS. Oxaliplatin (3 months v 6 months) With 6 Months of Fluoropyrimidine as Adjuvant Therapy in Patients With Stage II/III Colon Cancer: KCSG CO09-07. J Clin Oncol. 2022 Nov 20;40(33):3868-3877. Epub 2022 Jun 30. link to original article link to PMC article PubMed NCT01092481
CIRCULATE-IDEA: NCT05174169

FLOX

FLOX: Fluorouracil, Leucovorin, OXaliplatin

Example orders

Example orders for FLOX in colon cancer

Regimen

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

Preceding treatment

Surgery

Chemotherapy

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

8-week cycle for 3 cycles

References

NSABP C-07: Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, Zapas JL, Goodwin JW, Fehrenbacher L, Ramanathan RK, Conley BA, Flynn PJ, Soori G, Colman LK, Levine EA, Lanier KS, Wolmark N. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007 Jun 1;25(16):2198-204. Epub 2007 Apr 30. link to original article contains dosing details in manuscript PubMed NCT00004931
1. Update: Yothers G, O'Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, Wolmark N. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011 Oct 1;29(28):3768-74. Epub 2011 Aug 22. link to original article link to PMC article PubMed

FOLFOX4

FOLFOX4: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Regimen

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

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

Preceding treatment

Surgery

Chemotherapy

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

14-day cycle for 12 cycles

References

MOSAIC: André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004 Jun 3;350(23):2343-51. link to original article contains dosing details in manuscript PubMed NCT00275210
1. Update: André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009 Jul 1;27(19):3109-16. Epub 2009 May 18. link to original article PubMed
2. Update: André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, Scriva A, Hickish T, Tabernero J, Van Laethem JL, Banzi M, Maartense E, Shmueli E, Carlsson GU, Scheithauer W, Papamichael D, Möehler M, Landolfi S, Demetter P, Colote S, Tournigand C, Louvet C, Duval A, Fléjou JF, de Gramont A. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol. 2015 Dec 10;33(35):4176-87. Epub 2015 Nov 2. link to original article PubMed
AVANT: de Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, Cunningham D, Cartwright TH, Hecht JR, Rivera F, Im SA, Bodoky G, Salazar R, Maindrault-Goebel F, Shacham-Shmueli E, Bajetta E, Makrutzki M, Shang A, André T, Hoff PM. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012 Dec;13(12):1225-33. Epub 2012 Nov 16. link to original article contains dosing details in abstract PubMed NCT00112918
1. Update: André T, Vernerey D, Im SA, Bodoky G, Buzzoni R, Reingold S, Rivera F, McKendrick J, Scheithauer W, Ravit G, Fountzilas G, Yong WP, Isaacs R, Österlund P, Liang JT, Creemers GJ, Rakez M, Van Cutsem E, Cunningham D, Tabernero J, de Gramont A. Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group. Ann Oncol. 2020 Feb;31(2):246-256. Epub 2019 Dec 18. link to original article PubMed
PETACC-8: Taieb J, Tabernero J, Mini E, Subtil F, Folprecht G, Van Laethem JL, Thaler J, Bridgewater J, Petersen LN, Blons H, Collette L, Van Cutsem E, Rougier P, Salazar R, Bedenne L, Emile JF, Laurent-Puig P, Lepage C; PETACC-8 Study Investigators. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Jul;15(8):862-73. Epub 2014 Jun 11. link to original article PubMed NCT00265811
IDEA: Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018 Mar 29;378(13):1177-1188. link to original article does not contain dosing details link to PMC article PubMed NCT01308086
1. Subgroup analysis: Souglakos J, Boukovinas I, Kakolyris S, Xynogalos S, Ziras N, Athanasiadis A, Androulakis N, Christopoulou A, Vaslamatzis M, Ardavanis A, Emmanouilides C, Bompolaki I, Kourousis C, Makrantonakis P, Christofyllakis C, Athanasiadis E, Kentepozidis N, Karampeazis A, Katopodi U, Anagnosopoulos A, Papadopoulos G, Prinarakis E, Kalisperi A, Mavroudis D, Georgoulias V; Hellenic Oncology Research Group. Three versus six months adjuvant FOLFOX or CAPOX for high risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project. Ann Oncol. 2019 Aug 1;30(8):1304-1310. Epub 2019 Jun 22. link to original article PubMed
2. Update: André T, Meyerhardt J, Iveson T, Sobrero A, Yoshino T, Souglakos I, Grothey A, Niedzwiecki D, Saunders M, Labianca R, Yamanaka T, Boukovinas I, Vernerey D, Meyers J, Harkin A, Torri V, Oki E, Georgoulias V, Taieb J, Shields A, Shi Q. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020 Dec;21(12):1620-1629. link to original article link to PMC article PubMed
TOSCA: Petrelli F, Rulli E, Labianca R, Lonardi S, Rosati G, Dotti K, Ronzoni M, Pella N, Pusceddu V, Banzi M, Zampino MG, Yasmina M, Marchetti P, Cantore M, Zaniboni A, Rimassa L, Ciuffreda L, Ferrari D, Zagonel V, Maiello E, Sobrero A; TOSCA Investigators. Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial. Ann Oncol. 2021 Jan;32(1):66-76. Epub 2020 Oct 21. link to original article PubMed NCT00646607

mFOLFOX6

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

Example orders

Example orders for mFOLFOX 6 in colon cancer

Regimen

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

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

Preceding treatment

Surgery, within 10 weeks

Chemotherapy

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

14-day cycle for 12 cycles

References

NSABP C-08: Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Colangelo LH, Lopa SH, Petrelli NJ, Goldberg RM, Atkins JN, Seay TE, Fehrenbacher L, O'Reilly S, Chu L, Azar CA, Wolmark N. Initial safety report of NSABP C-08: A randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol. 2009 Jul 10;27(20):3385-90. Epub 2009 May 4. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00096278
1. Update: Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Colangelo LH, Atkins JN, Seay TE, Fehrenbacher L, Goldberg RM, O'Reilly S, Chu L, Azar CA, Lopa S, Wolmark N. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011 Jan 1;29(1):11-6. Epub 2010 Oct 12. link to original article link to PMC article PubMed
2. Update: Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Lopa SH, Wolmark N. Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J Clin Oncol. 2013 Jan 20;31(3):359-64. Epub 2012 Dec 10. link to original article link to PMC article PubMed
IDEA: Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018 Mar 29;378(13):1177-1188. link to original article does not contain dosing details link to PMC article PubMed NCT01308086
1. Subgroup analysis: Souglakos J, Boukovinas I, Kakolyris S, Xynogalos S, Ziras N, Athanasiadis A, Androulakis N, Christopoulou A, Vaslamatzis M, Ardavanis A, Emmanouilides C, Bompolaki I, Kourousis C, Makrantonakis P, Christofyllakis C, Athanasiadis E, Kentepozidis N, Karampeazis A, Katopodi U, Anagnosopoulos A, Papadopoulos G, Prinarakis E, Kalisperi A, Mavroudis D, Georgoulias V; Hellenic Oncology Research Group. Three versus six months adjuvant FOLFOX or CAPOX for high risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project. Ann Oncol. 2019 Aug 1;30(8):1304-1310. Epub 2019 Jun 22. link to original article PubMed
2. Update: André T, Meyerhardt J, Iveson T, Sobrero A, Yoshino T, Souglakos I, Grothey A, Niedzwiecki D, Saunders M, Labianca R, Yamanaka T, Boukovinas I, Vernerey D, Meyers J, Harkin A, Torri V, Oki E, Georgoulias V, Taieb J, Shields A, Shi Q. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020 Dec;21(12):1620-1629. link to original article link to PMC article PubMed
IDEA France: André T, Vernerey D, Mineur L, Bennouna J, Desrame J, Faroux R, Fratte S, Hug de Larauze M, Paget-Bailly S, Chibaudel B, Bez J, Dauba J, Louvet C, Lepere C, Dupuis O, Becouarn Y, Mabro M, Egreteau J, Bouche O, Deplanque G, Ychou M, Galais MP, Ghiringhelli F, Dourthe LM, Bachet JB, Khalil A, Bonnetain F, de Gramont A, Taieb J; PRODIGE investigators, GERCOR, Fédération Française de Cancérologie Digestive, UNICANCER. Three versus 6 months of oxaliplatin-based adjuvant chemotherapy for patients with stage III colon cancer: disease-free survival results from a randomized, open-label, International Duration Evaluation of Adjuvant (IDEA) France, phase III trial. J Clin Oncol. 2018 May 20;36(15):1469-1477. Epub 2018 Apr 5. link to original article PubMed NCT00958737
TOSCA: Petrelli F, Rulli E, Labianca R, Lonardi S, Rosati G, Dotti K, Ronzoni M, Pella N, Pusceddu V, Banzi M, Zampino MG, Yasmina M, Marchetti P, Cantore M, Zaniboni A, Rimassa L, Ciuffreda L, Ferrari D, Zagonel V, Maiello E, Sobrero A; TOSCA Investigators. Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial. Ann Oncol. 2021 Jan;32(1):66-76. Epub 2020 Oct 21. link to original article PubMed NCT00646607
ACHIEVE-2: Yamazaki K, Yamanaka T, Shiozawa M, Manaka D, Kotaka M, Gamoh M, Shiomi A, Makiyama A, Munemoto Y, Rikiyama T, Fukunaga M, Ueki T, Shitara K, Shinkai H, Tanida N, Oki E, Sunami E, Ohtsu A, Maehara Y, Yoshino T. Oxaliplatin-based adjuvant chemotherapy duration (3 versus 6 months) for high-risk stage II colon cancer: the randomized phase III ACHIEVE-2 trial. Ann Oncol. 2021 Jan;32(1):77-84. Epub 2020 Oct 26. link to original article PubMed UMIN000013036
CALGB 80702: Meyerhardt JA, Shi Q, Fuchs CS, Meyer J, Niedzwiecki D, Zemla T, Kumthekar P, Guthrie KA, Couture F, Kuebler P, Bendell JC, Kumar P, Lewis D, Tan B, Bertagnolli M, Grothey A, Hochster HS, Goldberg RM, Venook A, Blanke C, O'Reilly EM, Shields AF. Effect of Celecoxib vs Placebo Added to Standard Adjuvant Therapy on Disease-Free Survival Among Patients With Stage III Colon Cancer: The CALGB/SWOG 80702 (Alliance) Randomized Clinical Trial. JAMA. 2021 Apr 6;325(13):1277-1286. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01150045
1. Dataset: Project Data Sphere
KCSG CO09-07: Kim ST, Kim SY, Lee J, Yun SH, Kim HC, Lee WY, Kim TW, Hong YS, Lim SB, Baek JY, Oh JH, Ahn JB, Shin SJ, Han SW, Kim SG, Kang SY, Sym SJ, Zang DY, Kim YH, Choi IS, Kang JH, Kim MJ, Park YS. Oxaliplatin (3 months v 6 months) With 6 Months of Fluoropyrimidine as Adjuvant Therapy in Patients With Stage II/III Colon Cancer: KCSG CO09-07. J Clin Oncol. 2022 Nov 20;40(33):3868-3877. Epub 2022 Jun 30. link to original article link to PMC article PubMed NCT01092481

mFOLFOX6 (L-Leucovorin)

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

Example orders

Example orders for mFOLFOX 6 in colon cancer

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

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

¹Reported efficacy is based on the 2022 update.

Preceding treatment

Surgery

Chemotherapy

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

14-day cycle for 6 cycles

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

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

Preceding treatment

Surgery

Chemotherapy

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

14-day cycle for 12 cycles

References

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

FULV

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

Example orders

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

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

Preceding treatment

Surgery

Chemotherapy

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

8-week cycle for 4 cycles

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wolmark et al. 1993 (NSABP C-03)	1987-1989	Phase 3 (E-de-esc)	MOF	Superior OS
Wolmark et al. 1999 (NSABP C-04)	1989-07 to 1990-12	Phase 3 (E-switch-ooc)	1. 5-FU & Levamisole	Might have superior OS (co-primary endpoint)
Wolmark et al. 1999 (NSABP C-04)	1989-07 to 1990-12	Phase 3 (E-switch-ooc)	2. FULV & Levamisole	Did not meet co-primary endpoints of DFS/OS
Haller et al. 2005 (Intergroup 0089)	1988-1992	Phase 3 (E-esc)	1. FULV; low-dose	Did not meet primary endpoint of OS
			2. FULV & Levamisole; LDLV	Did not meet primary endpoint of OS
			3. 5-FU & Levamisole	Did not meet primary endpoint of OS
Lembersky et al. 2006 (NSABP C-06)	1997-1999	Phase 3 (C)	Tegafur, Uracil, Folinic acid	Did not meet co-primary endpoints of DFS/OS
Saltz et al. 2007 (CALGB 89803)	1999-2001	Phase 3 (C)	IFL	Did not meet co-primary endpoints of DFS/OS
Kuebler et al. 2007 (NSABP C-07)	2000-2002	Phase 3 (C)	FLOX	Inferior DFS
Schmoll et al. 2007 (XELOXA)	2003-04 to 2004-10	Phase 3 (C)	CapeOx	Seems to have inferior OS¹

¹Reported efficacy for XELOXA is based on the 2015 update.
Note: this is often called the "Roswell Park regimen" but the original regimen described by Petrelli et al. 1987 & 1989 used a 5-FU dose of 600 mg/m².

Preceding treatment

Surgery

Chemotherapy

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

8-week cycle for 3 to 6 cycles

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

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

Preceding treatment

Surgery

Chemotherapy

Fluorouracil (5-FU) 600 mg/m² IV bolus once per day on days 1, 8, 15, 22, 29, 36, given second, 1 hour after start of leucovorin
Leucovorin (Folinic acid) 500 mg/m² IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, given first

8-week cycle for 4 cycles

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

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

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

Preceding treatment

Surgery

Chemotherapy

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

28-day cycle for 6 cycles

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

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

Preceding treatment

Surgery

Chemotherapy

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

28-day cycle for 6 cycles

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

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

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

Preceding treatment

Surgery

Chemotherapy

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

14-day cycle for 12 cycles

Regimen variant #7, 2000/1000

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

Preceding treatment

Surgery, within 3 weeks

Chemotherapy

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

28-day cycle for 12 cycles

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

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

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

Preceding treatment

Surgery

Chemotherapy

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

28-day cycle for 6 cycles

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

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

Preceding treatment

Surgery

Chemotherapy

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

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

References

NSABP C-03: Wolmark N, Rockette H, Fisher B, Wickerham DL, Redmond C, Fisher ER, Jones J, Mamounas EP, Ore L, Petrelli NJ, Spurr CL, Dimitrov N, Romond EH, Sutherland CM, Kardinal CG, DeFusco PA, Jochimsen P. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol. 1993 Oct;11(10):1879-87. link to original article contains dosing details in manuscript PubMed
1. Pooled update: Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. link to original article link to PMC article PubMed
Francini G, Petrioli R, Lorenzini L, Mancini S, Armenio S, Tanzini G, Marsili S, Aquino A, Marzocca G, Civitelli S, Mariani L, De Sando D, Bovenga S, Lorenzi M. Folinic acid and 5-fluorouracil as adjuvant chemotherapy in colon cancer. Gastroenterology. 1994 Apr;106(4):899-906. link to original article contains dosing details in manuscript PubMed
CALGB 8896: O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, Wieand HS. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997 Jan;15(1):246-50. link to original article contains dosing details in manuscript PubMed
1. Pooled update: Erlichman C, O'Connell M, Kahn M, Marsoni S, Torri V, Tardio B, Zaniboni A, Pancera G, Martignoni G, Labianca R, Barni A, Seitz JF, Milan C, Bedenne L, Giovannini M, Letreut YP, Skillings J, Shepard L, Zee B, Petrioli R, Francini G; International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol. 1999 May;17(5):1356-63. link to original article PubMed
NSABP C-05: Wolmark N, Bryant J, Smith R, Grem J, Allegra C, Hyams D, Atkins J, Dimitrov N, Oishi R, Prager D, Fehrenbacher L, Romond E, Colangelo L, Fisher B. Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst. 1998 Dec 2;90(23):1810-6. link to original article PubMed
1. Pooled update: Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. link to original article link to PMC article PubMed
NSABP C-04: Wolmark N, Rockette H, Mamounas E, Jones J, Wieand S, Wickerham DL, Bear HD, Atkins JN, Dimitrov NV, Glass AG, Fisher ER, Fisher B. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol. 1999 Nov;17(11):3553-9. link to original article contains dosing details in manuscript PubMed NCT00425152
1. Pooled update: Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. link to original article link to PMC article PubMed
Fountzilas G, Zisiadis A, Dafni U, Konstantaras C, Hatzitheoharis G, Papavramidis S, Bousoulegas A, Basdanis G, Giannoulis E, Dokmetzioglou J, Katsohis C, Nenopoulou E, Karvounis N, Briassoulis E, Aravantinos G, Kosmidis P, Skarlos D, Pavlidis N; Hellenic Cooperative Oncology Group. Fluorouracil and leucovorin with or without interferon alfa-2a as adjuvant treatment, in patients with high-risk colon cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Oncology. 2000 Apr;58(3):227-36. link to original article contains dosing details in abstract PubMed
Study 157-002: Punt CJ, Nagy A, Douillard JY, Figer A, Skovsgaard T, Monson J, Barone C, Fountzilas G, Riess H, Moylan E, Jones D, Dethling J, Colman J, Coward L, MacGregor S. Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study. Lancet. 2002 Aug 31;360(9334):671-7. link to original article contains dosing details in manuscript PubMed
GERCOR C96.1: Andre T, Colin P, Louvet C, Gamelin E, Bouche O, Achille E, Colbert N, Boaziz C, Piedbois P, Tubiana-Mathieu N, Boutan-Laroze A, Flesch M, Buyse M, de Gramont A. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol. 2003 Aug 1;21(15):2896-903. link to original article PubMed
1. Update: André T, Quinaux E, Louvet C, Colin P, Gamelin E, Bouche O, Achille E, Piedbois P, Tubiana-Mathieu N, Boutan-Laroze A, Flesch M, Lledo G, Raoul Y, Debrix I, Buyse M, de Gramont A. Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1. J Clin Oncol. 2007 Aug 20;25(24):3732-8. link to original article PubMed
MOSAIC: André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004 Jun 3;350(23):2343-51. link to original article contains dosing details in manuscript PubMed NCT00275210
1. Update: André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009 Jul 1;27(19):3109-16. Epub 2009 May 18. link to original article PubMed
2. Update: André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, Scriva A, Hickish T, Tabernero J, Van Laethem JL, Banzi M, Maartense E, Shmueli E, Carlsson GU, Scheithauer W, Papamichael D, Möehler M, Landolfi S, Demetter P, Colote S, Tournigand C, Louvet C, Duval A, Fléjou JF, de Gramont A. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol. 2015 Dec 10;33(35):4176-87. Epub 2015 Nov 2. link to original article PubMed
X-ACT: Twelves C, Wong A, Nowacki MP, Abt M, Burris HA 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005 Jun 30;352(26):2696-704. link to original article contains dosing details in manuscript PubMed NCT00009737
1. Update: Twelves C, Scheithauer W, McKendrick J, Seitz JF, Van Hazel G, Wong A, Díaz-Rubio E, Gilberg F, Cassidy J. Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy. Ann Oncol. 2012 May;23(5):1190-7. Epub 2011 Sep 6. link to original article PubMed
Intergroup 0089: Haller DG, Catalano PJ, Macdonald JS, O'Rourke MA, Frontiera MS, Jackson DV, Mayer RJ. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 2005 Dec 1;23(34):8671-8. link to original article contains dosing details in manuscript PubMed
NSABP C-06: Lembersky BC, Wieand HS, Petrelli NJ, O'Connell MJ, Colangelo LH, Smith RE, Seay TE, Giguere JK, Marshall ME, Jacobs AD, Colman LK, Soran A, Yothers G, Wolmark N. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 2006 May 1;24(13):2059-64. link to original article contains dosing details in manuscript PubMed NCT00378716
XELOXA: Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A, Maroun J, Price T, Lim R, Van Cutsem E, Park YS, McKendrick J, Topham C, Soler-Gonzalez G, de Braud F, Hill M, Sirzén F, Haller DG. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007 Jan 1;25(1):102-9. link to original article contains dosing details in manuscript PubMed NCT00069121
1. Update: Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011 Apr 10;29(11):1465-71. Epub 2011 Mar 7. link to original article contains dosing details in manuscript PubMed
2. Update: Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: Final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015 Nov 10;33(32):3733-40. Epub 2015 Aug 31. link to original article PubMed
NSABP C-07: Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, Zapas JL, Goodwin JW, Fehrenbacher L, Ramanathan RK, Conley BA, Flynn PJ, Soori G, Colman LK, Levine EA, Lanier KS, Wolmark N. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007 Jun 1;25(16):2198-204. Epub 2007 Apr 30. link to original article contains dosing details in abstract PubMed NCT00004931
1. Update: Yothers G, O'Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, Wolmark N. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011 Oct 1;29(28):3768-74. Epub 2011 Aug 22. link to original article link to PMC article PubMed
CALGB 89803: Saltz LB, Niedzwiecki D, Hollis D, Goldberg RM, Hantel A, Thomas JP, Fields AL, Mayer RJ. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol. 2007 Aug 10;25(23):3456-61. link to original article contains dosing details in manuscript PubMed NCT00003835
PETACC-1: Popov I, Carrato A, Sobrero A, Vincent M, Kerr D, Labianca R, Raffaele Bianco A, El-Serafi M, Bedenne L, Paillot B, Mini E, Sanches E, Welch J, Collette L, Praet M, Wils J. Raltitrexed (Tomudex) versus standard leucovorin-modulated bolus 5-fluorouracil: Results from the randomised phase III Pan-European Trial in Adjuvant Colon Cancer 01 (PETACC-1). Eur J Cancer. 2008 Oct;44(15):2204-11. Epub 2008 Aug 15. link to original article contains dosing details in manuscript PubMed
FFCD 9802: Ychou M, Raoul JL, Douillard JY, Gourgou-Bourgade S, Bugat R, Mineur L, Viret F, Becouarn Y, Bouché O, Gamelin E, Ducreux M, Conroy T, Seitz JF, Bedenne L, Kramar A. A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). Ann Oncol. 2009 Apr;20(4):674-80. Epub 2009 Jan 29. link to original article contains dosing details in abstract PubMed NCT00005979
Study 157-001: Fields AL, Keller A, Schwartzberg L, Bernard S, Kardinal C, Cohen A, Schulz J, Eisenberg P, Forster J, Wissel P. Adjuvant therapy with the monoclonal antibody edrecolomab plus fluorouracil-based therapy does not improve overall survival of patients with stage III colon cancer. J Clin Oncol. 2009 Apr 20;27(12):1941-7. Epub 2009 Mar 9. link to original article contains dosing details in manuscript PubMed
PETACC-3: Van Cutsem E, Labianca R, Bodoky G, Barone C, Aranda E, Nordlinger B, Topham C, Tabernero J, André T, Sobrero AF, Mini E, Greil R, Di Costanzo F, Collette L, Cisar L, Zhang X, Khayat D, Bokemeyer C, Roth AD, Cunningham D. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol. 2009 Jul 1;27(19):3117-25. Epub 2009 May 18. link to original article contains dosing details in abstract PubMed NCT00026273
Papadimitriou CA, Papakostas P, Karina M, Malettou L, Dimopoulos MA, Pentheroudakis G, Samantas E, Bamias A, Miliaras D, Basdanis G, Xiros N, Klouvas G, Bafaloukos D, Kafiri G, Papaspirou I, Pectasides D, Karanikiotis C, Economopoulos T, Efstratiou I, Korantzis I, Pisanidis N, Makatsoris T, Matsiakou F, Aravantinos G, Kalofonos HP, Fountzilas G; Hellenic Cooperative Oncology Group. A randomized phase III trial of adjuvant chemotherapy with irinotecan, leucovorin and fluorouracil versus leucovorin and fluorouracil for stage II and III colon cancer: a Hellenic Cooperative Oncology Group study. BMC Med. 2011 Jan 31;9:10. link to original article link to PMC article contains dosing details in abstract PubMed ACTRN12610000148077
PETACC-2: Köhne CH, Bedenne L, Carrato A, Bouché O, Popov I, Gaspà L, Valladares M, Rougier P, Gog C, Reichardt P, Wils J, Pignatti F, Biertz F; EORTC; FFCD; GETTD. A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: the Pan-European Trial in Adjuvant Colon Cancer 2 study. Eur J Cancer. 2013 May;49(8):1868-75. Epub 2013 Apr 6. link to original article PubMed NCT00004150

S-1 monotherapy

Regimen

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

Preceding treatment

Surgery

Chemotherapy

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

42-day cycle for 4 cycles

References

ACTS-CC: Yoshida M, Ishiguro M, Ikejiri K, Mochizuki I, Nakamoto Y, Kinugasa Y, Takagane A, Endo T, Shinozaki H, Takii Y, Mochizuki H, Kotake K, Kameoka S, Takahashi K, Watanabe T, Watanabe M, Boku N, Tomita N, Nakatani E, Sugihara K; ACTS-CC study group. S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial). Ann Oncol. 2014 Sep;25(9):1743-9. Epub 2014 Jun 18. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00660894

SOX

SOX: S-1, OXaliplatin

Regimen

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

Preceding treatment

Surgery

Chemotherapy

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

21-day cycle for 8 cycles

References

ACTS-CC 02: Sunami E, Kusumoto T, Ota M, SakamotoY, Yoshida K, Tomita N, Maeda A, Teshima J, Okabe M, Tanaka C, Yamauchi J, Itabashi M, Kotake K, Takahashi K, Baba H, Boku N, Aiba K, Ishiguro M, Morita S, Takenaka N, Okude R, Sugihara K. S-1 and oxaliplatin versus tegafur-uracil and leucovorin as postoperative adjuvant chemotherapy in patients with high-risk stage III colon cancer (ACTS-CC 02): a randomized, open-label, multicenter, phase 3, superiority trial. Clin Colorectal Cancer. 2020 Mar;19(1):22-31.e6. Epub 2019 Oct 18. link to original article contains dosing details in abstract PubMed JapicCTI-101073
1. Update: Watanabe J, Sasaki S, Kusumoto T, Sakamoto Y, Yoshida K, Tomita N, Maeda A, Teshima J, Yokota M, Tanaka C, Yamauchi J, Uetake H, Itabashi M, Takahashi K, Baba H, Kotake K, Boku N, Aiba K, Morita S, Takenaka N, Sugihara K. S-1 and oxaliplatin versus tegafur-uracil and leucovorin as post-operative adjuvant chemotherapy in patients with high-risk stage III colon cancer: updated 5-year survival of the phase III ACTS-CC 02 trial. ESMO Open. 2021 Apr;6(2):100077. Epub 2021 Mar 11. link to original article link to PMC article PubMed

Tegafur, Uracil, Folinic acid

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

Regimen variant #1, 300/75

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

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

Chemotherapy

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

35-day cycle for 5 cycles

Regimen variant #2, 300/90

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

Preceding treatment

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

Chemotherapy

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

35-day cycle for 5 cycles

References

NSABP C-06: Lembersky BC, Wieand HS, Petrelli NJ, O'Connell MJ, Colangelo LH, Smith RE, Seay TE, Giguere JK, Marshall ME, Jacobs AD, Colman LK, Soran A, Yothers G, Wolmark N. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 2006 May 1;24(13):2059-64. link to original article contains dosing details in manuscript PubMed NCT00378716
ACTS-CC: Yoshida M, Ishiguro M, Ikejiri K, Mochizuki I, Nakamoto Y, Kinugasa Y, Takagane A, Endo T, Shinozaki H, Takii Y, Mochizuki H, Kotake K, Kameoka S, Takahashi K, Watanabe T, Watanabe M, Boku N, Tomita N, Nakatani E, Sugihara K; ACTS-CC study group. S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial). Ann Oncol. 2014 Sep;25(9):1743-9. Epub 2014 Jun 18. link to original article link to PMC article PubMed NCT00660894
JFMC33-0502: Sadahiro S, Tsuchiya T, Sasaki K, Kondo K, Katsumata K, Nishimura G, Kakeji Y, Baba H, Sato S, Koda K, Yamaguchi Y, Morita T, Matsuoka J, Usuki H, Hamada C, Kodaira S. Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502. Ann Oncol. 2015 Nov;26(11):2274-80. Epub 2015 Sep 7. link to original article link to PMC article contains dosing details in abstract PubMed UMIN C000000245
ACTS-CC 02: Sunami E, Kusumoto T, Ota M, SakamotoY, Yoshida K, Tomita N, Maeda A, Teshima J, Okabe M, Tanaka C, Yamauchi J, Itabashi M, Kotake K, Takahashi K, Baba H, Boku N, Aiba K, Ishiguro M, Morita S, Takenaka N, Okude R, Sugihara K. S-1 and oxaliplatin versus tegafur-uracil and leucovorin as postoperative adjuvant chemotherapy in patients with high-risk stage III colon cancer (ACTS-CC 02): a randomized, open-label, multicenter, phase 3, superiority trial. Clin Colorectal Cancer. 2020 Mar;19(1):22-31.e6. Epub 2019 Oct 18. link to original article contains dosing details in manuscript PubMed JapicCTI-101073
1. Update: Watanabe J, Sasaki S, Kusumoto T, Sakamoto Y, Yoshida K, Tomita N, Maeda A, Teshima J, Yokota M, Tanaka C, Yamauchi J, Uetake H, Itabashi M, Takahashi K, Baba H, Kotake K, Boku N, Aiba K, Morita S, Takenaka N, Sugihara K. S-1 and oxaliplatin versus tegafur-uracil and leucovorin as post-operative adjuvant chemotherapy in patients with high-risk stage III colon cancer: updated 5-year survival of the phase III ACTS-CC 02 trial. ESMO Open. 2021 Apr;6(2):100077. Epub 2021 Mar 11. link to original article link to PMC article PubMed

Advanced or metastatic disease

See the colorectal cancer page for colorectal cancer regimens.

@@ Line 1: / Line 1: @@
-{| class="wikitable" style="text-align:center; width:100%;"
+<span id="BackToTop"></span>
-! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Page editor'''
+<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
-! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''
+[[#top|Back to Top]]
-|-
+</div>
-| style="background-color:#F0F0F0; width:15%" |[[File:RyanNguyen.jpg|frameless|upright=0.3|center]]
+{{#lst:Editorial board transclusions|gi}}
-| style="width:35%" |<big>[[User:Ryannguyen|Ryan Nguyen, DO]]<br>University of Illinois at Chicago<br>Chicago, IL</big><br>[https://www.linkedin.com/in/ryan-nguyen-0b12a432/ LinkedIn]
+''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!''
-| style="background-color:#F0F0F0; width:15%" |[[File:nkv.jpg|frameless|upright=0.3|center]]
+<br><big>'''Note: This page has recently been reorganized, with regimens intended more generically for colorectal cancer being moved to a [[Colorectal_cancer|dedicated page]]. Now, this page has adjuvant regimens specific to colon cancer. Please see the [[Rectal_cancer|'''rectal cancer page''']] for (neo-)adjuvant regimens specific to rectal cancer.</big>
-| style="width:35%" |<big>[[User:Neetavenepalli|Neeta K. Venepalli, MD, MBA]]<br>University of Illinois at Chicago<br>Chicago, IL</big>
+*See the [[Colon_cancer,_RAS_wild-type|'''RAS wild-type page''']] for biomarker-specific adjuvant regimens.</big>
-|-
-|}
-''Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the [[Colon_cancer_-_historical|historical regimens page]]. If you still can't find it, please let us know so we can add it!''
-<br><big>Note: the page has adjuvant and perioperative regimens specific to colon cancer as well as systemic regimens for the more general category of colorectal cancer.
-*See the [[Rectal_cancer|'''rectal cancer page''']] for regimens specific to rectal cancer.
-*See the [[Colon cancer, BRAF-mutated|'''BRAF-mutated page''']] for biomarker-specific regimens.
-*See the [[Colon cancer, Her2-amplified|'''HER2+ page''']] for biomarker-specific regimens.
-*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 23: / Line 13: @@
 |}
 {{TOC limit|limit=3}}
 =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.'''
 ==[http://www.asco.org/ ASCO]==
+*'''2022:''' Baxter et al. [https://doi.org/10.1200/jco.21.02538 Adjuvant Therapy for Stage II Colon Cancer: ASCO Guideline Update] [https://pubmed.ncbi.nlm.nih.gov/34936379/ PubMed]
+*'''2019:''' Lieu et al. [https://doi.org/10.1200/JCO.19.00281 Duration of oxaliplatin-containing adjuvant therapy for stage III colon cancer: ASCO Clinical Practice Guideline] [https://pubmed.ncbi.nlm.nih.gov/30986117/ PubMed]
+==[https://www.esmo.org/ ESMO]==
+*'''2021:''' Yoshino et al. [https://doi.org/10.1016/j.annonc.2021.08.1752 Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis treatment and follow-up of patients with localised colon cancer] [https://www.ncbi.nlm.nih.gov/pubmed/34411693 PubMed]
+*'''2020:''' Argilés et al. [https://doi.org/10.1016/j.annonc.2020.06.022 Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/32702383 PubMed]
+**'''2013:''' Labianca et al. [https://doi.org/10.1093/annonc/mdt354 Early Colon Cancer: ESMO Clinical Practice Guidelines] [https://www.ncbi.nlm.nih.gov/pubmed/24078664 PubMed]
+**'''2009:''' van Cutsem & Oliveira. [https://doi.org/10.1093/annonc/mdp126 Primary colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454461/ PubMed]
+**'''2008:''' van Cutsem & Oliveira. [https://doi.org/10.1093/annonc/mdn077 Colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456758/ PubMed]
+**'''2007:''' van Cutsem. [https://doi.org/10.1093/annonc/mdm021 Colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/17491030/ PubMed]
+**'''2005:''' van Cutsem & Kataja. [https://doi.org/10.1093/annonc/mdi808 ESMO Minimum Clinical Recommendations for diagnosis, adjuvant treatment and follow-up of colon cancer] [https://pubmed.ncbi.nlm.nih.gov/15888737/ PubMed]
+**'''2001:''' [https://doi.org/10.1023/a:1017492920758 ESMO Minimum Clinical Recommendations for diagnosis, adjuvant treatment and follow-up of colon cancer] [https://pubmed.ncbi.nlm.nih.gov/11583182/ PubMed]
+*'''2019:''' Stjepanovic et al. [https://doi.org/10.1093/annonc/mdz233 Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/31378807 PubMed]
-*'''2019:''' Lieu et al. [https://ascopubs.org/doi/full/10.1200/JCO.19.00281 Duration of oxaliplatin-containing adjuvant therapy for stage III colon cancer: ASCO Clinical Practice Guideline]
+==NCCN==
+*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428 NCCN Guidelines - Colon Cancer]
+*'''2021:''' Benson et al. [https://doi.org/10.6004/Jnccn.2021.0012 Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/33724754/ PubMed]
+*'''2017:''' Benson et al. [https://doi.org/10.6004/jnccn.2017.0036 Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology] [https://pubmed.ncbi.nlm.nih.gov/28275037/ PubMed]
+*'''2014:''' Benson et al. [https://doi.org/10.6004/jnccn.2014.0099 Colon Cancer, Version 3.2014] [https://pubmed.ncbi.nlm.nih.gov/24994923/ PubMed]
+*'''2013:''' Benson et al. [https://doi.org/10.6004/Jnccn.2013.0069 Localized colon cancer, version 3.2013: featured updates to the NCCN Guidelines.] [https://pubmed.ncbi.nlm.nih.gov/23667203/ PubMed]
+*'''2011:''' Benson et al. [https://doi.org/10.6004/Jnccn.2011.0104 Colon cancer.] [https://pubmed.ncbi.nlm.nih.gov/22056656/ PubMed]
+*'''2009:''' Engstrom et al. [https://doi.org/10.6004/Jnccn.2009.0056 NCCN Clinical Practice Guidelines in Oncology: colon cancer.] [https://pubmed.ncbi.nlm.nih.gov/19755046/ PubMed]
+*'''2007:''' Engstrom et al. Colon cancer. [https://pubmed.ncbi.nlm.nih.gov/17977501/ PubMed]
+*'''2005:''' Engstrom et al. [https://doi.org/10.6004/Jnccn.2005.0024 Colon cancer clinical practice guidelines in oncology.] [https://pubmed.ncbi.nlm.nih.gov/16038639/ PubMed]
+*'''2003:''' Engstrom et al. [https://doi.org/10.6004/Jnccn.2003.0006 Colon cancer. Clinical practice guidelines in oncology.] [https://pubmed.ncbi.nlm.nih.gov/19764149/ PubMed]
-==[http://www.esmo.org/ ESMO]==
+=Perioperative therapy=
+==mFOLFOX6 (L-Leucovorin) {{#subobject:8uy6d7|Regimen=1}}==
-*'''2019:''' Stjepanovic et al. [https://academic.oup.com/annonc/article/30/10/1558/5543095 Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-*'''2016:''' Van Cutsem et al. [https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Management-of-Patients-with-Metastatic-Colorectal-Cancer ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.] [https://www.ncbi.nlm.nih.gov/pubmed/27380959 PubMed]
+<div class="toccolours" style="background-color:#c8a2c8">
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-===Older===
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
-*'''2013:''' Labianca et al. [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]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-*'''2013:''' Balmaña et al. [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]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-==[http://www.jsccr.jp/en/index.html Japanese Society for Cancer of the Colon and Rectum]==
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10022855/ Morton et al. 2023 (FOxTROT)]
-*'''2016:''' Watanabe et al. [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]
+|2008-05-15 to 2016-12-23
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-==[https://www.nccn.org/ NCCN]==
+|[[#mFOLFOX6_.28L-Leucovorin.29_2|mFOLFOX6]]; adjuvant
+| style="background-color:#91cf60" |Seems to have superior rate of residual or recurrent disease within 2 years (primary endpoint)<br>Rate: 16.9% vs 21.5%<br>(RR 0.72, 95% CI 0.54-0.98)
-*[https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf NCCN Guidelines - Colon Cancer]
+|-
+|}
-==[http://www.siog.org/ SIOG]==
+''Note: FOxTROT was a 2 x 2 factorial trial, with a sub-randomization to panitumumab, or not, for patients with KRASwt tumors. See paper for details.''
+<div class="toccolours" style="background-color:#eeeeee">
-*'''2014:''' Papamichael et al. [https://academic.oup.com/annonc/article/26/3/463/222917 Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013]
+===Neoadjuvant {{#subobject:30juz2|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[Levoleucovorin (Fusilev)]] 175 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''
+'''14-day cycle for 3 cycles, followed by:'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Definitive===
+<div class="toccolours" style="background-color:#b3e2cd">
+====Local therapy====
+*[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Adjuvant===
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[Levoleucovorin (Fusilev)]] 175 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''
+'''14-day cycle for 9 cycles'''
+</div></div></div>
+===References===
+#'''FOxTROT:''' Morton D, Seymour M, Magill L, Handley K, Glasbey J, Glimelius B, Palmer A, Seligmann J, Laurberg S, Murakami K, West N, Quirke P, Gray R. Preoperative Chemotherapy for Operable Colon Cancer: Mature Results of an International Randomized Controlled Trial. J Clin Oncol. 2023 Mar 10;41(8):1541-1552. Epub 2023 Jan 19. [https://doi.org/10.1200/JCO.22.00046 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10022855/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/36657089/ PubMed] [https://clinicaltrials.gov/study/NCT00647530 NCT00647530]
 =Adjuvant therapy=
 ==Capecitabine monotherapy {{#subobject:7b50df|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:ed4e3f|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|Comparator
-|-
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa043116 Twelves et al. 2005 (X-ACT)]
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
-|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]
-| style="background-color:#91cf60" |Seems to have superior OS (*)
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30172-3/fulltext Kerr et al. 2016 (QUASAR 2)]
-| style="background-color:#1a9851" |Phase III (C)
-|Capecitabine & Bevacizumab
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
 |-
-|[https://www.thelancet.com/journals/langas/article/PIIS2468-1253(17)30297-2/fulltext Hamaguchi et al. 2017 (JCOG0910)]
+|[https://doi.org/10.1056/NEJMoa043116 Twelves et al. 2005 (X-ACT)]
-| style="background-color:#1a9851" |Phase III (C)
+|1998-2001
-|S-1
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior DFS
+|[[#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.nature.com/articles/s41416-019-0410-0 Tomita et al. 2019 (JFMC37-0801)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6461756/ Tomita et al. 2019 (JFMC37-0801)]
-| style="background-color:#1a9851" |Phase III (C)
+|2008-09 to 2009-12
-|Capecitabine x 12 mo
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Capecitabine_monotherapy|Capecitabine]] x 12 mo
 | style="background-color:#fee08b" |Might have inferior DFS
 |-
 |}
-''Note: reported 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#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 '''21-day cycle for 8 cycles'''
+</div></div>
 ===References===
+#'''X-ACT:''' Twelves C, Wong A, Nowacki MP, Abt M, Burris HA 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005 Jun 30;352(26):2696-704. [https://doi.org/10.1056/NEJMoa043116 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15987918/ PubMed] [https://clinicaltrials.gov/study/NCT00009737 NCT00009737]
-#'''X-ACT:''' Twelves C, Wong A, Nowacki MP, Abt M, Burris HA 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005 Jun 30;352(26):2696-704. [https://www.nejm.org/doi/full/10.1056/NEJMoa043116 link to original article] '''contains verified protocol''' [https://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://doi.org/10.1093/annonc/mdr366 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21896539/ PubMed]
-##'''Update:''' Twelves C, Scheithauer W, McKendrick J, Seitz JF, Van Hazel G, Wong A, Díaz-Rubio E, Gilberg F, Cassidy J. Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy. Ann Oncol. 2012 May;23(5):1190-7. Epub 2011 Sep 6. [https://academic.oup.com/annonc/article/23/5/1190/192299 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21896539 PubMed]
+#'''JFMC37-0801:''' Tomita N, Kunieda K, Maeda A, Hamada C, Yamanaka T, Sato T, Yoshida K, Boku N, Nezu R, Yamaguchi S, Mishima H, Sadahiro S, Muro K, Ishiguro M, Sakamoto J, Saji S, Maehara Y. Phase III randomised trial comparing 6 vs 12-month of capecitabine as adjuvant chemotherapy for patients with stage III colon cancer: final results of the JFMC37-0801 study. Br J Cancer. 2019 Apr;120(7):689-696. Epub 2019 Mar 5. [https://doi.org/10.1038/s41416-019-0410-0 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6461756/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30833647/ PubMed]
-#'''QUASAR 2:''' Kerr RS, Love S, Segelov E, Johnstone E, Falcon B, Hewett P, Weaver A, Church D, Scudder C, Pearson S, Julier P, Pezzella F, Tomlinson I, Domingo E, Kerr DJ. Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial. Lancet Oncol. 2016 Nov;17(11):1543-1557. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30172-3/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27660192 PubMed]
-#'''JCOG0910:''' Hamaguchi T, Shimada Y, Mizusawa J, Kinugasa Y, Kanemitsu Y, Ohue M, Fujii S, Takiguchi N, Yatsuoka T, Takii Y, Ojima H, Masuko H, Kubo Y, Mishima H, Yamaguchi T, Bando H, Sato T, Kato T, Nakamura K, Fukuda H, Moriya Y. Capecitabine versus S-1 as adjuvant chemotherapy for patients with stage III colorectal cancer (JCOG0910): an open-label, non-inferiority, randomised, phase 3, multicentre trial. Lancet Gastroenterol Hepatol. 2018 Jan;3(1):47-56. Epub 2017 Oct 24. [https://www.thelancet.com/journals/langas/article/PIIS2468-1253(17)30297-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29079411 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://www.nature.com/articles/s41416-019-0410-0 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30833647 PubMed]
 ==CapeOx {{#subobject:cf9acc|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 CapeOx: '''<u>Cape</u>'''citabine & '''<u>Ox</u>'''aliplatin
 <br>CAPOX: '''<u>CAP</u>'''ecitabine & '''<u>OX</u>'''aliplatin
 <br>XELOX: '''<u>XEL</u>'''oda (Capecitabine) & '''<u>OX</u>'''aliplatin
 ===Example orders===
 *[[Example orders for CapeOx (XELOX) in colon cancer]]
+<div class="toccolours" style="background-color:#eeeeee">
-===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#Comparative_efficacy|Comparative 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-de-esc)
+|2012-08-01 to 2014-06-30
-|[[#CapeOx|CapeOx]] 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#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+**Some references specify from the evening of day 1 to the morning of day 15 (28 doses per cycle)
 *[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
 '''21-day cycle for 4 cycles'''
+</div></div><br>
-===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#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
+!style="width: 20%"|Comparator
-|[http://jco.ascopubs.org/content/25/1/102.long Schmoll et al. 2007 (XELOXA)]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]
-| style="background-color:#91cf60" |Seems to have superior OS (*)
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445286/ Pectasides et al. 2015]
+|[https://doi.org/10.1200/jco.2006.08.1075 Schmoll et al. 2007 (XELOXA)]
-| style="background-color:#1a9851" |Phase III (C)
+|2003-04 to 2004-10
-|[[#mFOLFOX6|mFOLFOX6]]
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
+|[[#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.ncbi.nlm.nih.gov/pmc/articles/PMC5237801/ Snoeren et al. 2017 (HEPATICA)]
+|[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
-|CapeOx & Bevacizumab
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
+|1a. [[#CapeOx|CapeOx]] x 3 mo<br>1b. [[#mFOLFOX6|mFOLFOX6]] x 3 mo
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext Iveson et al. 2018 (SCOT)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#CapeOx|CapeOx]] x 3 mo
 | style="background-color:#eeee01" |Seems to have non-inferior DFS
 |-
 |}
-''Note: HEPATICA enrolled patients with resected colorectal liver metastases. Reported efficacy for XELOXA is based on the 2015 update.''
+''<sup>1</sup>Reported efficacy for XELOXA is based on the 2015 update.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 **Some references specify from the evening of day 1 to the morning of day 15 (28 doses per cycle)
 *[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
 '''21-day cycle for 8 cycles'''
+</div></div>
 ===References===
+#'''XELOXA:''' Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A, Maroun J, Price T, Lim R, Van Cutsem E, Park YS, McKendrick J, Topham C, Soler-Gonzalez G, de Braud F, Hill M, Sirzén F, Haller DG. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007 Jan 1;25(1):102-9. [https://doi.org/10.1200/jco.2006.08.1075 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17194911/ PubMed] [https://clinicaltrials.gov/study/NCT00069121 NCT00069121]
-#'''XELOXA:''' Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A, Maroun J, Price T, Lim R, Van Cutsem E, Park YS, McKendrick J, Topham C, Soler-Gonzalez G, de Braud F, Hill M, Sirzén F, Haller DG. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007 Jan 1;25(1):102-9. [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. [https://doi.org/10.1200/jco.2010.33.6297 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21383294/ PubMed]
-##'''Update:''' Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011 Apr 10;29(11):1465-71. Epub 2011 Mar 7. [http://jco.ascopubs.org/content/29/11/1465.long link to original article] [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. [https://doi.org/10.1200/jco.2015.60.9107 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26324362/ PubMed]
-##'''Update:''' Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: Final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015 Nov 10;33(32):3733-40. Epub 2015 Aug 31. [http://jco.ascopubs.org/content/33/32/3733.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26324362 PubMed]
+#'''IDEA:''' Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018 Mar 29;378(13):1177-1188. [https://doi.org/10.1056/NEJMoa1713709 link to original article] '''does not contain dosing details''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6426127/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29590544/ PubMed] [https://clinicaltrials.gov/study/NCT01308086 NCT01308086]
-#Pectasides D, Karavasilis V, Papaxoinis G, Gourgioti G, Makatsoris T, Raptou G, Vrettou E, Sgouros J, Samantas E, Basdanis G, Papakostas P, Bafaloukos D, Kotoula V, Kalofonos HP, Scopa CD, Pentheroudakis G, Fountzilas G. Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or stage III colorectal cancer. BMC Cancer. 2015 May 10;15:384. [https://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1406-7 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445286/ link to PMC article] [https://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]
-#'''HEPATICA:''' Snoeren N, van Hillegersberg R, Schouten SB, Bergman AM, van Werkhoven E, Dalesio O, Tollenaar RA, Verheul HM, van der Sijp J, Borel Rinkes IH, Voest EE; Hepatica study group. Randomized phase III study to assess efficacy and safety of adjuvant CAPOX with or without bevacizumab in patients after resection of colorectal liver metastases: HEPATICA study. Neoplasia. 2017 Feb;19(2):93-99. Epub 2017 Jan 12. [https://www.clinicalkey.com/#!/content/playContent/1-s2.0-S1476558616301701 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237801/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28088688 PubMed]
+##'''Update:''' André T, Meyerhardt J, Iveson T, Sobrero A, Yoshino T, Souglakos I, Grothey A, Niedzwiecki D, Saunders M, Labianca R, Yamanaka T, Boukovinas I, Vernerey D, Meyers J, Harkin A, Torri V, Oki E, Georgoulias V, Taieb J, Shields A, Shi Q. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020 Dec;21(12):1620-1629. [https://doi.org/10.1016/S1470-2045(20)30527-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7786835/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33271092/ PubMed]
-#'''IDEA:''' Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018 Mar 29;378(13):1177-1188. [https://www.nejm.org/doi/full/10.1056/NEJMoa1713709 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29590544 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. [https://doi.org/10.1001/jamaoncol.2019.2572 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743062/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31513248/ PubMed] UMIN000008543
-##'''Subgroup analysis:''' Souglakos J, Boukovinas I, Kakolyris S, Xynogalos S, Ziras N, Athanasiadis A, Androulakis N, Christopoulou A, Vaslamatzis M, Ardavanis A, Emmanouilides C, Bompolaki I, Kourousis C, Makrantonakis P, Christofyllakis C, Athanasiadis E, Kentepozidis N, Karampeazis A, Katopodi U, Anagnosopoulos A, Papadopoulos G, Prinarakis E, Kalisperi A, Mavroudis D, Georgoulias V. 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://academic.oup.com/annonc/article/30/8/1304/5522015 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31228203 PubMed]
+##'''Update:''' Yoshino T, Oki E, Misumi T, Kotaka M, Manaka D, Eto T, Hasegawa J, Takagane A, Nakamura M, Kato T, Munemoto Y, Nakamura F, Bando H, Taniguchi H, Sakamoto Y, Shiozawa M, Nishi M, Horiuchi T, Yamagishi H, Sakamoto J, Mizushima T, Ohtsu A, Mori M. Final Analysis of 3 Versus 6 Months of Adjuvant Oxaliplatin and Fluoropyrimidine-Based Therapy in Patients With Stage III Colon Cancer: The Randomized Phase III ACHIEVE Trial. J Clin Oncol. 2022 Oct 10;40(29):3419-3429. Epub 2022 May 5. [https://doi.org/10.1200/jco.21.02628 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35512259/ PubMed]
-#'''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]
+#'''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]
+#'''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]
-==Fluorouracil & Folinic acid {{#subobject:a93a|Regimen=1}}==
+#'''CIRCULATE-IDEA:''' [https://clinicaltrials.gov/study/NCT05174169 NCT05174169]
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FULV: 5-'''<u>FU</u>''' & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid)
-<br>LV5FU2: '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid) & '''<u>5-FU</u>''' for '''<u>2</u>''' days
-===Example orders===
-*[[Example orders for 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV) in colon cancer]]
-*[[Example orders for 5-FU & high-dose Leucovorin (Roswell Park regimen/HDLV) in colon cancer]]
-===Variant #1, 500/200, 6 out of 8 weeks {{#subobject:2c3f1b|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038965/ Papadimitriou et al. 2011]
-| style="background-color:#1a9851" |Phase III (C)
-|IFL
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
-'''8-week cycle for 4 cycles'''
-===Variant #2, 500/500, 6 out of 8 weeks {{#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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://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-de-esc)
-|[[Colon_cancer_-_historical#MOF|MOF]]
-| style="background-color:#1a9850" |Superior OS
-|-
-| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/JCO.1999.17.11.3553 Wolmark et al. 1999 (NSABP C-04)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ooc)
-|1. [[Colon_cancer_-_historical#Fluorouracil_.26_Levamisole|5-FU & Levamisole]]
-| style="background-color:#d9ef8b" |Might have superior OS
-|-
-|2. 5-FU, Leucovorin, Levamisole
-| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS/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-esc)
-|1. [[#Fluorouracil_.26_Folinic_acid|5-FU & LV]]; low-dose
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|2. LDLV & Levamisole
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|3. 5-FU & Levamisole
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[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" |Did not meet primary endpoints of DFS/OS
-|-
-|[http://jco.ascopubs.org/content/25/1/102.long Schmoll et al. 2007 (XELOXA)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#CapeOx|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
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2007.11.2144 Saltz et al. 2007 (CALGB 89803)]
-| style="background-color:#1a9851" |Phase III (C)
-|IFL
-| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS/OS
-|-
-|}
-''Note: this is often called the "Roswell Park regimen" but the original regimen described by Petrelli et al. 1987 & 1989 used a 5-FU dose of 600 mg/m<sup>2</sup>.''
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, 29, 36, '''given second, 1 hour after start of leucovorin'''
-*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, '''given first'''
-'''8-week cycle for 3 to 6 cycles'''
-===Variant #3, 600/500, 6 out of 8 weeks ("Roswell Park regimen") {{#subobject:50ybe0|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.karger.com/Article/Abstract/12105 Fountzilas et al. 2000]
-| style="background-color:#1a9851" |Phase III (C)
-|FULV & IFN alfa-2a
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, 29, 36, '''given second, 1 hour after start of leucovorin'''
-*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, '''given first'''
-'''8-week cycle for 4 cycles'''
-===Variant #4, 1850/1000 {{#subobject:588afe|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673695906967/fulltext Marsoni et al. 1995 (IMPACT<sub>CRC</sub>)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Observation|Observation]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-''Note: this was the lower bound of 5-FU dose for the three included RCTs. This study should not be confused with the studies of the same name in breast cancer and prostate cancer.''
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV once per day on days 1 to 5
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5
-'''28-day cycle for 6 cycles'''
-===Variant #5, 1850/2500 ("NCI schedule") {{#subobject:7cc2b9|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://academic.oup.com/jnci/article/90/23/1810/2520545 Wolmark et al. 1998 (NSABP C-05)]
-| style="background-color:#1a9851" |Phase III (C)
-|FULV & Interferon alfa
-| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS/OS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, '''given second'''
-*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first'''
-'''28-day cycle for 6 cycles'''
-===Variant #6, 2000/400 ("de Gramont regimen"/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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2003.10.065 André et al. 2003 (GERCOR C96.1)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Fluorouracil_.26_Folinic_acid|FULV]]; monthly
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa032709 André et al. 2004 (MOSAIC)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFOX4|FOLFOX4]]
-| style="background-color:#fc8d59" |Seems to have inferior OS (*)
-|-
-|[https://academic.oup.com/annonc/article/20/4/674/205923 Ychou et al. 2009 (FFCD 9802)]
-| style="background-color:#1a9851" |Phase III (C)
-|IFL
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2008.21.6663 Van Cutsem et al. 2009 (PETACC-3)]
-| style="background-color:#1a9851" |Phase III (C)
-|IFL
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-|-
-|}
-''Reported efficacy for MOSAIC is based on the 2009 update.''
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first'''
-'''14-day cycle for 12 cycles'''
-===Variant #7, 2125/100 ("Mayo Clinic regimen") {{#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#Comparative_efficacy|Comparative Efficacy]]
-|-
-||[https://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
-|-
-|[https://www.ejcancer.com/article/S0959-8049(08)00535-2/fulltext Popov et al. 2008 (PETACC-1)]
-| style="background-color:#1a9851" |Phase III (C)
-|Raltitrexed
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior RFS/OS
-|-
-|[https://www.ejcancer.com/article/S0959-8049(13)00094-4/fulltext Köhne et al. 2013 (PETACC-2)]
-| style="background-color:#1a9851" |Phase III (C)
-|1. LV5FU2<br> 2. AIO regimen<br> 3. TTD regimen
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS60
-|-
-|}
-''Note: efficacy for X-ACT is based on the 2011 update. Dosing details for PETACC-1 could not be confirmed from the abstract.''
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''
-'''28-day cycle for 6 cycles'''
-===Variant #8, 2125/100, with cycle elongation ("Mayo Clinic regimen") {{#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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/15/1/246.long O'Connell et al. 1997]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Observation|Observation]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140673602098367/fulltext Punt et al. 2002 (Study 157-002)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. FULV & Edrecolomab
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|2. [[Colon_cancer_-_historical#Edrecolomab_monotherapy|Edrecolomab]]
-| 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-de-esc)
-|1. [[#Fluorouracil_.26_Folinic_acid|5-FU & LV]]; high-dose
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|2. LDLV & Levamisole
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|3. 5-FU & Levamisole
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2008.18.5710 Fields et al. 2009 (Study 157-001)]
-| style="background-color:#1a9851" |Phase III (C)
-|FULV & Edrecolomab
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''
-'''28-day cycle for 3 cycles, then 35-day cycle for 3 cycles'''
-===Variant #9, 2800/400 (LV5FUs) {{#subobject:476348|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/20/12/1964/210839 Ychou et al. 2009]
-| style="background-color:#1a9851" |Phase III (C)
-|FOLFIRI
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Complete surgical resection of colorectal liver metastases]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''14-day cycle for 12 cycles'''
-===References===
-#'''NSABP C-03:''' Wolmark N, Rockette H, Fisher B, Wickerham DL, Redmond C, Fisher ER, Jones J, Mamounas EP, Ore L, Petrelli NJ, Spurr CL, Dimitrov N, Romond EH, Sutherland CM, Kardinal CG, DeFusco PA, Jochimsen P. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol. 1993 Oct;11(10):1879-87. [https://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]
-##'''Pooled update:''' Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. [https://link.springer.com/article/10.1245%2Fs10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20082144 PubMed]
-#'''IMPACT:''' Marsoni S, Labianca R, Pancera G, Torri V, Zaniboni A, Erlichman C, Pater J, Shepherd L, Zee B, Seitz JF, Milan C, Pignon JP; International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet. 1995 Apr 15;345(8955):939-44. [https://www.thelancet.com/journals/lancet/article/PIIS0140673695906967/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7715291 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]
-##'''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://ascopubs.org/doi/full/10.1200/JCO.1999.17.5.1356 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10334519 PubMed]
-#'''NSABP C-05:''' Wolmark N, Bryant J, Smith R, Grem J, Allegra C, Hyams D, Atkins J, Dimitrov N, Oishi R, Prager D, Fehrenbacher L, Romond E, Colangelo L, Fisher B. Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst. 1998 Dec 2;90(23):1810-6. [https://academic.oup.com/jnci/article/90/23/1810/2520545 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9839521 PubMed]
-##'''Pooled update:''' Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. [https://link.springer.com/article/10.1245%2Fs10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/10.1200/JCO.1999.17.11.3553 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10550154 PubMed]
-##'''Pooled update:''' Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. [https://link.springer.com/article/10.1245%2Fs10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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. Fluorouracil and leucovorin with or without interferon alfa-2a as adjuvant treatment, in patients with high-risk colon cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Oncology. 2000 Apr;58(3):227-36. [https://www.karger.com/Article/Abstract/12105 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10765125 PubMed]
-#'''Study 157-002:''' Punt CJ, Nagy A, Douillard JY, Figer A, Skovsgaard T, Monson J, Barone C, Fountzilas G, Riess H, Moylan E, Jones D, Dethling J, Colman J, Coward L, MacGregor S. Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study. Lancet. 2002 Aug 31;360(9334):671-7. [https://www.thelancet.com/journals/lancet/article/PIIS0140673602098367/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/10.1200/JCO.2003.10.065 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/10.1200/JCO.2007.12.2234 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17704423 PubMed]
-#'''MOSAIC:''' André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004 Jun 3;350(23):2343-51. [https://www.nejm.org/doi/full/10.1056/NEJMoa032709 link to original article] '''contains verified protocol''' [https://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. [https://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. [https://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. [https://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]
-#'''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]
-##'''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. [https://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]
-#'''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://ascopubs.org/doi/full/10.1200/JCO.2007.11.2144 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17687149 PubMed]
-#'''PETACC-1:''' Popov I, Carrato A, Sobrero A, Vincent M, Kerr D, Labianca R, Raffaele Bianco A, El-Serafi M, Bedenne L, Paillot B, Mini E, Sanches E, Welch J, Collette L, Praet M, Wils J. Raltitrexed (Tomudex) versus standard leucovorin-modulated bolus 5-fluorouracil: Results from the randomised phase III Pan-European Trial in Adjuvant Colon Cancer 01 (PETACC-1). Eur J Cancer. 2008 Oct;44(15):2204-11. Epub 2008 Aug 15. [https://www.ejcancer.com/article/S0959-8049(08)00535-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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://academic.oup.com/annonc/article/20/4/674/205923 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19179549 PubMed]
-#'''Study 157-001:''' Fields AL, Keller A, Schwartzberg L, Bernard S, Kardinal C, Cohen A, Schulz J, Eisenberg P, Forster J, Wissel P. Adjuvant therapy with the monoclonal antibody edrecolomab plus fluorouracil-based therapy does not improve overall survival of patients with stage III colon cancer. J Clin Oncol. 2009 Apr 20;27(12):1941-7. Epub 2009 Mar 9. [https://ascopubs.org/doi/full/10.1200/JCO.2008.18.5710 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/10.1200/JCO.2008.21.6663 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19451425 PubMed]
-#Ychou M, Hohenberger W, Thezenas S, Navarro M, Maurel J, Bokemeyer C, Shacham-Shmueli E, Rivera F, Kwok-Keung Choi C, Santoro A. A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer. Ann Oncol. 2009 Dec;20(12):1964-70. Epub 2009 Jun 30. [https://academic.oup.com/annonc/article/20/12/1964/210839 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19567451 PubMed]
-#Papadimitriou CA, Papakostas P, Karina M, Malettou L, Dimopoulos MA, Pentheroudakis G, Samantas E, Bamias A, Miliaras D, Basdanis G, Xiros N, Klouvas G, Bafaloukos D, Kafiri G, Papaspirou I, Pectasides D, Karanikiotis C, Economopoulos T, Efstratiou I, Korantzis I, Pisanidis N, Makatsoris T, Matsiakou F, Aravantinos G, Kalofonos HP, Fountzilas G. A randomized phase III trial of adjuvant chemotherapy with irinotecan, leucovorin and fluorouracil versus leucovorin and fluorouracil for stage II and III colon cancer: a Hellenic Cooperative Oncology Group study. BMC Med. 2011 Jan 31;9:10. [https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-10 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038965/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21281463 PubMed]
-#'''PETACC-2:''' Köhne CH, Bedenne L, Carrato A, Bouché O, Popov I, Gaspà L, Valladares M, Rougier P, Gog C, Reichardt P, Wils J, Pignatti F, Biertz F. A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: the Pan-European Trial in Adjuvant Colon Cancer 2 study. Eur J Cancer. 2013 May;49(8):1868-75. Epub 2013 Apr 6. [https://www.ejcancer.com/article/S0959-8049(13)00094-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23571150 PubMed]
-==Fluorouracil & Levoleucovorin {{#subobject:a93a7t|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Variant #1, 370/25, weekly {{#subobject:1d257d|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02214-5/fulltext Gray et al. 2000 (QUASAR)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. 5-FU & HDLV
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|2. 5-FU, LDLV, Levamisole<br> 3. 5-FU, HDLV, Levamisole
-| style="background-color:#d9ef8b" |Might have superior OS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV bolus once on day 1
-*[[Levoleucovorin (Fusilev)]] 25 mg/m<sup>2</sup> IV bolus once on day 1
-'''7-day cycle for 30 cycles'''
-===Variant #2, 1850/125, q4wk {{#subobject:acc8d1|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02214-5/fulltext Gray et al. 2000 (QUASAR)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. 5-FU & HDLV
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|2. 5-FU, LDLV, Levamisole<br> 3. 5-FU, HDLV, Levamisole
-| style="background-color:#d9ef8b" |Might have superior OS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
-*[[Levoleucovorin (Fusilev)]] 25 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
-'''28-day cycle for 6 cycles'''
-===References===
-#'''QUASAR:''' Gray RG, Kerr DJ, McConkey CC, Williams NS, Hills RK; QUASAR Collaborative Group. Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. Lancet. 2000 May 6;355(9215):1588-96. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02214-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10821362 PubMed]
-##'''Update:''' Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ; Quasar Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007 Dec 15;370(9604):2020-9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61866-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18083404 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#Comparative_efficacy|Comparative 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-esc)
+|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#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, 29, 36, '''given third, 1 hour after start of leucovorin'''
-*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, '''given second'''
+*[[Leucovorin (Folinic acid)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, '''given second'''
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 15, 29, '''given first'''
 '''8-week cycle for 3 cycles'''
+</div></div>
 ===References===
+#'''NSABP C-07:''' Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, Zapas JL, Goodwin JW, Fehrenbacher L, Ramanathan RK, Conley BA, Flynn PJ, Soori G, Colman LK, Levine EA, Lanier KS, Wolmark N. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007 Jun 1;25(16):2198-204. Epub 2007 Apr 30. [https://doi.org/10.1200/jco.2006.08.2974 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17470851/ PubMed] [https://clinicaltrials.gov/study/NCT00004931 NCT00004931]
-#'''NSABP C-07:''' Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, Zapas JL, Goodwin JW, Fehrenbacher L, Ramanathan RK, Conley BA, Flynn PJ, Soori G, Colman LK, Levine EA, Lanier KS, Wolmark N. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007 Jun 1;25(16):2198-204. Epub 2007 Apr 30. [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]
+##'''Update:''' Yothers G, O'Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, Wolmark N. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011 Oct 1;29(28):3768-74. Epub 2011 Aug 22. [https://doi.org/10.1200/JCO.2011.36.4539 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188282/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21859995/ PubMed]
-##'''Update:''' Yothers G, O'Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, Wolmark N. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011 Oct 1;29(28):3768-74. Epub 2011 Aug 22. [https://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]
 ==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#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa032709 André et al. 2004 (MOSAIC)]
+|[https://doi.org/10.1056/NEJMoa032709 André et al. 2004 (MOSAIC)]
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
+|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
-|1. FOLFOX4 & Bevacizumab
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#FOLFOX4_.26_Bevacizumab_999|FOLFOX4 & Bevacizumab]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|2. XELOX & Bevacizumab
+|2. [[#CapeOx_.26_Bevacizumab_999|XELOX & Bevacizumab]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70227-X/fulltext Taieb et al. 2014 (PETACC-8)]
+|[https://doi.org/10.1016/S1470-2045(14)70227-X Taieb et al. 2014 (PETACC-8)]
-| style="background-color:#1a9851" |Phase III (C)
+|2005-2009
-|FOLFOX4 & Cetuximab
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#FOLFOX4_.26_Cetuximab_999|FOLFOX4 & Cetuximab]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1713709 Grothey et al. 2018 (IDEA)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6426127/ Grothey et al. 2018 (IDEA)]
-| style="background-color:#1a9851" |Phase III (C)
+|2007-2015
-|FOLFOX4 x 6
+| style="background-color:#1a9851" |Phase 3 (C)
+|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#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with leucovorin'''
 '''14-day cycle for 12 cycles'''
+</div></div>
 ===References===
+#'''MOSAIC:''' André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004 Jun 3;350(23):2343-51. [https://doi.org/10.1056/NEJMoa032709 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15175436/ PubMed] [https://clinicaltrials.gov/study/NCT00275210 NCT00275210]
-#'''MOSAIC:''' André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004 Jun 3;350(23):2343-51. [https://www.nejm.org/doi/full/10.1056/NEJMoa032709 link to original article] '''contains verified protocol''' [https://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. [https://doi.org/10.1200/JCO.2008.20.6771 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19451431/ PubMed]
-##'''Update:''' André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009 Jul 1;27(19):3109-16. Epub 2009 May 18. [https://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. [https://doi.org/10.1200/JCO.2015.63.4238 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26527776/ PubMed]
-##'''Update:''' André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, Scriva A, Hickish T, Tabernero J, Van Laethem JL, Banzi M, Maartense E, Shmueli E, Carlsson GU, Scheithauer W, Papamichael D, Möehler M, Landolfi S, Demetter P, Colote S, Tournigand C, Louvet C, Duval A, Fléjou JF, de Gramont A. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol. 2015 Dec 10;33(35):4176-87. Epub 2015 Nov 2. [https://ascopubs.org/doi/full/10.1200/JCO.2015.63.4238 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26527776 PubMed]
+#'''AVANT:''' de Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, Cunningham D, Cartwright TH, Hecht JR, Rivera F, Im SA, Bodoky G, Salazar R, Maindrault-Goebel F, Shacham-Shmueli E, Bajetta E, Makrutzki M, Shang A, André T, Hoff PM. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012 Dec;13(12):1225-33. Epub 2012 Nov 16. [https://doi.org/10.1016/S1470-2045(12)70509-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/23168362/ PubMed] [https://clinicaltrials.gov/study/NCT00112918 NCT00112918]
-#'''AVANT:''' de Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, Cunningham D, Cartwright TH, Hecht JR, Rivera F, Im SA, Bodoky G, Salazar R, Maindrault-Goebel F, Shacham-Shmueli E, Bajetta E, Makrutzki M, Shang A, André T, Hoff PM. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012 Dec;13(12):1225-33. Epub 2012 Nov 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70509-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23168362 PubMed]
+##'''Update:''' André T, Vernerey D, Im SA, Bodoky G, Buzzoni R, Reingold S, Rivera F, McKendrick J, Scheithauer W, Ravit G, Fountzilas G, Yong WP, Isaacs R, Österlund P, Liang JT, Creemers GJ, Rakez M, Van Cutsem E, Cunningham D, Tabernero J, de Gramont A. Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group. Ann Oncol. 2020 Feb;31(2):246-256. Epub 2019 Dec 18. [https://doi.org/10.1016/j.annonc.2019.12.006 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31959341/ PubMed]
-#'''PETACC-8:''' Taieb J, Tabernero J, Mini E, Subtil F, Folprecht G, Van Laethem JL, Thaler J, Bridgewater J, Petersen LN, Blons H, Collette L, Van Cutsem E, Rougier P, Salazar R, Bedenne L, Emile JF, Laurent-Puig P, Lepage C; PETACC-8 Study Investigators. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Jul;15(8):862-73. Epub 2014 Jun 11. [https://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]
+#'''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://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]
-##'''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. 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://academic.oup.com/annonc/article/30/8/1304/5522015 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31228203 PubMed]
+##'''Subgroup analysis:''' Souglakos J, Boukovinas I, Kakolyris S, Xynogalos S, Ziras N, Athanasiadis A, Androulakis N, Christopoulou A, Vaslamatzis M, Ardavanis A, Emmanouilides C, Bompolaki I, Kourousis C, Makrantonakis P, Christofyllakis C, Athanasiadis E, Kentepozidis N, Karampeazis A, Katopodi U, Anagnosopoulos A, Papadopoulos G, Prinarakis E, Kalisperi A, Mavroudis D, Georgoulias V; Hellenic Oncology Research Group. Three versus six months adjuvant FOLFOX or CAPOX for high risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project. Ann Oncol. 2019 Aug 1;30(8):1304-1310. Epub 2019 Jun 22. [https://doi.org/10.1093/annonc/mdz193 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31228203/ PubMed]
+##'''Update:''' André T, Meyerhardt J, Iveson T, Sobrero A, Yoshino T, Souglakos I, Grothey A, Niedzwiecki D, Saunders M, Labianca R, Yamanaka T, Boukovinas I, Vernerey D, Meyers J, Harkin A, Torri V, Oki E, Georgoulias V, Taieb J, Shields A, Shi Q. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020 Dec;21(12):1620-1629. [https://doi.org/10.1016/S1470-2045(20)30527-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7786835/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33271092/ PubMed]
+#'''TOSCA:''' Petrelli F, Rulli E, Labianca R, Lonardi S, Rosati G, Dotti K, Ronzoni M, Pella N, Pusceddu V, Banzi M, Zampino MG, Yasmina M, Marchetti P, Cantore M, Zaniboni A, Rimassa L, Ciuffreda L, Ferrari D, Zagonel V, Maiello E, Sobrero A; TOSCA Investigators. Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial. Ann Oncol. 2021 Jan;32(1):66-76. Epub 2020 Oct 21. [https://doi.org/10.1016/j.annonc.2020.10.477 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33098997/ PubMed] [https://clinicaltrials.gov/study/NCT00646607 NCT00646607]
 ==mFOLFOX6 {{#subobject:32d6c5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
 ===Example orders===
 *[[Example orders for mFOLFOX 6 in colon cancer]]
+<div class="toccolours" style="background-color:#eeeeee">
-===Variant #1, 3 months {{#subobject:205ad6|Variant=1}}===
+===Regimen {{#subobject:30juz2|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#Comparative_efficacy|Comparative 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)]
-| style="background-color:#1a9851" |Phase III (E-de-esc)
-|mFOLFOX6 x 6 mo
-| style="background-color:#eeee01" |Seems to have non-inferior DFS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 350 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''
-'''14-day cycle for 6 cycles'''
-===Variant #2, 6 months (LCV 200 mg/m<sup>2</sup>) {{#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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445286/ Pectasides et al. 2015]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#CapeOx|CAPOX]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]], within 10 weeks
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''
-'''14-day cycle for 12 cycles'''
-===Variant #3, 6 months (LCV 350 mg/m<sup>2</sup>) {{#subobject:308ic7|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext Iveson et al. 2018 (SCOT)]
-| style="background-color:#1a9851" |Phase III (C)
-|mFOLFOX6 x 3 mo
-| style="background-color:#eeee01" |Seems to have non-inferior DFS
-|-
-|}
-====Preceding treatment====
-*[[Surgery#Colorectal_cancer_surgery|Surgery]], within 10 weeks
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 350 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''
-'''14-day cycle for 12 cycles'''
-===Variant #4, 6 months (LCV 400 mg/m<sup>2</sup>) {{#subobject:30juz2|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#Comparative_efficacy|Comparative 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)
+|[[Colon_cancer_-_historical#mFOLFOX6-B|mFOLFOX6-B]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1713709 Grothey et al. 2018 (IDEA)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6426127/ Grothey et al. 2018 (IDEA)]
-| style="background-color:#1a9851" |Phase III (C)
+|2007-2015
-|mFOLFOX6 x 3 mo
+| style="background-color:#1a9851" |Phase 3 (C)
+|1a. [[#FOLFOX4|FOLFOX4]] x 6<br>1b. [[#mFOLFOX6|mFOLFOX6]] x 3 mo<br>1c. [[#CapeOx|CapeOx]] x 3 mo
 | style="background-color:#ffffbf" |Inconclusive whether non-inferior DFS36
 |-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2017.76.0355 André et al. 2018 (IDEA France)]
+|[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 3 mo
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#mFOLFOX6_2|mFOLFOX6]] x 3 mo
 | style="background-color:#91cf60" |Seems to have superior DFS
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8025124/ Meyerhardt et al. 2021 (CALGB 80702)]
+|2010-2015
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#mFOLFOX6_.26_Celecoxib_999|mFOLFOX6 & Celecoxib]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
 |}
+''Note: CALGB 80702 was a 2 x 2 factorial trial, with the other comparison being 3 vs 6 months of mFOLFOX6. This comparison was made as part of the IDEA collaborative and is reported separately.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]], within 10 weeks
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''
 '''14-day cycle for 12 cycles'''
+</div></div>
 ===References===
 <!-- Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL. -->
+#'''NSABP C-08:''' Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Colangelo LH, Lopa SH, Petrelli NJ, Goldberg RM, Atkins JN, Seay TE, Fehrenbacher L, O'Reilly S, Chu L, Azar CA, Wolmark N. Initial safety report of NSABP C-08: A randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol. 2009 Jul 10;27(20):3385-90. Epub 2009 May 4. [https://doi.org/10.1200/jco.2009.21.9220 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717026/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19414665/ PubMed] [https://clinicaltrials.gov/study/NCT00096278 NCT00096278]
+## '''Update:''' Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Colangelo LH, Atkins JN, Seay TE, Fehrenbacher L, Goldberg RM, O'Reilly S, Chu L, Azar CA, Lopa S, Wolmark N. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011 Jan 1;29(1):11-6. Epub 2010 Oct 12. [https://doi.org/10.1200/JCO.2010.30.0855 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055856/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20940184/ PubMed]
+## '''Update:''' Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Lopa SH, Wolmark N. Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J Clin Oncol. 2013 Jan 20;31(3):359-64. Epub 2012 Dec 10. [https://doi.org/10.1200/JCO.2012.44.4711 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732014/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23233715/ PubMed]
+#'''IDEA:''' Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018 Mar 29;378(13):1177-1188. [https://doi.org/10.1056/NEJMoa1713709 link to original article] '''does not contain dosing details''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6426127/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29590544/ PubMed] [https://clinicaltrials.gov/study/NCT01308086 NCT01308086]
+##'''Subgroup analysis:''' Souglakos J, Boukovinas I, Kakolyris S, Xynogalos S, Ziras N, Athanasiadis A, Androulakis N, Christopoulou A, Vaslamatzis M, Ardavanis A, Emmanouilides C, Bompolaki I, Kourousis C, Makrantonakis P, Christofyllakis C, Athanasiadis E, Kentepozidis N, Karampeazis A, Katopodi U, Anagnosopoulos A, Papadopoulos G, Prinarakis E, Kalisperi A, Mavroudis D, Georgoulias V; Hellenic Oncology Research Group. Three versus six months adjuvant FOLFOX or CAPOX for high risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project. Ann Oncol. 2019 Aug 1;30(8):1304-1310. Epub 2019 Jun 22. [https://doi.org/10.1093/annonc/mdz193 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31228203/ PubMed]
+##'''Update:''' André T, Meyerhardt J, Iveson T, Sobrero A, Yoshino T, Souglakos I, Grothey A, Niedzwiecki D, Saunders M, Labianca R, Yamanaka T, Boukovinas I, Vernerey D, Meyers J, Harkin A, Torri V, Oki E, Georgoulias V, Taieb J, Shields A, Shi Q. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020 Dec;21(12):1620-1629. [https://doi.org/10.1016/S1470-2045(20)30527-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7786835/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33271092/ PubMed]
+#'''IDEA France:''' André T, Vernerey D, Mineur L, Bennouna J, Desrame J, Faroux R, Fratte S, Hug de Larauze M, Paget-Bailly S, Chibaudel B, Bez J, Dauba J, Louvet C, Lepere C, Dupuis O, Becouarn Y, Mabro M, Egreteau J, Bouche O, Deplanque G, Ychou M, Galais MP, Ghiringhelli F, Dourthe LM, Bachet JB, Khalil A, Bonnetain F, de Gramont A, Taieb J; PRODIGE investigators, GERCOR, Fédération Française de Cancérologie Digestive, UNICANCER. Three versus 6 months of oxaliplatin-based adjuvant chemotherapy for patients with stage III colon cancer: disease-free survival results from a randomized, open-label, International Duration Evaluation of Adjuvant (IDEA) France, phase III trial. J Clin Oncol. 2018 May 20;36(15):1469-1477. Epub 2018 Apr 5. [https://doi.org/10.1200/JCO.2017.76.0355 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29620995/ PubMed] [https://clinicaltrials.gov/study/NCT00958737 NCT00958737]
+#'''TOSCA:''' Petrelli F, Rulli E, Labianca R, Lonardi S, Rosati G, Dotti K, Ronzoni M, Pella N, Pusceddu V, Banzi M, Zampino MG, Yasmina M, Marchetti P, Cantore M, Zaniboni A, Rimassa L, Ciuffreda L, Ferrari D, Zagonel V, Maiello E, Sobrero A; TOSCA Investigators. Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial. Ann Oncol. 2021 Jan;32(1):66-76. Epub 2020 Oct 21. [https://doi.org/10.1016/j.annonc.2020.10.477 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33098997/ PubMed] [https://clinicaltrials.gov/study/NCT00646607 NCT00646607]
+#'''ACHIEVE-2:''' Yamazaki K, Yamanaka T, Shiozawa M, Manaka D, Kotaka M, Gamoh M, Shiomi A, Makiyama A, Munemoto Y, Rikiyama T, Fukunaga M, Ueki T, Shitara K, Shinkai H, Tanida N, Oki E, Sunami E, Ohtsu A, Maehara Y, Yoshino T. Oxaliplatin-based adjuvant chemotherapy duration (3 versus 6 months) for high-risk stage II colon cancer: the randomized phase III ACHIEVE-2 trial. Ann Oncol. 2021 Jan;32(1):77-84. Epub 2020 Oct 26. [https://doi.org/10.1016/j.annonc.2020.10.480 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33121997/ PubMed] UMIN000013036
+#'''CALGB 80702:''' Meyerhardt JA, Shi Q, Fuchs CS, Meyer J, Niedzwiecki D, Zemla T, Kumthekar P, Guthrie KA, Couture F, Kuebler P, Bendell JC, Kumar P, Lewis D, Tan B, Bertagnolli M, Grothey A, Hochster HS, Goldberg RM, Venook A, Blanke C, O'Reilly EM, Shields AF. Effect of Celecoxib vs Placebo Added to Standard Adjuvant Therapy on Disease-Free Survival Among Patients With Stage III Colon Cancer: The CALGB/SWOG 80702 (Alliance) Randomized Clinical Trial. JAMA. 2021 Apr 6;325(13):1277-1286. [https://doi.org/10.1001/jama.2021.2454 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8025124/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33821899/ PubMed] [https://clinicaltrials.gov/study/NCT01150045 NCT01150045]
+##'''Dataset:''' [https://data.projectdatasphere.org/projectdatasphere/html/content/489 Project Data Sphere]
+#'''KCSG CO09-07:''' Kim ST, Kim SY, Lee J, Yun SH, Kim HC, Lee WY, Kim TW, Hong YS, Lim SB, Baek JY, Oh JH, Ahn JB, Shin SJ, Han SW, Kim SG, Kang SY, Sym SJ, Zang DY, Kim YH, Choi IS, Kang JH, Kim MJ, Park YS. Oxaliplatin (3 months v 6 months) With 6 Months of Fluoropyrimidine as Adjuvant Therapy in Patients With Stage II/III Colon Cancer: KCSG CO09-07. J Clin Oncol. 2022 Nov 20;40(33):3868-3877. Epub 2022 Jun 30. [https://doi.org/10.1200/jco.21.02962 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9671755/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35772045/ PubMed] [https://clinicaltrials.gov/study/NCT01092481 NCT01092481]
-#'''NSABP C-08:''' Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Colangelo LH, Lopa SH, Petrelli NJ, Goldberg RM, Atkins JN, Seay TE, Fehrenbacher L, O'Reilly S, Chu L, Azar CA, Wolmark N. Initial safety report of NSABP C-08: A randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol. 2009 Jul 10;27(20):3385-90. Epub 2009 May 4. [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]
+==mFOLFOX6 (L-Leucovorin) {{#subobject:32d6d7|Regimen=1}}==
-##'''Update:''' Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Colangelo LH, Atkins JN, Seay TE, Fehrenbacher L, Goldberg RM, O'Reilly S, Chu L, Azar CA, Lopa S, Wolmark N. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011 Jan 1;29(1):11-6. [https://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]
+mFOLFOX6: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-##'''Update:''' Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Lopa SH, Wolmark N. Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J Clin Oncol. 2013 Jan 20;31(3):359-64. [https://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]
-#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]
-#'''IDEA:''' Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018 Mar 29;378(13):1177-1188. [https://www.nejm.org/doi/full/10.1056/NEJMoa1713709 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29590544 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. 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://academic.oup.com/annonc/article/30/8/1304/5522015 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31228203 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://ascopubs.org/doi/full/10.1200/JCO.2017.76.0355 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29620995 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]
-==mFOLFOX6 (L-Leucovorin) {{#subobject:32d6c5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
 ===Example orders===
 *[[Example orders for mFOLFOX 6 in colon cancer]]
+<div class="toccolours" style="background-color:#eeeeee">
-===Variant #1, 3 months {{#subobject:205ad6|Variant=1}}===
+===Regimen variant #1, 3 months, 200 mg/m<sup>2</sup> L-LCV {{#subobject:38ig9a|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#Comparative_efficacy|Comparative 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-de-esc)
+|2012-08-01 to 2014-06-30
-|mFOLFOX6 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#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[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)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
-*[[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'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with L-folinic acid'''
 '''14-day cycle for 6 cycles'''
+</div></div><br>
-===Variant #2, 6 months {{#subobject:372bh7|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Regimen variant #2, 6 months, 200 mg/m<sup>2</sup> L-LCV {{#subobject:38guh7|Variant=1}}===
-! style="width: 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#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext Iveson et al. 2018 (SCOT)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743062/ Yoshino et al. 2019 (ACHIEVE)]
-| style="background-color:#1a9851" |Phase III (C)
+|2012-08-01 to 2014-06-30
-|mFOLFOX6 x 3 mo
+| style="background-color:#1a9851" |Phase 3 (C)
+|1a. [[#CapeOx|CapeOx]] x 3 mo<br>1b. [[#mFOLFOX6|mFOLFOX6]] x 3 mo
 | style="background-color:#eeee01" |Seems to have non-inferior DFS
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-*[[Surgery#Colorectal_cancer_surgery|Surgery]], within 10 weeks
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Levoleucovorin (Fusilev)]] 175 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
+*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with folinic acid'''
 '''14-day cycle for 12 cycles'''
+</div></div>
 ===References===
+#'''ACHIEVE:''' Yoshino T, Yamanaka T, Oki E, Kotaka M, Manaka D, Eto T, Hasegawa J, Takagane A, Nakamura M, Kato T, Munemoto Y, Takeuchi S, Bando H, Taniguchi H, Gamoh M, Shiozawa M, Mizushima T, Saji S, Maehara Y, Ohtsu A, Mori M. Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer: The ACHIEVE Phase 3 Randomized Clinical Trial. JAMA Oncol. 2019 Nov 1;5(11):1574-1581. Erratum in: JAMA Oncol. 2019 Nov 1;5(11):1643. Epub 2019 Sep 12. Erratum in: JAMA Oncol. 2019 Dec 19. [https://doi.org/10.1001/jamaoncol.2019.2572 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743062/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31513248/ PubMed] UMIN000008543
-#'''SCOT:''' Iveson TJ, Kerr RS, Saunders MP, Cassidy J, Hollander NH, Tabernero J, Haydon A, Glimelius B, Harkin A, Allan K, McQueen J, Scudder C, Boyd KA, Briggs A, Waterston A, Medley L, Wilson C, Ellis R, Essapen S, Dhadda AS, Harrison M, Falk S, Raouf S, Rees C, Olesen RK, Propper D, Bridgewater J, Azzabi A, Farrugia D, Webb A, Cunningham D, Hickish T, Weaver A, Gollins S, Wasan HS, Paul J. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2018 Apr;19(4):562-578. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30093-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29611518 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]
+==FULV {{#subobject:a93a|Regimen=1}}==
-==Observation==
+FULV: 5-'''<u>FU</u>''' & '''<u>L</u>'''euco'''<u>V</u>'''orin
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<br>LV5FU2: '''<u>L</u>'''euco'''<u>V</u>'''orin & '''<u>5-FU</u>''' for '''<u>2</u>''' days
+===Example orders===
+*[[Example orders for 5-FU & low-dose Leucovorin (Mayo Clinic regimen - LDLV) in colon cancer]]
+*[[Example orders for 5-FU & high-dose Leucovorin (Roswell Park regimen - HDLV) in colon cancer]]
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 500/200, 6 out of 8 weeks {{#subobject:2c3f1b|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|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/PMC3038965/ Papadimitriou et al. 2011]
-|}
+|1999-2004
-===Regimen, stage II disease===
+| style="background-color:#1a9851" |Phase 3 (C)
-{| class="wikitable" style="width: 100%; text-align:center;"
+|[[#IFL_999|IFL]]
-! style="width: 25%" |Study
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/10.1200/jco.1995.13.12.2936 Moertel et al. 1995 (INT-0035)]
-| style="background-color:#1a9851" |Phase III (C)
-|5-FU & Levamisole
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02214-5/fulltext Gray et al. 2000 (QUASAR)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|[https://www.karger.com/Article/Abstract/84595 Hartung et al. 2005]
-| style="background-color:#1a9851" |Phase III (C)
-|[[Colon_cancer_-_historical#Edrecolomab_monotherapy|Edrecolomab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360441/ Schippinger et al. 2007]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://link.springer.com/article/10.1007%2Fs00384-008-0543-8 Laffer et al. 2008 (SAKK 40/87)]
-| style="background-color:#1a9851" |Phase III (C)
-|1. Portal venous 5-FU & Mitomycin<br> 2. 5-FU & Mitomycin
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157980/ Niedzwiecki et al. 2011 (CALGB 9581)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[Colon_cancer_-_historical#Edrecolomab_monotherapy|Edrecolomab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-''No systemic treatment after surgery for stage II colon cancer.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
-===Regimen, stage III disease===
+<div class="toccolours" style="background-color:#b3e2cd">
-{| class="wikitable" style="width: 100%; text-align:center;"
+====Chemotherapy====
-! style="width: 25%" |Study
+*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
-! style="width: 25%" |Comparator
+'''8-week cycle for 4 cycles'''
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 500/500, 6 out of 8 weeks {{#subobject:489be0|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM198403223101201 Lessner et al. 1984]
+|[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"
-|1. 5-FU & Semustine<br> 2. 5-FU, Semustine, BCG<br> 3. BCG
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-258-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://academic.oup.com/jnci/article-abstract/80/1/30/886027 Wolmark et al. 1988 (NSABP C-01)]
+|} -->
-| style="background-color:#1a9851" |Phase III (C)
+|1987-1989
-|1. [[Colon_cancer_-_historical#MOF|MOF]]<br> 2. BCG
+| style="background-color:#1a9851" |Phase 3 (E-de-esc)
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)
+|[[Colon_cancer_-_historical#MOF|MOF]]
+| style="background-color:#1a9850" |Superior OS
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1988.6.6.947 Panettiere et al. 1988 (SWOG S7510)]
+| rowspan="2" |[https://doi.org/10.1200/JCO.1999.17.11.3553 Wolmark et al. 1999 (NSABP C-04)]
-| style="background-color:#1a9851" |Phase III (C)
+|rowspan=2|1989-07 to 1990-12
-|1. 5-FU & Semustine<br> 2. 5-FU, Semustine, BCG
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
-| style="background-color:#ffffbf" |Did not meet primary endpoint
+|1. [[Colon_cancer_-_historical#Fluorouracil_.26_Levamisole|5-FU & Levamisole]]
+| style="background-color:#d9ef8b" |Might have superior OS (co-primary endpoint)
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1990.8.9.1466 Wolmark et al. 1990 (NSABP C-02)]
+|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
-|Portal venous chemotherapy
-| style="background-color:#fee08b" |Might have inferior OS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PII0140-6736(92)91708-G/fulltext Fielding et al. 1992 (AXIS-CRC)]
+| rowspan="3" |[https://doi.org/10.1200/jco.2004.00.5686 Haller et al. 2005 (Intergroup 0089)]
-| style="background-color:#1a9851" |Phase III (C)
+|rowspan=3|1988-1992
-|Portal venous chemotherapy
+| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-esc)
+|1. [[#FULV|FULV]]; low-dose
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(94)92398-1/fulltext Riethmüller et al. 1994]
+|2. [[Colon_cancer_-_historical#FULV_.26_Levamisole|FULV & Levamisole]]; LDLV
-| style="background-color:#1a9851" |Phase III (C)
-|[[Colon_cancer_-_historical#Edrecolomab_monotherapy|Edrecolomab]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673695903402/fulltext Laffer et al. 1995 (SAKK 40/81)]
-| style="background-color:#1a9851" |Phase III (C)
-|Portal venous chemotherapy
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673695906967/fulltext Marsoni et al. 1995 (IMPACT<sub>CRC</sub>)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]
-| 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" |Did not meet primary endpoint of OS
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1421018/ Vaillant et al. 2000]
+|3. [[Colon_cancer_-_historical#Fluorouracil_.26_Levamisole|5-FU & Levamisole]]
-| style="background-color:#1a9851" |Phase III (C)
-|IP 5-FU
-| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS60/OS60
-|-
-|[https://link.springer.com/article/10.1007%2Fs00384-008-0543-8 Laffer et al. 2008 (SAKK 40/87)]
-| style="background-color:#1a9851" |Phase III (C)
-|1. Portal venous 5-FU & Mitomycin<br> 2. 5-FU & Mitomycin
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010179/ Hasegawa et al. 2016]
+|[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
-|[[#Tegafur.2C_Uracil.2C_Folinic_acid|Tegafur, Uracil, Leucovorin]]
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#d73027" |Inferior RFS
+|[[#Tegafur.2C_Uracil.2C_Folinic_acid|Tegafur, Uracil, Folinic acid]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of DFS/OS
 |-
-|}
+|[https://doi.org/10.1200/JCO.2007.11.2144 Saltz et al. 2007 (CALGB 89803)]
-''No systemic treatment after surgery. The AXIS trial is named "AXIS-CRC" here so as not to confuse it with the AXIS trial in renal cell carcinoma. IMPACT should not be confused with the studies of the same name in breast cancer and prostate cancer. Reported efficacy for NSABP C-01 is based on the 2004 update.''
+|1999-2001
-====Preceding treatment====
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#IFL_999|IFL]]
-*[[Surgery#Colorectal_cancer_surgery|Surgery]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of DFS/OS
-===References===
-#Lessner HE, Mayer RJ, Ellenberg SS, Holyoke ED; Gastrointestinal Tumor Study Group. Adjuvant therapy of colon cancer--results of a prospectively randomized trial. N Engl J Med. 1984 Mar 22;310(12):737-43. [https://www.nejm.org/doi/full/10.1056/NEJM198403223101201 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6366550 PubMed]
-#'''NSABP C-01:''' Wolmark N, Fisher B, Rockette H, Redmond C, Wickerham DL, Fisher ER, Jones J, Glass A, Lerner H, Lawrence W, Prager D, Wexler M, Evans J, Cruz A, Dimitrov N, Jochimsen P; Other NSABP Investigators. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst. 1988 Mar 2;80(1):30-6. [https://academic.oup.com/jnci/article-abstract/80/1/30/886027 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3276901 PubMed]
-##'''Update:''' Smith RE, Colangelo L, Wieand HS, Begovic M, Wolmark N. Randomized trial of adjuvant therapy in colon carcinoma: 10-year results of NSABP protocol C-01. J Natl Cancer Inst. 2004 Aug 4;96(15):1128-32. [https://academic.oup.com/jnci/article/96/15/1128/2520926 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15292384 PubMed]
-##'''Pooled update:''' Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. [https://link.springer.com/article/10.1245%2Fs10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20082144 PubMed]
-#'''SWOG S7510:''' Panettiere FJ, Goodman PJ, Costanzi JJ, Cruz AB Jr, Vaitkevicius VK, McCracken JD, Brownlee RW, Laufman L, Stephens RL, Bonnet J, Bottomley R, Rivkin S, Fletcher W, Oishi N, Chen TT. Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study. J Clin Oncol. 1988 Jun;6(6):947-54. [https://ascopubs.org/doi/abs/10.1200/JCO.1988.6.6.947 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3286830 PubMed]
-#Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, Veeder MH, Mailliard JA. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990 Feb 8;322(6):352-8. [https://www.nejm.org/doi/full/10.1056/NEJM199002083220602 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2300087 PubMed]
-##'''Update:''' Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Tangen CM, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, Veeder MH, Mailliard JA. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med. 1995 Mar 1;122(5):321-6. [http://annals.org/aim/article-abstract/708455/fluorouracil-plus-levamisole-effective-adjuvant-therapy-after-resection-stage-iii link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7847642 PubMed]
-#'''NSABP C-02:''' Wolmark N, Rockette H, Wickerham DL, Fisher B, Redmond C, Fisher ER, Potvin M, Davies RJ, Jones J, Robidoux A, Wexler M, Gordon P, Cruz AB, Horsley S, Nims TA, Thirlwell M, Phillips WA, Prager D, Stern HS, Lerner HJ, Frazier TG. Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: preliminary results of National Surgical Adjuvant Breast and Bowel Project protocol C-02. J Clin Oncol. 1990 Sep;8(9):1466-75. [https://ascopubs.org/doi/abs/10.1200/JCO.1990.8.9.1466 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2202789 PubMed]
-##'''Pooled update:''' Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. [https://link.springer.com/article/10.1245%2Fs10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20082144 PubMed]
-#'''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]
-#'''SAKK 40/81:''' Laffer U, Metzger U, Aeberhard P, Maibach R, Castiglione M, Goldhirsch A; Swiss Group for Clinical Cancer Research (SAKK). Long-term results of single course of adjuvant intraportal chemotherapy for colorectal cancer. Lancet. 1995 Feb 11;345(8946):349-53. [https://www.thelancet.com/journals/lancet/article/PIIS0140673695903402/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7845115 PubMed]
-#'''IMPACT:''' Marsoni S, Labianca R, Pancera G, Torri V, Zaniboni A, Erlichman C, Pater J, Shepherd L, Zee B, Seitz JF, Milan C, Pignon JP; International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet. 1995 Apr 15;345(8955):939-44. [https://www.thelancet.com/journals/lancet/article/PIIS0140673695906967/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7715291 PubMed]
-#'''INT-0035:''' Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Tangen CM, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, Veeder MH, Mailliard JA; North Central Cancer Treatment Group; Southwest Oncology Group; Eastern Cooperative Oncology Group. Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes' B2 colon cancer. J Clin Oncol. 1995 Dec;13(12):2936-43. [https://ascopubs.org/doi/10.1200/jco.1995.13.12.2936 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8523058 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]
-##'''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://ascopubs.org/doi/full/10.1200/JCO.1999.17.5.1356 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10334519 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]
-#Vaillant JC, Nordlinger B, Deuffic S, Arnaud JP, Pelissier E, Favre JP, Jaeck D, Fourtanier G, Grandjean JP, Marre P, Letoublon C. Adjuvant intraperitoneal 5-fluorouracil in high-risk colon cancer: a multicenter phase III trial. Ann Surg. 2000 Apr;231(4):449-56. [https://insights.ovid.com/pubmed?pmid=10749603 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1421018/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/10749603 PubMed]
-#'''QUASAR:''' Gray RG, Kerr DJ, McConkey CC, Williams NS, Hills RK; QUASAR Collaborative Group. Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. Lancet. 2000 May 6;355(9215):1588-96. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02214-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10821362 PubMed]
-##'''Update:''' Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ; Quasar Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007 Dec 15;370(9604):2020-9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61866-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18083404 PubMed]
-#Hartung G, Hofheinz RD, Dencausse Y, Sturm J, Kopp-Schneider A, Dietrich G, Fackler-Schwalbe I, Bornbusch D, Gonnermann M, Wojatschek C, Lindemann W, Eschenburg H, Jost K, Edler L, Hochhaus A, Queisser W. Adjuvant therapy with edrecolomab versus observation in stage II colon cancer: a multicenter randomized phase III study. Onkologie. 2005 Jun;28(6-7):347-50. Epub 2005 Jun 2. [https://www.karger.com/Article/Abstract/84595 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15933423 PubMed]
-#Schippinger W, Samonigg H, Schaberl-Moser R, Greil R, Thödtmann R, Tschmelitsch J, Jagoditsch M, Steger GG, Jakesz R, Herbst F, Hofbauer F, Rabl H, Wohlmuth P, Gnant M, Thaler J; Austrian Breast and Colorectal Cancer Study Group. A prospective randomised phase III trial of adjuvant chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer. Br J Cancer. 2007 Oct 22;97(8):1021-7. Epub 2007 Sep 25. [https://www.nature.com/articles/6604011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360441/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/17895886 PubMed]
-#'''SAKK 40/87:''' Laffer U, Metzger U, Aeberhard P, Lorenz M, Harder F, Maibach R, Zuber M, Herrmann R. Adjuvant perioperative portal vein or peripheral intravenous chemotherapy for potentially curative colorectal cancer: long-term results of a randomized controlled trial. Int J Colorectal Dis. 2008 Dec;23(12):1233-41. Epub 2008 Aug 8. [https://link.springer.com/article/10.1007%2Fs00384-008-0543-8 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18688620 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. [https://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]
-==Placebo==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1200/jco.2006.08.2974 Kuebler et al. 2007 (NSABP C-07)]
-|}
+|2000-2002
+| style="background-color:#1a9851" |Phase 3 (C)
-===Regimen===
+|[[#FLOX|FLOX]]
-{| class="wikitable" style="width: 100%; text-align:center;"
+| style="background-color:#d73027" |Inferior DFS
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2010.29.6244 Midgley et al. 2010 (VICTOR)]
+|[https://doi.org/10.1200/jco.2006.08.1075 Schmoll et al. 2007 (XELOXA)]
-| style="background-color:#1a9851" |Phase III (C)
+|2003-04 to 2004-10
-|Rofecoxib
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|[[#CapeOx|CapeOx]]
+| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
 |-
 |}
-''No active antineoplastic treatment.''
+''<sup>1</sup>Reported efficacy for XELOXA is based on the 2015 update.''<br>
+''Note: this is often called the "Roswell Park regimen" but the original regimen described by Petrelli et al. 1987 & 1989 used a 5-FU dose of 600 mg/m<sup>2</sup>.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, 29, 36, '''given second, 1 hour after start of leucovorin'''
+*[[Leucovorin (Folinic acid)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, '''given first'''
+'''8-week cycle for 3 to 6 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-===References===
+===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;"
-#'''VICTOR:''' Midgley RS, McConkey CC, Johnstone EC, Dunn JA, Smith JL, Grumett SA, Julier P, Iveson C, Yanagisawa Y, Warren B, Langman MJ, Kerr DJ. Phase III randomized trial assessing rofecoxib in the adjuvant setting of colorectal cancer: final results of the VICTOR trial. J Clin Oncol. 2010 Oct 20;28(30):4575-80. Epub 2010 Sep 13. [https://ascopubs.org/doi/full/10.1200/JCO.2010.29.6244 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20837956 PubMed]
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
-==SOX {{#subobject:617cc1|Regimen=1}}==
+!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]]
+|[https://www.karger.com/Article/Abstract/12105 Fountzilas et al. 2000]
-|}
+|1989-1997
-SOX: '''<u>S</u>'''-1, '''<u>OX</u>'''aliplatin
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#FULV_.26_Interferon_alfa-2a_999|FULV & IFN alfa-2a]]
-===Regimen {{#subobject:c80e20|Variant=1}}===
+| style="background-color:#ffffbf" |Did not meet primary endpoint of 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.clinical-colorectal-cancer.com/article/S1533-0028(19)30449-9/abstract Sunami et al. 2019 (ACTS-CC 02)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Colon_cancer#Tegafur.2C_Uracil.2C_Folinic_acid|Tegafur, Uracil, Folinic Acid]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[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'''
-*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+*[[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)]] 100 mg/m<sup>2</sup> IV once on day 1
+'''8-week cycle for 4 cycles'''
+</div></div><br>
-'''21-day cycle for 8 cycles'''
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, 1850/100 ("Mayo Clinic regimen") {{#subobject:4bnc36|Variant=1}}===
-===References===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
-#'''ACTS-CC 02:''' Sunami E, Kusumoto T, Ota M, SakamotoY, Yoshida K, Tomita N, Maeda A, Teshima J, Okabe M, Tanaka C, Yamauchi J, Itabashi M, Kotake K, Takahashi K, Baba H, Boku N, Aiba K, Ishiguro M, Morita S, Takenaka N, Okude R, Sugihara K. S-1 and oxaliplatin versus tegafur-uracil and leucovorin as postoperative adjuvant chemotherapy in patients with high-risk stage III colon cancer (ACTS-CC 02): a randomized, open-label, multicenter, phase 3, superiority trial. Clinical Colorectal Cancer (2019). Epub Oct 2019. [https://www.clinical-colorectal-cancer.com/article/S1533-0028(19)30449-9/fulltext link to original article]
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-==Tegafur, Uracil, Folinic acid {{#subobject:5ed2aa|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]]
+|[https://doi.org/10.1016/j.ejca.2008.07.002 Popov et al. 2008 (PETACC-1)]
-|}
+|NR-1999
-UFT + LV: '''<u>UFT</u>''' (Tegafur and uracil) & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid)
+| style="background-color:#1a9851" |Phase 3 (C)
-===Variant #1, 300/75 {{#subobject:8cc7d8|Variant=1}}===
+|[[#Raltitrexed_monotherapy_999|Raltitrexed]]
-{| class="wikitable" style="width: 100%; text-align:center;"
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior RFS/OS
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143094/ Yoshida et al. 2014 (ACTS-CC)]
-| style="background-color:#1a9851" |Phase III (C)
-|S-1
-| style="background-color:#eeee01" |Non-inferior DFS
-|-
-|[https://www.ejcancer.com/article/S0959-8049(14)00724-2/fulltext Shimada et al. 2014 (JCOG0205)]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]
-| style="background-color:#eeee01" |Non-inferior DFS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621030/ Sadahiro et al. 2015 (JFMC33-0502)]
-| style="background-color:#1a9851" |Phase III (C)
-|UFT + LV weekly x 18 mo
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010179/ Hasegawa et al. 2016]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Observation|Observation]]
-| style="background-color:#1a9850" |Superior RFS
-|-
-|[https://link.springer.com/article/10.1007%2Fs00595-017-1555-1 Miyake et al. 2018]
-| style="background-color:#1a9851" |Phase III (C)
-|UFT/PSK
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior DFS36
 |-
 |}
-''Note: Miyake et al. 2018 does not contain treatment details in the abstract.''
+''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]]
-*JCOG0205: [[Surgery#Colorectal_cancer_surgery|Surgery]] with D2/D3 lymph node dissection
+</div>
-*Hasegawa et al. 2016: [[Surgery#Metastasectomy|Surgical resection of colorectal cancer liver metastases]], within 8 weeks
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''
-*[[Tegafur and uracil (UFT)]] 100 mg/m<sup>2</sup> PO every 8 hours on days 1 to 28
+*[[Leucovorin (Folinic acid)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''
-*[[Folinic acid (Leucovorin)]] 25 mg PO every 8 hours on days 1 to 28
+'''28-day cycle for 6 cycles'''
+</div></div><br>
-'''35-day cycle for 5 cycles'''
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #5, 1850/2500 ("NCI schedule") {{#subobject:7cc2b9|Variant=1}}===
-===Variant #2, 300/90 {{#subobject:643dbb|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#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/24/13/2059.long Lembersky et al. 2006 (NSABP C-06)]
+|[https://academic.oup.com/jnci/article/90/23/1810/2520545 Wolmark et al. 1998 (NSABP C-05)]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+|1991-1994
-|[[#Fluorouracil_.26_Folinic_acid|5-FU & Leucovorin]]
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS/OS
+|[[#FULV_.26_Interferon_alfa_999|FULV & Interferon alfa]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of DFS/OS
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-*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)]] 370 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, '''given second'''
-*[[Tegafur and uracil (UFT)]] 100 mg/m<sup>2</sup> PO every 8 hours on days 1 to 28
+*[[Leucovorin (Folinic acid)]] 500 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first'''
-*[[Folinic acid (Leucovorin)]] 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===
-<!-- 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]
-#'''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://academic.oup.com/annonc/article/25/9/1743/2801231 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143094/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24942277 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.ejcancer.com/article/S0959-8049(14)00724-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24958736 PubMed]
-#'''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://academic.oup.com/annonc/article/26/11/2274/263547 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621030/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26347106 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]
-#Miyake Y, Nishimura J, Kato T, Ikeda M, Tsujie M, Hata T, Takemasa I, Mizushima T, Yamamoto H, Sekimoto M, Nezu R, Doki Y, Mori M; Multi-center Clinical Study Group of Osaka, Colorectal Cancer Treatment Group (MCSGO). Phase III trial comparing UFT + PSK to UFT + LV in stage IIB, III colorectal cancer (MCSGO-CCTG). Surg Today. 2018 Jan;48(1):66-72. Epub 2017 Jun 20. [https://link.springer.com/article/10.1007%2Fs00595-017-1555-1 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28634730 PubMed]
-=Therapy for oligometastatic disease, including perioperative therapy and hyperthermic intra-peritoneal chemotherapy=
-==Fluorouracil & Folinic acid {{#subobject:e9bcc2|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:12cfb6|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2006.06.8353 Portier et al. 2006 (FFCD 9002)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Observation_2|Observation]]
-| style="background-color:#d9ef8b" |Might have superior PFS (*)
-|-
-|}
-''Reported efficacy is based on the 2008 pooled update.''
-====Preceding treatment====
-*[[Surgery#Surgical_resection|Surgical resection of oligometastatic disease]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second'''
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given first'''
 '''28-day cycle for 6 cycles'''
+</div></div><br>
-===References===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #6, 2000/400 ("de Gramont regimen"/LV5FU2) {{#subobject:685f89|Variant=1}}===
-#'''FFCD 9002:''' Portier G, Elias D, Bouche O, Rougier P, Bosset JF, Saric J, Belghiti J, Piedbois P, Guimbaud R, Nordlinger B, Bugat R, Lazorthes F, Bedenne L. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol. 2006 Nov 1;24(31):4976-82. [https://ascopubs.org/doi/full/10.1200/JCO.2006.06.8353 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17075115 PubMed]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-##'''Pooled update:''' Mitry E, Fields AL, Bleiberg H, Labianca R, Portier G, Tu D, Nitti D, Torri V, Elias D, O'Callaghan C, Langer B, Martignoni G, Bouché O, Lazorthes F, Van Cutsem E, Bedenne L, Moore MJ, Rougier P. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol. 2008 Oct 20;26(30):4906-11. Epub 2008 Sep 15. [https://ascopubs.org/doi/full/10.1200/JCO.2008.17.3781 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18794541 PubMed]
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
-==FOLFIRI {{#subobject:a051ec|Regimen=1}}==
+!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]]
+|[https://doi.org/10.1200/JCO.2003.10.065 André et al. 2003 (GERCOR C96.1)]
-|}
+|1996-1999
-FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
+| style="background-color:#1a9851" |Phase 3 (C)
-===Regimen {{#subobject:0e95b6|Variant=1}}===
+|[[#FULV|FULV]]; monthly
-{| class="wikitable" style="width: 100%; text-align:center;"
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://ar.iiarjournals.org/content/32/4/1387.long Fiorentini et al. 2012]
+|[https://doi.org/10.1056/NEJMoa032709 André et al. 2004 (MOSAIC)]
-| style="background-color:#1a9851" |Phase III (C)
+|1998-2001
-|DEBIRI
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#fc8d59" |Seems to have inferior OS
+|[[#FOLFOX4|FOLFOX4]]
+| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
 |-
-|}
+|[https://doi.org/10.1093/annonc/mdn680 Ychou et al. 2009 (FFCD 9802)]
-====Chemotherapy====
+|1998-2002
+| style="background-color:#1a9851" |Phase 3 (C)
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second on day 1''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
+|[[#IFL_999|IFL]]
-*[[Folinic acid (Leucovorin)]] 100 mg/m<sup>2</sup> IV over 120 minutes once on day 1, '''given first, with irinotecan'''
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 120 minutes once on day 1, '''given first, with leucovorin'''
-'''14-day cycle for 8 cycles'''
-===References===
-#Fiorentini G, Aliberti C, Tilli M, Mulazzani L, Graziano F, Giordani P, Mambrini A, Montagnani F, Alessandroni P, Catalano V, Coschiera P. Intra-arterial infusion of irinotecan-loaded drug-eluting beads (DEBIRI) versus intravenous therapy (FOLFIRI) for hepatic metastases from colorectal cancer: final results of a phase III study. Anticancer Res. 2012 Apr;32(4):1387-95. Erratum in: Anticancer Res. 2013 Nov;33(11):5211. [http://ar.iiarjournals.org/content/32/4/1387.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22493375 PubMed]
-==FOLFOX4 {{#subobject:58d3ec|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1200/JCO.2008.21.6663 Van Cutsem et al. 2009 (PETACC-3)]
-|}
+|2000-2002
-FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
+| style="background-color:#1a9851" |Phase 3 (C)
-===Regimen {{#subobject:dfc57d|Variant=1}}===
+|[[#IFL_999|IFL]]
-{| class="wikitable" style="width: 100%; text-align:center;"
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277487/ Nordlinger et al. 2008 (EORTC 40983)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Observation_2|Observation]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|[https://academic.oup.com/annonc/article/26/2/340/2800608 Hebbar et al. 2014 (MIROX)]
-| style="background-color:#1a9851" |Phase III (C)
-|FOLFOX7-FOLFIRI
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS24
 |-
 |}
-''Note: this is the regimen as described by de Gramont et al. 2000; EORTC 40983 refers to this protocol. In MIROX, the treatment could be given perioperatively or postoperatively.''
+''<sup>1</sup>Reported efficacy for MOSAIC is based on the 2015 update.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-*[[Surgery#Surgical_resection|Surgical resection of oligometastatic disease]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with leucovorin'''
-'''14-day cycle for 6 cycles before surgery, and 6 cycles after surgery (12 cycles total)'''
-===References===
-#'''EORTC 40983:''' Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T; 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]
-#'''MIROX:''' Hebbar M, Chibaudel B, André T, Mineur L, Smith D, Louvet C, Dutel JL, Ychou M, Legoux JL, Mabro M, Faroux R, Auby D, Brusquant D, Khalil A, Truant S, Hadengue A, Dalban C, Gayet B, Paye F, Pruvot FR, Bonnetain F, Landi B, Flesch M, Carola E, Martin P, Vaillant E, de Gramont A; Group Coopérateur Multidisciplinaire en Oncologie (GERCOR) Group. FOLFOX4 versus sequential dose-dense FOLFOX7 followed by FOLFIRI in patients with resectable metastatic colorectal cancer (MIROX): a pragmatic approach to chemotherapy timing with perioperative or postoperative chemotherapy from an open-label, randomized phase III trial. Ann Oncol. 2015 Feb;26(2):340-7. Epub 2014 Nov 17. Erratum in: Ann Oncol. 2015 May;26(5):1040. Taieb, J [removed]; Brucker, P [removed]. [https://academic.oup.com/annonc/article/26/2/340/2800608 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25403578 PubMed]
-==mFOLFOX6 (L-Leucovorin) {{#subobject:8fig59|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:e300fa|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.sciencedirect.com/science/article/pii/S0959804915008631 Cashin et al. 2016 (SPS-1)]
-| style="background-color:#1a9851" |Randomized (C)
-|[[#Intraperitoneal_5-FU|IP 5-FU & LV]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV once on day 1
 '''14-day cycle for 12 cycles'''
+</div></div><br>
-===References===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #7, 2000/1000 {{#subobject:6igjc9|Variant=1}}===
-#'''SPS-1:''' Cashin PH, Mahteme H, Spång N, Syk I, Frödin JE, Torkzad M, Glimelius B, Graf W. Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial. Eur J Cancer. 2016 Jan;53:155-62. Epub 2016 Jan 2. [https://www.sciencedirect.com/science/article/pii/S0959804915008631 link to SD article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26751236 PubMed]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
-==Hepatic arterial chemotherapy==
+!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"
-===Regimen===
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-259-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
-{| 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#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673694907501/fulltext Allen-Mersh et al. 1994]
+|} -->
-| style="background-color:#1a9851" |Phase III (E-esc)
+|1985-1990
-|Best supportive care
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-| style="background-color:#91cf60" |Seems to have superior OS
+|[[Colon_cancer_-_null_regimens#Observation_2|Observation]]
-|-
+| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>OS60: 79% vs 65%
-|[https://www.nejm.org/doi/full/10.1056/NEJM199912303412702 Kemeny et al. 1999]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Observation_2|Observation]]
-| style="background-color:#91cf60" |Seems to have superior OS
 |-
 |}
-''Of historic interest; unlikely to be completed.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*[[Surgery#Colorectal_cancer_surgery|Surgery]], within 3 weeks
-*[[Surgery#Surgical_resection|Surgical resection of oligometastatic disease]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 5
-*[[Floxuridine (FUDR)]]
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5
+'''28-day cycle for 12 cycles'''
-====Supportive medications====
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Dexamethasone (Decadron)]]
+===Regimen variant #8, 2125/100 ("Mayo Clinic regimen") {{#subobject:4bd336|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-===References===
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
-#Allen-Mersh TG, Earlam S, Fordy C, Abrams K, Houghton J. Quality of life and survival with continuous hepatic-artery floxuridine infusion for colorectal liver metastases. Lancet. 1994 Nov 5;344(8932):1255-60. [https://www.thelancet.com/journals/lancet/article/PIIS0140673694907501/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7526096 PubMed]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-#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]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-==Intraperitoneal 5-FU {{#subobject:581aec|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+||[https://doi.org/10.1056/NEJMoa043116 Twelves et al. 2005 (X-ACT)]
-|}
+|1998-2001
-===Regimen {{#subobject:1ac57d|Variant=1}}===
+| style="background-color:#1a9851" |Phase 3 (C)
-{| class="wikitable" style="width: 100%; text-align:center;"
+|[[#Capecitabine_monotherapy|Capecitabine]]
-! style="width: 25%" |Study
+| style="background-color:#fee08b" |Might have inferior OS<sup>1</sup>
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.sciencedirect.com/science/article/pii/S0959804915008631 Cashin et al. 2016 (SPS-1)]
+|[https://doi.org/10.1016/j.ejca.2008.07.002 Popov et al. 2008 (PETACC-1)]
-| style="background-color:#1a9851" |Randomized (E-switch-ooc)
+|NR-1999
-|[[#mFOLFOX6_2|mFOLFOX6]]
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#91cf60" |Seems to have superior OS
+|[[#Raltitrexed_monotherapy_999|Raltitrexed]]
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior RFS/OS
 |-
-|}
+|[https://doi.org/10.1016/j.ejca.2013.01.030 Köhne et al. 2013 (PETACC-2)]
-====Preceding treatment====
+|1999-2004
+| style="background-color:#1a9851" |Phase 3 (C)
-*Cytoreductive surgery
+|1. [[#FULV|FULV]]; LV5FU2<br>2. [[#FULV|FULV]]; AIO regimen<br> 3. [[#FULV|FULV]]; TTD regimen
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS60
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 550 mg/m<sup>2</sup>/day IP continuous infusion over 6 days, started on day 1 (total dose per cycle: 3300 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 30 mg/m<sup>2</sup>/day IV once on day 1, '''given 60 minutes after start of 5-FU IP infusion'''
-'''1-month cycle for 6 cycles'''
-===References===
-#'''SPS-1:''' Cashin PH, Mahteme H, Spång N, Syk I, Frödin JE, Torkzad M, Glimelius B, Graf W. Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial. Eur J Cancer. 2016 Jan;53:155-62. Epub 2016 Jan 2. [https://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]]
+|[https://doi.org/10.1200/jco.2006.08.1075 Schmoll et al. 2007 (XELOXA)]
-|}
+|2003-04 to 2004-10
-===Regimen {{#subobject:f86ab6|Variant=1}}===
+| style="background-color:#1a9851" |Phase 3 (C)
-{| class="wikitable" style="width: 100%; text-align:center;"
+|[[#CapeOx|XELOX]]
-! style="width: 25%" |Study
+| style="background-color:#fc8d59" |Seems to have inferior OS<sup>2</sup>
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2003.04.187 Verwaal et al. 2003]
-| style="background-color:#1a9851" |Phase III (E-switch-ooc)
-|[[#Fluorouracil_.26_Folinic_acid_3|5-FU & LV (modified Laufman regimen)]]
-| style="background-color:#91cf60" |Seems to have superior OS
 |-
 |}
+''<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====
+*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-*Cytoreductive surgery
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''
+*[[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">
-*Hyperthermic [[Mitomycin (Mutamycin)]] 17.5 mg/m<sup>2</sup> IP once, then 8.8 mg/m<sup>2</sup> every 30 minutes (maximum dose of 70 mg)
+===Regimen variant #9, 2125/100, with cycle elongation ("Mayo Clinic regimen") {{#subobject:e24014|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-'''One treatment'''
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
-===References===
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
-#Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003 Oct 15;21(20):3737-43. [https://ascopubs.org/doi/full/10.1200/JCO.2003.04.187 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14551293 PubMed]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-==Observation==
-{| 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#Comparative_efficacy|Comparative 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://ascopubs.org/doi/full/10.1200/JCO.2006.06.8353 Portier et al. 2006 (FFCD 9002)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Fluorouracil_.26_Folinic_acid_2|5-FU & LV]]
-| style="background-color:#fee08b" |Might have inferior PFS (*)
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277487/ Nordlinger et al. 2008 (EORTC 40983)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFOX4_2|FOLFOX4]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|}
-''No treatment other than surgical resection of oligometastatic disease. Reported efficacy for FFCD 9002 is based on the 2008 pooled update.''
-===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]
-#'''FFCD 9002:''' Portier G, Elias D, Bouche O, Rougier P, Bosset JF, Saric J, Belghiti J, Piedbois P, Guimbaud R, Nordlinger B, Bugat R, Lazorthes F, Bedenne L. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol. 2006 Nov 1;24(31):4976-82. [https://ascopubs.org/doi/full/10.1200/JCO.2006.06.8353 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17075115 PubMed]
-##'''Pooled update:''' Mitry E, Fields AL, Bleiberg H, Labianca R, Portier G, Tu D, Nitti D, Torri V, Elias D, O'Callaghan C, Langer B, Martignoni G, Bouché O, Lazorthes F, Van Cutsem E, Bedenne L, Moore MJ, Rougier P. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol. 2008 Oct 20;26(30):4906-11. Epub 2008 Sep 15. [https://ascopubs.org/doi/full/10.1200/JCO.2008.17.3781 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18794541 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%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-|[https://academic.oup.com/annonc/article-abstract/28/6/1288/3102942 Kwakman et al. 2017 (SALTO)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#S-1_monotherapy|S-1]]
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints (*)
-| style="background-color:#d73027" |Higher incidence of hand-foot syndrome
-|-
-|}
-''Note: this trial had a primary toxicity endpoint; this dose was intended for patients at least 70 years old; reported efficacy is based on the 2019 update.''
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-'''21-day cycles'''
-===Variant #2, 2500 mg/m<sup>2</sup>/day {{#subobject:303fab|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-|[http://jco.ascopubs.org/content/19/8/2282.long Hoff et al. 2001]
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
-|[[#Fluorouracil_.26_Folinic_acid_3|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-RT-switch-ic)
-|[[#Fluorouracil_.26_Folinic_acid_3|5-FU + Folinic acid]]
-| style="background-color:#eeee01" |Equivalent ORR
-|
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext Koopman et al. 2007 (CAIRO)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[Complex_multipart_regimens#CAIRO|See link]]
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#CAIRO|See link]]
-|
-|-
-| rowspan="2" |[https://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)
-|1. [[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]
-| style="background-color:#d73027" |Inferior PFS
-|
-|-
-|2. 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)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#S-1_monotherapy|S-1]]
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints (*)
-| style="background-color:#d73027" |Higher incidence of hand-foot syndrome
-|-
-|}
-''Note: SALTO had a primary toxicity endpoint; this dose was intended for patients less than 70 years old; reported efficacy is based on the 2019 update.''
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-'''21-day cycles'''
-====Subsequent treatment====
-*CAIRO, upon progression: [[#Irinotecan_monotherapy_2|Irinotecan]]
-===References===
-<!-- Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, Georgia, May 15-18, 1999. -->
-#Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001 Apr 15;19(8):2282-92. [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]
-#'''CAIRO:''' Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. [https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17630036 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. [https://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]
-##'''Update:''' Kwakman JJM, van Werkhoven E, Simkens LHJ, van Rooijen JM, van de Wouw YAJ, Tije AJT, Creemers GM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, Punt CJA. Updated Survival Analysis of the Randomized Phase III Trial of S-1 Versus Capecitabine in the First-Line Treatment of Metastatic Colorectal Cancer by the Dutch Colorectal Cancer Group. Clin Colorectal Cancer. 2019 Jun;18(2):e229-e230. Epub 2019 Jan 29. [https://www.clinical-colorectal-cancer.com/article/S1533-0028(18)30531-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30782413 PubMed]
-==Capecitabine & Bevacizumab {{#subobject:408d3d|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CB: '''<u>C</u>'''apecitabine & '''<u>B</u>'''evacizumab
-===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#Comparative_efficacy|Comparative 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-esc)
-|[[#Capecitabine_monotherapy_2|Capecitabine]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[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#Comparative_efficacy|Comparative Efficacy]]
-|-
-||[https://ascopubs.org/doi/full/10.1200/JCO.2009.27.7723 Tebbutt et al. 2010 (AGITG MAX)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Capecitabine_monotherapy_2|Capecitabine]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===References===
-#'''AGITG MAX:''' Tebbutt NC, Wilson K, Gebski VJ, Cummins MM, Zannino D, van Hazel GA, Robinson B, Broad A, Ganju V, Ackland SP, Forgeson G, Cunningham D, Saunders MP, Stockler MR, Chua Y, Zalcberg JR, Simes RJ, Price TJ. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group randomized phase III MAX study. J Clin Oncol. 2010 Jul 1;28(19):3191-8. Epub 2010 Jun 1. [https://ascopubs.org/doi/full/10.1200/JCO.2009.27.7723 link to original article] [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] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24028813 PubMed]
-#'''XELAVIRI:''' Modest DP, Fischer von Weikersthal L, Decker T, Vehling-Kaiser U, Uhlig J, Schenk M, Freiberg-Richter J, Peuser B, Denzlinger C, Peveling Genannt Reddemann C, Graeven U, Schuch G, Schwaner I, Stahler A, Jung A, Kirchner T, Held S, Stintzing S, Giessen-Jung C, Heinemann V; XELAVIRI/AIO KRK0110 Investigators. Sequential Versus Combination Therapy of Metastatic Colorectal Cancer Using Fluoropyrimidines, Irinotecan, and Bevacizumab: A Randomized, Controlled Study-XELAVIRI (AIO KRK0110). J Clin Oncol. 2019 Jan 1;37(1):22-32. Epub 2018 Nov 2. [https://ascopubs.org/doi/full/10.1200/JCO.18.00052 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30388045 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
-<br>COX: '''<u>C</u>'''apecitabine & '''<u>OX</u>'''aliplatin
-===Example orders===
-*[[Example orders for CapeOx (XELOX) in colon cancer]]
-===Variant #1, 850/130 {{#subobject:d1897d|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[http://jco.ascopubs.org/content/26/21/3523.full Hochster et al. 2008 (TREE-1)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. bFOL
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints
-|-
-|2. [[#mFOLFOX6_3|mFOLFOX6]]
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints
-|-
-|}
-''Note: TREE-1 did not have any primary endpoints.''
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 850 mg/m<sup>2</sup> PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
-**In TREE-2, based on safety data from TREE-1, the initial dose was decreased to 850 mg/m<sup>2</sup> PO twice per day. Patients with a CrCl of 30 to 50 mL/min/1.73m<sup>2</sup> received 650 mg/m<sup>2</sup> PO twice per day
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''21-day cycles'''
-===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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/25/27/4217.long Porschen et al. 2007]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|FUFOX
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 70 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 8
-'''21-day cycles'''
-===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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/25/27/4224.long Díaz-Rubio et al. 2007]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FUOX|FUOX]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
-|-
-| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 Cassidy et al. 2008 (NO16966)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#FOLFOX4_2|FOLFOX4]]<br> 2. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|3. [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-| rowspan="2" |[http://jco.ascopubs.org/content/26/12/2013.long Saltz et al. 2008 (NO16966)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]<br> 2. [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|3. [[#FOLFOX4_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-switch-ic)
-|[[#mFOLFOX6_3|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" |Did not meet primary endpoint of OS (*)
-|-
-|[http://jco.ascopubs.org/content/30/29/3596.long Hoff et al. 2012 (HORIZON II)]
-| style="background-color:#1a9851" |Phase III (C)
-|1. CAPOX & Cediranib<br> 2. FOLFOX4 & Cediranib<br> 3. mFOLFOX6 & Cediranib
-| style="background-color:#fc8d59" |Seems to have inferior PFS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext Hong et al. 2012 (SMC 2008-03-012)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#SOX_2|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 twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
-**Note: In Saltz et al. 2008 and SMC 2008-03-012 capecitabine was described as being given 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''21-day cycles (see note)'''
-====Subsequent treatment====
-*SMC 2008-03-012: Optional [[#Capecitabine_monotherapy|capecitabine maintenance]] after 9 cycles
-===References===
-#Porschen R, Arkenau HT, Kubicka S, Greil R, Seufferlein T, Freier W, Kretzschmar A, Graeven U, Grothey A, Hinke A, Schmiegel W, Schmoll HJ; AIO Colorectal Study Group. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol. 2007 Sep 20;25(27):4217-23. Epub 2007 Jun 4. [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. [https://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]
-##'''Update:''' Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, Kenny SL, Kay E, Hodgkinson E, Pope M, Rogers P, Wasan H, Falk S, Gollins S, Hickish T, Bessell EM, Propper D, Kennedy MJ, Kaplan R, Maughan TS; MRC COIN Trial Investigators. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011 Jul;12(7):642-53. Epub 2011 Jun 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70102-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159416/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21641867 PubMed]
-#'''HORIZON II:''' Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. [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]
-#'''SMC 2008-03-012:''' Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23062232 PubMed]
-##'''Update:''' Kim ST, Hong YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Lee JW, Jo SJ, Park YS. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: updated results from a phase 3 trial. BMC Cancer. 2014 Nov 26;14:883. [https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-14-883 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289339/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25424120 PubMed]
-==CapeOx & Bevacizumab {{#subobject:62d39f|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CapeOX & Bevacizumab: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin, Bevacizumab
-<br>CAPOX-B: '''<u>CAP</u>'''ecitabine, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-<br>XELOX & Bevacizumab: '''<u>XEL</u>'''oda, '''<u>OX</u>'''aliplatin, Bevacizumab
-===Variant #1, 850/130/7.5 {{#subobject:618554|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-| 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-switch-ic)
-|1. bFOL & Bevacizumab
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints
-| style="background-color:#ffffbf" |Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
-|-
-|2. [[#mFOLFOX6_.26_Bevacizumab|mFOLFOX6 & Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints
-| style="background-color:#ffffbf" |Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 850 mg/m<sup>2</sup> PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
-**In TREE-2, patients with a CrCl of 30 to 50 mL/min/1.73m<sup>2</sup> received 650 mg/m<sup>2</sup> PO twice per day
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[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#Comparative_efficacy|Comparative 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.ncbi.nlm.nih.gov/pmc/articles/PMC3267817/ Díaz-Rubio et al. 2012 (MACRO)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://academic.oup.com/annonc/article/24/9/2335/202863 Johnsson et al. 2013 (Nordic ACT)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62004-3/fulltext Simkens et al. 2015 (CAIRO3)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycle for 6 cycles'''
-====Subsequent treatment====
-*CAIRO2: [[#Capecitabine_.26_Bevacizumab_2|Capecitabine & Bevacizumab maintenance]]
-*MACRO: [[#Bevacizumab_monotherapy|Bevacizumab]] versus XELOX & Bevacizumab maintenance
-*Nordic ACT: [[#Bevacizumab_monotherapy|Bevacizumab]] versus Erlotinib & Bevacizumab maintenance
-*CAIRO3: [[#Capecitabine_.26_Bevacizumab_2|Capecitabine & Bevacizumab maintenance]] versus [[#Observation_3|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 Cassidy et al. 2008 (NO16966)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[#FOLFOX4_2|FOLFOX4]]<br> 2. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|3. [[#CapeOx_2|XELOX]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-| rowspan="2" |[http://jco.ascopubs.org/content/26/12/2013.long Saltz et al. 2008 (NO16966)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[#FOLFOX4_3|FOLFOX4]]<br> 2. [[#CapeOx_2|XELOX]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|3. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-|[https://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" |Did not meet primary endpoint of ORR
-|-
-|}
-''Note:  N016966 specified that initial treatment could be given up to 16 cycles, but then could continue beyond that for patients who did not have progression of disease.''
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
-**Note: In Saltz et al. 2008--the same study as Cassidy et al. 2008--capecitabine was described as being given 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV over 30 to 90 minutes once on day 1, '''given first'''
-'''21-day cycles'''
-===References===
-<!-- Presented in part at the 31st European Society of Medical Oncology Congress, Istanbul, Turkey, September 29- October 3, 2006; the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Orlando, FL, January 19-21, 2007; and the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007. -->
-#'''NO16966:''' Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. [https://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]
-##'''Subgroup analysis:''' Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009 Jul 2;361(1):98-9. Erratum in: N Engl J Med. 2011 Sep 1;365(9):869. [https://www.nejm.org/doi/10.1056/NEJMc0904160 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19571295 PubMed]
-#'''MACRO:''' Díaz-Rubio E, Gómez-España A, Massutí B, Sastre J, Abad A, Valladares M, Rivera F, Safont MJ, Martínez de Prado P, Gallén M, González E, Marcuello E, Benavides M, Fernández-Martos C, Losa F, Escudero P, Arrivi A, Cervantes A, Dueñas R, López-Ladrón A, Lacasta A, Llanos M, Tabernero JM, Antón A, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors. First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study. Oncologist. 2012;17(1):15-25. Epub 2012 Jan 10. [http://theoncologist.alphamedpress.org/content/17/1/15.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267817/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22234633 PubMed]
-#'''Nordic ACT:''' Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. [https://academic.oup.com/annonc/article/24/9/2335/202863 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23788755 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext Koopman et al. 2007 (CAIRO)]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[Complex_multipart_regimens#CAIRO|See link]]
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#CAIRO|See link]]
-|-
-| rowspan="2" |[http://jco.ascopubs.org/content/25/30/4779.long Fuchs et al. 2007 (BICC-C)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. [[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#fc8d59" |Seems to have inferior PFS
-|-
-|2. [[#IFL|mIFL]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|[https://academic.oup.com/annonc/article/19/5/920/167346 Köhne et al. 2007 (EORTC 40015)]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FOLFIRI_2|FOLFIRI]] +/- Celecoxib
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366 Moehler et al. 2009a]
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|}
-''Note: EORTC 40015 was closed prematurely.''
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-'''21-day cycles'''
-====Subsequent treatment====
-*CAIRO, with progression: [[#CapeOx_3|CapeOx]]
-===References===
-#'''CAIRO:''' Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. [https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17630036 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]
-#'''EORTC 40015:''' Köhne CH, De Greve J, Hartmann JT, Lang I, Vergauwe P, Becker K, Braumann D, Joosens E, Müller L, Janssens J, Bokemeyer C, Reimer P, Link H, Späth-Schwalbe E, Wilke HJ, Bleiberg H, Van Den Brande J, Debois M, Bethe U, Van Cutsem E. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer: EORTC study 40015. Ann Oncol. 2008 May;19(5):920-6. Epub 2007 Dec 6. [https://academic.oup.com/annonc/article/19/5/920/167346 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18065406 PubMed]
-#Moehler M, Sprinzl MF, Abdelfattah M, Schimanski CC, Adami B, Godderz W, Majer K, Flieger D, Teufel A, Siebler J, Hoehler T, Galle PR, Kanzler S. Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients. World J Gastroenterol. 2009 Jan 28;15(4):449-56. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366 link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366/ link to PMC article] [https://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, 750/150/7.5 {{#subobject:ed3172|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://academic.oup.com/annonc/article/24/9/2335/202863 Johnsson et al. 2013 (Nordic ACT)]
+|[https://doi.org/10.1200/jco.1997.15.1.246 O'Connell et al. 1997 (CALGB 8896)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-260-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
 |-
-|}
+|} -->
-''This dose was recommended for patients older than 65 years.''
+|1988-02 to 1989-08
-====Chemotherapy====
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Colon_cancer_-_null_regimens#Observation|Observation]]
-*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV once on day 1
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycle for 6 cycles'''
-====Subsequent treatment====
-*[[#Bevacizumab_monotherapy|Bevacizumab]] versus Erlotinib & Bevacizumab maintenance
-===Variant #2, 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.18.00052 Modest et al. 2018 (XELAVIRI)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Capecitabine_.26_Bevacizumab|Cape-Bev]]
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior TFS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV once on day 1
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===Variant #3, 1000/180/7.5 {{#subobject:852626|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://academic.oup.com/annonc/article/24/9/2335/202863 Johnsson et al. 2013 (Nordic ACT)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycle for 6 cycles'''
-====Subsequent treatment====
-*[[#Bevacizumab_monotherapy|Bevacizumab]] versus Erlotinib & Bevacizumab maintenance
-===Variant #4, 1000/200/7.5 {{#subobject:88c136|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653366 Moehler et al. 2009a]
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV once on day 1
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===Variant #5, 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466131/ Pectasides et al. 2012]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI-Bev]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 240 mg/m<sup>2</sup> IV once on day 1
-*[[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]
-#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]
-#'''Nordic ACT:''' Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. [https://academic.oup.com/annonc/article/24/9/2335/202863 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23788755 PubMed]
-#'''XELAVIRI:''' Modest DP, Fischer von Weikersthal L, Decker T, Vehling-Kaiser U, Uhlig J, Schenk M, Freiberg-Richter J, Peuser B, Denzlinger C, Peveling Genannt Reddemann C, Graeven U, Schuch G, Schwaner I, Stahler A, Jung A, Kirchner T, Held S, Stintzing S, Giessen-Jung C, Heinemann V; XELAVIRI/AIO KRK0110 Investigators. Sequential Versus Combination Therapy of Metastatic Colorectal Cancer Using Fluoropyrimidines, Irinotecan, and Bevacizumab: A Randomized, Controlled Study-XELAVIRI (AIO KRK0110). J Clin Oncol. 2019 Jan 1;37(1):22-32. Epub 2018 Nov 2. [https://ascopubs.org/doi/full/10.1200/JCO.18.00052 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30388045 PubMed]
-==Fluorouracil monotherapy {{#subobject:a3995f|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Variant #1, 400 mg/m<sup>2</sup> intermittent bolus {{#subobject:323429|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/9/5/535/142141 Borner et al. 1998]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Fluorouracil_.26_Folinic_acid_3|5-FU & LV]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
-'''1-month cycles'''
-===Variant #2, 450 mg/m<sup>2</sup> intermittent bolus {{#subobject:54acz9|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pubmed/2667324 Molinaro et al. 1989]
-| style="background-color:#1a9851" |Phase III (C)
-|Epirubicin
-| style="background-color:#1a9850" |Superior ORR
-|-
-|}
-''Note: this dose was used for those who had previously been exposed to radiotherapy.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 450 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
-'''28-day cycles'''
-===Variant #3, 500 mg/m<sup>2</sup> intermittent bolus {{#subobject:545429|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.4.425 Lokich et al. 1989]
-| style="background-color:#1a9851" |Phase III (C)
-|PVI 5-FU
-| style="background-color:#d73027" |Inferior ORR
-|-
-|[https://www.ncbi.nlm.nih.gov/pubmed/2667324 Molinaro et al. 1989]
-| style="background-color:#1a9851" |Phase III (C)
-|Epirubicin
-| style="background-color:#1a9850" |Superior ORR
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
-'''4- to 5-week cycles'''
-===Variant #4, 600 mg/m<sup>2</sup>/week {{#subobject:768cajb|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/6/9/948/141837 Smyth et al. 1995 (F-trial)]
-| style="background-color:#1a9851" |Phase III (C)
-|TCNU
-| style="background-color:#ffffbf" |Did not meet efficacy endpoint
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
-'''7-day cycles'''
-===Variant #5, 600 mg/m<sup>2</sup>/week, 6 out of 8 weeks {{#subobject:76acae|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1986.4.4.565 Richards et al. 1986]
-| style="background-color:#1a9851" |Phase III (C)
-|MMF
-| style="background-color:#ffffbf" |Did not meet efficacy endpoints
-|-
-|[https://journals.lww.com/amjclinicaloncology/Fulltext/2002/02000/A_Phase_III_Study_of_5_Fluorouracil_Versus.4.aspx Kalofonos et al. 2002]
-| style="background-color:#1a9851" |Phase III (C)
-|1. 5-FU & IFN alfa<br> 2. [[#Fluorouracil_.26_Folinic_acid_3|5-FU & LV]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, 29, 36
-'''8-week cycles'''
-===Variant #6, weekly bolus with CI lead-in {{#subobject:b3b13d|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1995.13.6.1297 Hill et al. 1995]
-| style="background-color:#1a9851" |Phase III (C)
-|5-FU & IFN alfa-2b
-| style="background-color:#ffffbf" |Did not meet efficacy endpoints
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.10.2674 Greco et al. 1996]
-| style="background-color:#1a9851" |Phase III (C)
-|5-FU & IFN alfa-2a
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] as follows:
-**Cycle 1: 750 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose: 3750 mg/m<sup>2</sup>)
-**Cycle 2 onwards: 750 mg/m<sup>2</sup> IV once on day 1
-'''7-day cycles'''
-===Variant #7, weekly CI {{#subobject:cbf24c|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/9/7/727/274760 Aranda et al. 1998]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Fluorouracil_.26_Folinic_acid_3|Mayo Clinic regimen]]
-| style="background-color:#91cf60" |Seems to have superior ORR
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 1750 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 3500 mg/m<sup>2</sup>)
-'''7-day cycles'''
-===Variant #8, PVI ("Lokich regimen") {{#subobject:88b2a1|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.4.425 Lokich et al. 1989]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|Bolus 5-FU
-| style="background-color:#1a9850" |Superior ORR
-|-
-|[https://academic.oup.com/jnci/article/88/10/668/894396 Hansen et al. 1996]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|Bolus 5-FU
-| style="background-color:#1a9850" |Superior TTP
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08514-8/fulltext Maughan et al. 2002]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#Fluorouracil_.26_Folinic_acid_3|de Gramont regimen]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|2. Raltitrexed
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion
-'''Continued indefinitely'''
-===Variant #9, load to toxicity {{#subobject:31493b|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010301%2991%3A5%3C1020%3A%3AAID-CNCR1093%3E3.0.CO%3B2-V Witte et al. 2001]
-| style="background-color:#1a9851" |Phase III (C)
-|5-FU & Levamisole
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] as follows:
-**Cycle 1: 480 mg/m<sup>2</sup> IV once per day on days 1 to 5, then 240 mg/m<sup>2</sup> every other day to toxicity or six additional doses
-**Cycle 2 onwards: 480 mg/m<sup>2</sup> IV once per day on days 1 to 5
-'''6-week cycle for 1 cycle, then 5-week cycles'''
-===References===
-#Richards F 2nd, Case LD, White DR, Muss HB, Spurr CL, Jackson DV, Cooper MR, Zekan P, Cruz J, Stuart JJ, Capizzi RL, McCulloch JH, McFarland JA, Kincaid WR, Harding RW, Pope E, McMahan R, Wellls HB. Combination chemotherapy (5-fluorouracil, methyl-CCNU, mitomycin C) versus 5-fluorouracil alone for advanced previously untreated colorectal carcinoma: a phase III study of the Piedmont Oncology Association. J Clin Oncol. 1986 Apr;4(4):565-70. [https://ascopubs.org/doi/abs/10.1200/JCO.1986.4.4.565 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3514806 PubMed]
-#Lokich JJ, Ahlgren JD, Gullo JJ, Philips JA, Fryer JG. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol. 1989 Apr;7(4):425-32. [https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.4.425 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2926468 PubMed]
-#Molinaro P, Lafleur F, Blum RH. A phase III randomized trial of epirubicin versus 5-fluorouracil in metastatic rectal/sigmoid adenocarcinoma. Am J Clin Oncol. 1989 Aug;12(4):332-4. [https://www.ncbi.nlm.nih.gov/pubmed/2667324 PubMed]
-#Hill M, Norman A, Cunningham D, Findlay M, Nicolson V, Hill A, Iveson A, Evans C, Joffe J, Nicolson M, Hickish T. Royal Marsden phase III trial of fluorouracil with or without interferon alfa-2b in advanced colorectal cancer. J Clin Oncol. 1995 Jun;13(6):1297-302. [https://ascopubs.org/doi/abs/10.1200/JCO.1995.13.6.1297 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7751874 PubMed]
-#Smyth JF, Hardcastle JD, Denton G, Alderson D, Grace RH, Mansi JL, Yosef HM, Nordle O, Lauri H, Wählby S. Two phase III trials of tauromustine (TCNU) in advanced colorectal cancer. Ann Oncol. 1995 Nov;6(9):948-9. [https://academic.oup.com/annonc/article/6/9/948/141837 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8624301 PubMed]
-#Hansen RM, Ryan L, Anderson T, Krzywda B, Quebbeman E, Benson A 3rd, Haller DG, Tormey DC. Phase III study of bolus versus infusion fluorouracil with or without cisplatin in advanced colorectal cancer. J Natl Cancer Inst. 1996 May 15;88(10):668-74. [https://academic.oup.com/jnci/article/88/10/668/894396 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8627643 PubMed]
-#Greco FA, Figlin R, York M, Einhorn L, Schilsky R, Marshall EM, Buys SS, Froimtchuk MJ, Schuller J, Schuchter L, Buyse M, Ritter L, Man A, Yap AK. Phase III randomized study to compare interferon alfa-2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer. J Clin Oncol. 1996 Oct;14(10):2674-81. [https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.10.2674 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8874326 PubMed]
-#Aranda E, Díaz-Rubio E, Cervantes A, Antón-Torres A, Carrato A, Massutí T, Tabernero JM, Sastre J, Trés A, Aparicio J, López-Vega JM, Barneto I, García-Conde J. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol. 1998 Jul;9(7):727-31. [https://academic.oup.com/annonc/article/9/7/727/274760 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9739438 PubMed]
-#Witte RS, Cnaan A, Mansour EG, Barylak E, Harris JE, Schutt AJ. Comparison of 5-fluorouracil alone, 5-fluorouracil with levamisole, and 5-fluorouracil with hepatic irradiation in the treatment of patients with residual, nonmeasurable, intra-abdominal metastasis after undergoing resection for colorectal carcinoma. Cancer. 2001 Mar 1;91(5):1020-8. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0142%2820010301%2991%3A5%3C1020%3A%3AAID-CNCR1093%3E3.0.CO%3B2-V link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11251955 PubMed]
-#Kalofonos HP, Nicolaides C, Samantas E, Mylonakis N, Aravantinos G, Dimopoulos MA, Gennatas C, Kouvatseas G, Giannoulis E, Dervenis C, Basdanis G, Pavlidis N, Androulakis I, Fountzilas G; Hellenic Cooperative Oncology Group (HeCOG). A phase III study of 5-fluorouracil versus 5-fluorouracil plus interferon alpha 2b versus 5-fluorouracil plus leucovorin in patients with advanced colorectal cancer: a Hellenic Cooperative Oncology Group (HeCOG) study. Am J Clin Oncol. 2002 Feb;25(1):23-30. [https://journals.lww.com/amjclinicaloncology/Fulltext/2002/02000/A_Phase_III_Study_of_5_Fluorouracil_Versus.4.aspx link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11823690 PubMed]
-#Maughan TS, James RD, Kerr DJ, Ledermann JA, McArdle C, Seymour MT, Cohen D, Hopwood P, Johnston C, Stephens RJ; British MRC Colorectal Cancer Working Party. Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2002 May 4;359(9317):1555-63. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08514-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12047964 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, 400/80 ("modified Laufman regimen") {{#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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://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====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1
-*[[Folinic acid (Leucovorin)]] 80 mg/m<sup>2</sup> IV once on day 1
-'''7-day cycle for up to 26 cycles (6 months)'''
-===Variant #2, 450/200 {{#subobject:24e32a|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.10.2682 Kosmidis et al. 1996]
-| style="background-color:#1a9851" |Phase III (C)
-|FULV & IFN alfa-2b
-| style="background-color:#1a9850" |Superior OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 450 mg/m<sup>2</sup> IV bolus once on day 1, '''given halfway through'''
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''7-day cycles'''
-===Variant #3, 500/20 {{#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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/14/8/2274.long Jäger et al. 1996]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Fluorouracil_.26_Folinic_acid_3|FULV]]; high-dose
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once on day 1, '''given second, 1 hour after start of leucovorin'''
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''7-day cycles'''
-===Variant #4, 500/200, 6 out of 8 weeks {{#subobject:f7ed72|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/13/1/87/143714 Blanke et al. 2002]
-| style="background-color:#1a9851" |Phase III (C)
-|FULV & Trimetrexate
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
-'''8-week cycles'''
-===Variant #5, 600/500 ("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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1987.5.10.1559 Petrelli et al. 1987]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[#Fluorouracil_monotherapy|5-FU]]<br> 2. 5-FU & MTX
-| style="background-color:#1a9850" |Superior ORR
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.10.1419 Petrelli et al. 1989]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[#Fluorouracil_monotherapy|5-FU]]<br> 2. 5-FU & LDLV
-| style="background-color:#d9ef8b" |Might have superior OS
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1994.12.1.14 Buroker et al. 1994]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Fluorouracil_.26_Folinic_acid_3|FULV]]; Mayo Clinic regimen
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%
-|-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19951115)76:10%3C1709::AID-CNCR2820761006%3E3.0.CO;2-5 Jones et al. 1995]
-| style="background-color:#1a9851" |Phase III (C)
-|MFL
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|[http://jco.ascopubs.org/content/21/1/60.full Kabbinavar et al. 2003 (AVF0780)]
-| style="background-color:#1a9851" |Randomized Phase II (C)
-|FULV & Bevacizumab
-| style="background-color:#fee08b" |Might have inferior OS
-|-
-|}
-''Note: the original regimen described by Petrelli et al. 1987 & 1989 used a 5-FU dose of 600 mg/m<sup>2</sup>.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 500 to 600 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22, 29, 36, '''given second, 1 hour after start of leucovorin'''
-*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, '''given first'''
-'''8-week cycles'''
-===Variant #6, 1500/400 {{#subobject:be5dfd|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2007.13.3934 Gamelin et al. 2008]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Fluorouracil_.26_Folinic_acid_3|FULV]]; PK-guided
-| style="background-color:#fee08b" |Might have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 1500 mg/m<sup>2</sup> IV over 8 hours once on day 1
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV bolus every 4 hours on day 1, '''given before and 4 hours into 5-FU infusion''' (total dose per cycle: 400 mg/m<sup>2</sup>)
-'''7-day cycles'''
-===Variant #7, 1850/1000 {{#subobject:566afe|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1995.13.4.921 Man et al. 1995 (Corfu-A)]
-| style="background-color:#1a9851" |Phase III (E-switch-ooc)
-|5-FU & IFN alfa-2a
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.11.3320 Goldberg et al. 1997]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[#Fluorouracil_.26_Levoleucovorin|FULV]]; low-dose LV<br> 2. [[#Fluorouracil_.26_Folinic_acid_3|FULV]]; oral LV
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV once per day on days 1 to 5
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5
-'''28-day cycle for 2 cycles, then 35-day cycles'''
-===Variant #8, 2000/100 {{#subobject:d429aa|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/9/5/535/142141 Borner et al. 1998]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Fluorouracil_monotherapy|5-FU]]
 | 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)]
-====Chemotherapy====
+|rowspan=3|1988-1992
+| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-de-esc)
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 5
+|1. [[#FULV|FULV]]; high-dose
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 5
-'''1-month cycles'''
-===Variant #9, 2000/400 (LV5FU2 aka "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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.1997.15.2.808 de Gramont et al. 1997 (FFCD 9101)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Fluorouracil_.26_Folinic_acid_3|FULV]]; 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)
-|1. [[#IFL|IFL]]<br> 2. [[#FOLFIRI_2|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_3|FOLFOX4]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08514-8/fulltext Maughan et al. 2002]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#Fluorouracil_monotherapy|Lokich regimen]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|2. Raltitrexed
+|2. [[Colon_cancer_-_historical#FULV_.26_Levamisole|FULV & Levamisole]]; LDLV
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)12388-4/fulltext Kerr et al. 2003]
+|3. [[Colon_cancer_-_historical#Fluorouracil_.26_Levamisole|5-FU & Levamisole]]
-| style="background-color:#1a9851" |Phase III (C)
-|IHA LV5FU2
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)12461-0/fulltext Maughan et al. 2003]
+| rowspan="2" |[https://doi.org/10.1016/s0140-6736(02)09836-7 Punt et al. 2002 (Study 157-002)]
-| style="background-color:#1a9851" |Phase III (C)
+|rowspan=2|1995-1999
-|Intermittent LV5FU2
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#FULV_.26_Edrecolomab_999|FULV & Edrecolomab]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-| rowspan="2" |[https://www.karger.com/Article/Abstract/94357 Ducreux et al. 2006 (FFCD 9601)]
+|2. [[Colon_cancer_-_historical#Edrecolomab_monotherapy|Edrecolomab]]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. ldLV5FU2<br> 2. [[#Fluorouracil_monotherapy|5-FU]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|2. Raltitrexed
-| style="background-color:#91cf60" |Seems to have superior PFS
-|-
-|[https://academic.oup.com/annonc/article/20/2/244/165904 Cunningham et al. 2008]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFOX4_3|FOLFOX4]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-| rowspan="2" |[https://academic.oup.com/annonc/article/27/1/121/2196319 Aparicio et al. 2015 (FFCD 2001-02)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#FOLFIRI_2|"Classic" FOLFIRI]]<br> 2. [[#FOLFIRI_2|"Simplified" FOLFIRI]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|3. sLV5FU2
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-''Note: Maughan et al. 2003 randomized patients to 12 weeks of treatment with re-treatment upon progression, versus continuous treatment. There was no difference in outcome between the two arms. FFCD 2001-02 enrolled elderly (75 or older) patients.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first'''
-'''14-day cycles (see note)'''
-===Variant #10, 2000/1000 {{#subobject:d539aa|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article-abstract/2/9/673/229114 Labianca et al. 1991]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Fluorouracil_monotherapy|5-FU]]
-| style="background-color:#91cf60" |Seems to have superior ORR
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV over 15 minutes once per day on days 1 to 5
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5
-'''28-day cycles'''
-===Variant #11, 2125/100 ("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#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19890315)63:6%2B%3C1026::AID-CNCR2820631307%3E3.0.CO;2-R O'Connell 1989]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#Fluorouracil_monotherapy|5-FU]]
 | style="background-color:#91cf60" |Seems to have superior OS
 |-
-|[[#Fluorouracil_.26_Folinic_acid_3|FULV]]; HDLV
+|[https://doi.org/10.1200/JCO.2008.18.5710 Fields et al. 2009 (Study 157-001)]
-| style="background-color:#ffffbf" |Did not meet primary efficacy endpoint
+|1995-1999
-|-
+| style="background-color:#1a9851" |Phase 3 (C)
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.10.1407 Poon et al. 1989]
+|[[#FULV_.26_Edrecolomab_999|FULV & Edrecolomab]]
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#Fluorouracil_monotherapy|5-FU]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1994.12.1.14 Buroker et al. 1994]
-| style="background-color:#1a9851" |Phase III (E-de-esc)
-|[[#Fluorouracil_.26_Folinic_acid_3|FULV]]; Roswell Park regimen
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.1997.15.2.808 de Gramont et al. 1997 (FFCD 9101)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Fluorouracil_.26_Folinic_acid_3|FULV]]; LV5FU2
-| style="background-color:#d73027" |Inferior PFS
-|-
-|[https://academic.oup.com/annonc/article/9/7/727/274760 Aranda et al. 1998]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Fluorouracil_monotherapy|High-dose 5-FU]]
-| style="background-color:#fc8d59" |Seems to have inferior ORR
-|-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 Saltz et al. 2000]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#IFL|IFL]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|2. [[#Irinotecan_monotherapy|Irinotecan]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|[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:#eeee01" |Equivalent ORR
-|-
-|[https://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 OS
-|-
-|[https://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
-|-
-|[https://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" |Did not meet primary endpoint of TTP
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2003.11.122 Köhne et al. 2003 (EORTC 40952)]
-| style="background-color:#1a9851" |Phase III (C)
-|1. FU24h<br> 2. FU24h + LV
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://academic.oup.com/annonc/article/17/3/437/146088 Chong et al. 2005]
-| style="background-color:#1a9851" |Phase III (C)
-|FULV & 3H1
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://academic.oup.com/annonc/article/17/3/443/146259 Hospers et al. 2006]
-| style="background-color:#1a9851" |Phase III (C)
-|FOLFOX6
-| style="background-color:#fc8d59" |Seems to have inferior PFS
 |-
 |}
-''Note: not all manuscripts explicitly describe the timing described here; O'Connell 1989 is the clearest.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#Colorectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''
+*[[Leucovorin (Folinic acid)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''
+'''28-day cycle for 3 cycles, then 35-day cycle for 3 cycles'''
-'''28-day cycle for 3 cycles, then 35-day cycle for 3 cycles (see note)'''
+</div></div>
-===Variant #12, 2560/175 (reduced-dose sLV5FU2) {{#subobject:d246ce|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109515/ Seymour et al. 2011 (MRC FOCUS2)]
-| style="background-color:#1a9851" |Phase III (C)
-|1. [[#Capecitabine_monotherapy_2|Capecitabine]]<br> 2. [[#CapeOx_2|CapeOx]]<br> 3. OxFU
-| style="background-color:#fee08b" |Might have inferior PFS (see note)
-| style="background-color:#ffffbf" |Similar QoL (see note)
-|-
-|}
-''Note: efficacy comparison was to oxaliplatin-containing regimens; QoL comparison was to capecitabine-containing regimens.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 320 mg/m<sup>2</sup> IV bolus once on day 1, then 2240 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2560 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 175 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''14-day cycles'''
-===Variant #13, 2600/500 {{#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#Comparative_efficacy|Comparative 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)
-|1. [[#IFL|IFL]]<br> 2. [[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 2600 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
-*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV once on day 1
-'''7-day cycles'''
-===Variant #14, 2800/350 ("modified de Gramont regimen") {{#subobject:a28e0a|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376131/ Cheeseman et al. 2002]
-| style="background-color:#91cf61" |Non-randomized
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61087-3/fulltext Seymour et al. 2007 (MRC FOCUS)]
-| style="background-color:#1a9851" |Phase III (C)
-|-
-|}
-''Note: it is not completely clear from the abstract whether this was the protocol used in MRC FOCUS, although it is alluded to in the Cheeseman et al. 2002 publication. Also, efficacy results for MRC FOCUS are complex and will be added in the future (to be completed).''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>), '''given second'''
-*[[Folinic acid (Leucovorin)]] 350 mg IV over 2 hours once on day 1, '''given first'''
-====Supportive medications====
-*No routine prophylactic [[:Category:Emesis_prevention|antiemetics]] and [[:Category:Anti-diarrheals|antidiarrheal]] medications were used, but patients could use [[Metoclopramide (Reglan)]] prn nausea and [[Loperamide (Imodium)]] prn diarrhea.
-'''14-day cycles'''
-===Variant #15, 2800/400 (sLV5FU2) {{#subobject:9bdfa8|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancetonc/article/PIIS1470204511701991/fulltext Ducreux et al. 2011 (FFCD 2000-05)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[Complex_multipart_regimens#FFCD_2000-05|See link]]
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#FFCD_2000-05|See link]]
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''14-day cycles'''
-====Subsequent treatment====
-*Upon progression: [[#mFOLFOX6_4|mFOLFOX6]]
-===Variant #16, other {{#subobject:8f03e1|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ejcancer.com/article/0959-8049(94)00360-H/pdf Heys et al. 1995]
-| style="background-color:#1a9851" |Phase III (C)
-|FULV & rIL2
-| style="background-color:#fee08b" |Might have inferior OS
-|-
-|[https://www.ejcancer.com/article/S0959-8049(98)00397-9/fulltext Hausmaninger et al. 1999]
-| style="background-color:#1a9851" |Phase III (C)
-|FULV & IFN alfa-2c
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2000.18.1.136 Giacchetti et al. 2000]
-| style="background-color:#1a9851" |Phase III (C)
-|Chronomodulated FOLFOX
-| style="background-color:#fc8d59" |Seems to have inferior PFS
-|-
-|}
-''See papers for details.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]]
-*[[Folinic acid (Leucovorin)]]
 ===References===
+#'''NSABP C-03:''' Wolmark N, Rockette H, Fisher B, Wickerham DL, Redmond C, Fisher ER, Jones J, Mamounas EP, Ore L, Petrelli NJ, Spurr CL, Dimitrov N, Romond EH, Sutherland CM, Kardinal CG, DeFusco PA, Jochimsen P. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol. 1993 Oct;11(10):1879-87. [https://doi.org/10.1200/JCO.1993.11.10.1879 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8410113/ PubMed]
+##'''Pooled update:''' Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. [https://link.springer.com/article/10.1245/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]
+#Francini G, Petrioli R, Lorenzini L, Mancini S, Armenio S, Tanzini G, Marsili S, Aquino A, Marzocca G, Civitelli S, Mariani L, De Sando D, Bovenga S, Lorenzi M. Folinic acid and 5-fluorouracil as adjuvant chemotherapy in colon cancer. Gastroenterology. 1994 Apr;106(4):899-906. [https://doi.org/10.1016/0016-5085(94)90748-x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8143995/ PubMed]
+#'''CALGB 8896:''' O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, Wieand HS. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997 Jan;15(1):246-50. [https://doi.org/10.1200/jco.1997.15.1.246 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8996149/ PubMed]
+##'''Pooled update:''' Erlichman C, O'Connell M, Kahn M, Marsoni S, Torri V, Tardio B, Zaniboni A, Pancera G, Martignoni G, Labianca R, Barni A, Seitz JF, Milan C, Bedenne L, Giovannini M, Letreut YP, Skillings J, Shepard L, Zee B, Petrioli R, Francini G; International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol. 1999 May;17(5):1356-63. [https://doi.org/10.1200/JCO.1999.17.5.1356 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10334519/ PubMed]
+#'''NSABP C-05:''' Wolmark N, Bryant J, Smith R, Grem J, Allegra C, Hyams D, Atkins J, Dimitrov N, Oishi R, Prager D, Fehrenbacher L, Romond E, Colangelo L, Fisher B. Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst. 1998 Dec 2;90(23):1810-6. [https://academic.oup.com/jnci/article/90/23/1810/2520545 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9839521/ PubMed]
+##'''Pooled update:''' Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. [https://link.springer.com/article/10.1245/s10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20082144/ PubMed]
+#'''NSABP C-04:''' Wolmark N, Rockette H, Mamounas E, Jones J, Wieand S, Wickerham DL, Bear HD, Atkins JN, Dimitrov NV, Glass AG, Fisher ER, Fisher B. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol. 1999 Nov;17(11):3553-9. [https://doi.org/10.1200/JCO.1999.17.11.3553 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10550154/ PubMed] [https://clinicaltrials.gov/study/NCT00425152 NCT00425152]
+##'''Pooled update:''' Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. [https://link.springer.com/article/10.1245/s10434-009-0881-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935319/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20082144/ PubMed]
+#Fountzilas G, Zisiadis A, Dafni U, Konstantaras C, Hatzitheoharis G, Papavramidis S, Bousoulegas A, Basdanis G, Giannoulis E, Dokmetzioglou J, Katsohis C, Nenopoulou E, Karvounis N, Briassoulis E, Aravantinos G, Kosmidis P, Skarlos D, Pavlidis N; Hellenic Cooperative Oncology Group. Fluorouracil and leucovorin with or without interferon alfa-2a as adjuvant treatment, in patients with high-risk colon cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Oncology. 2000 Apr;58(3):227-36. [https://www.karger.com/Article/Abstract/12105 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10765125/ PubMed]
+#'''Study 157-002:''' Punt CJ, Nagy A, Douillard JY, Figer A, Skovsgaard T, Monson J, Barone C, Fountzilas G, Riess H, Moylan E, Jones D, Dethling J, Colman J, Coward L, MacGregor S. Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study. Lancet. 2002 Aug 31;360(9334):671-7. [https://doi.org/10.1016/s0140-6736(02)09836-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12241873/ PubMed]
+#'''GERCOR C96.1:''' Andre T, Colin P, Louvet C, Gamelin E, Bouche O, Achille E, Colbert N, Boaziz C, Piedbois P, Tubiana-Mathieu N, Boutan-Laroze A, Flesch M, Buyse M, de Gramont A. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol. 2003 Aug 1;21(15):2896-903. [https://doi.org/10.1200/JCO.2003.10.065 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12885807/ PubMed]
+##'''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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15175436/ PubMed] [https://clinicaltrials.gov/study/NCT00275210 NCT00275210]
+##'''Update:''' André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009 Jul 1;27(19):3109-16. Epub 2009 May 18. [https://doi.org/10.1200/JCO.2008.20.6771 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19451431/ PubMed]
+##'''Update:''' André T, 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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15987918/ PubMed] [https://clinicaltrials.gov/study/NCT00009737 NCT00009737]
+##'''Update:''' Twelves C, Scheithauer W, McKendrick J, Seitz JF, Van Hazel G, Wong A, Díaz-Rubio E, Gilberg F, Cassidy J. Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy. Ann Oncol. 2012 May;23(5):1190-7. Epub 2011 Sep 6. [https://doi.org/10.1093/annonc/mdr366 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21896539/ PubMed]
+<!-- Presented in part at the 33rd Annual Meeting of the American Society of Clinical Oncology, Denver, CO, May 20, 1997. -->
+#'''Intergroup 0089:''' Haller DG, Catalano PJ, Macdonald JS, O'Rourke MA, Frontiera MS, Jackson DV, Mayer RJ. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 2005 Dec 1;23(34):8671-8. [https://doi.org/10.1200/jco.2004.00.5686 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16314627/ PubMed]
+<!-- Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 13-17, 2004. -->
+#'''NSABP C-06:''' Lembersky BC, Wieand HS, Petrelli NJ, O'Connell MJ, Colangelo LH, Smith RE, Seay TE, Giguere JK, Marshall ME, Jacobs AD, Colman LK, Soran A, Yothers G, Wolmark N. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 2006 May 1;24(13):2059-64. [https://doi.org/10.1200/jco.2005.04.7498 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16648506/ PubMed] [https://clinicaltrials.gov/study/NCT00378716 NCT00378716]
+#'''XELOXA:''' Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A, Maroun J, Price T, Lim R, Van Cutsem E, Park YS, McKendrick J, Topham C, Soler-Gonzalez G, de Braud F, Hill M, Sirzén F, Haller DG. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007 Jan 1;25(1):102-9. [https://doi.org/10.1200/jco.2006.08.1075 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17194911/ PubMed] [https://clinicaltrials.gov/study/NCT00069121 NCT00069121]
+##'''Update:''' Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011 Apr 10;29(11):1465-71. Epub 2011 Mar 7. [https://doi.org/10.1200/jco.2010.33.6297 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383294/ PubMed]
+##'''Update:''' Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: Final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015 Nov 10;33(32):3733-40. Epub 2015 Aug 31. [https://doi.org/10.1200/jco.2015.60.9107 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26324362/ PubMed]
+#'''NSABP C-07:''' Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, Zapas JL, Goodwin JW, Fehrenbacher L, Ramanathan RK, Conley BA, Flynn PJ, Soori G, Colman LK, Levine EA, Lanier KS, Wolmark N. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007 Jun 1;25(16):2198-204. Epub 2007 Apr 30. [https://doi.org/10.1200/jco.2006.08.2974 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/17470851/ PubMed] [https://clinicaltrials.gov/study/NCT00004931 NCT00004931]
+##'''Update:''' Yothers G, O'Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, Wolmark N. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011 Oct 1;29(28):3768-74. Epub 2011 Aug 22. [https://doi.org/10.1200/JCO.2011.36.4539 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188282/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21859995/ PubMed]
+#'''CALGB 89803:''' Saltz LB, Niedzwiecki D, Hollis D, Goldberg RM, Hantel A, Thomas JP, Fields AL, Mayer RJ. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol. 2007 Aug 10;25(23):3456-61. [https://doi.org/10.1200/JCO.2007.11.2144 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17687149/ PubMed] [https://clinicaltrials.gov/study/NCT00003835 NCT00003835]
+#'''PETACC-1:''' Popov I, Carrato A, Sobrero A, Vincent M, Kerr D, Labianca R, Raffaele Bianco A, El-Serafi M, Bedenne L, Paillot B, Mini E, Sanches E, Welch J, Collette L, Praet M, Wils J. Raltitrexed (Tomudex) versus standard leucovorin-modulated bolus 5-fluorouracil: Results from the randomised phase III Pan-European Trial in Adjuvant Colon Cancer 01 (PETACC-1). Eur J Cancer. 2008 Oct;44(15):2204-11. Epub 2008 Aug 15. [https://doi.org/10.1016/j.ejca.2008.07.002 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18707870/ PubMed]
+#'''FFCD 9802:''' Ychou M, Raoul JL, Douillard JY, Gourgou-Bourgade S, Bugat R, Mineur L, Viret F, Becouarn Y, Bouché O, Gamelin E, Ducreux M, Conroy T, Seitz JF, Bedenne L, Kramar A. A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). Ann Oncol. 2009 Apr;20(4):674-80. Epub 2009 Jan 29. [https://doi.org/10.1093/annonc/mdn680 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19179549/ PubMed] [https://clinicaltrials.gov/study/NCT00005979 NCT00005979]
+#'''Study 157-001:''' Fields AL, Keller A, Schwartzberg L, Bernard S, Kardinal C, Cohen A, Schulz J, Eisenberg P, Forster J, Wissel P. Adjuvant therapy with the monoclonal antibody edrecolomab plus fluorouracil-based therapy does not improve overall survival of patients with stage III colon cancer. J Clin Oncol. 2009 Apr 20;27(12):1941-7. Epub 2009 Mar 9. [https://doi.org/10.1200/JCO.2008.18.5710 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19273708/ PubMed]
+#'''PETACC-3:''' Van Cutsem E, Labianca R, Bodoky G, Barone C, Aranda E, Nordlinger B, Topham C, Tabernero J, André T, Sobrero AF, Mini E, Greil R, Di Costanzo F, Collette L, Cisar L, Zhang X, Khayat D, Bokemeyer C, Roth AD, Cunningham D. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol. 2009 Jul 1;27(19):3117-25. Epub 2009 May 18. [https://doi.org/10.1200/JCO.2008.21.6663 link to original article] '''contains dosing details in abstract''' [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://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-10 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038965/ link to PMC article] '''contains dosing details in abstract''' [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]
-#Petrelli N, Herrera L, Rustum Y, Burke P, Creaven P, Stulc J, Emrich LJ, Mittelman A. A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol. 1987 Oct;5(10):1559-65. [https://ascopubs.org/doi/abs/10.1200/JCO.1987.5.10.1559 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2443619 PubMed]
+==S-1 monotherapy {{#subobject:5gh25a|Regimen=1}}==
-#O'Connell MJ. A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer: a Mayo Clinic/North Central Cancer Treatment Group study. Cancer. 1989 Mar 15;63(6 Suppl):1026-30. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19890315)63:6%2B%3C1026::AID-CNCR2820631307%3E3.0.CO;2-R link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2465076 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
-#Poon MA, O'Connell MJ, Moertel CG, Wieand HS, Cullinan SA, Everson LK, Krook JE, Mailliard JA, Laurie JA, Tschetter LK, Wiesenfeld M. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol. 1989 Oct;7(10):1407-18. [https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.10.1407 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2476530 PubMed]
+===Regimen {{#subobject:8cug1c|Variant=1}}===
-##'''Update:''' Poon MA, O'Connell MJ, Wieand HS, Krook JE, Gerstner JB, Tschetter LK, Levitt R, Kardinal CG, Mailliard JA. Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol. 1991 Nov;9(11):1967-72. [https://ascopubs.org/doi/abs/10.1200/JCO.1991.9.11.1967 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1941055 PubMed]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-#Petrelli N, Douglass HO Jr, Herrera L, Russell D, Stablein DM, Bruckner HW, Mayer RJ, Schinella R, Green MD, Muggia FM, Megibow A, Greenwald ES, Bukowski RM, Harris J, Levin B, Gaynor E, Loutfi A, Kaiser MH, Barkin JS, Benedetto P, Woolley PV, Nauta R, Weaver DW, Leichman LP; Gastrointestinal Tumor Study Group. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. J Clin Oncol. 1989 Oct;7(10):1419-26. Erratum in: J Clin Oncol 1990 Jan;8(1):185. [https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.10.1419 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2674331 PubMed]
+!style="width: 20%"|Study
-#Labianca R, Pancera G, Aitini E, Barni S, Beretta A, Beretta GD, Cesana B, Comella G, Cozzaglio L, Cristoni M, Spagnolli P, Frontini L, Gottardi O, Martignoni G, Scapaticci R, Smerieri F, Vinci M, Zadro A, Zaniboni A, Luporini G. Folinic acid + 5-fluorouracil (5-FU) versus equidose 5-FU in advanced colorectal cancer: phase III study of 'GISCAD' (Italian Group for the Study of Digestive Tract Cancer). Ann Oncol. 1991 Oct;2(9):673-9. [https://academic.oup.com/annonc/article-abstract/2/9/673/229114 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1742223 PubMed]
+!style="width: 20%"|Dates of enrollment
-#Buroker TR, O'Connell MJ, Wieand HS, Krook JE, Gerstner JB, Mailliard JA, Schaefer PL, Levitt R, Kardinal CG, Gesme DH Jr. Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol. 1994 Jan;12(1):14-20. [https://ascopubs.org/doi/abs/10.1200/JCO.1994.12.1.14 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7677801 PubMed]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-#'''Corfu-A:''' Man A, Levi J, Weinerman B, Kjaer M, Yap AKL; Corfu-A Study Group. Phase III randomized study of two fluorouracil combinations with either interferon alfa-2a or leucovorin for advanced colorectal cancer. J Clin Oncol. 1995 Apr;13(4):921-8. [https://ascopubs.org/doi/abs/10.1200/JCO.1995.13.4.921 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7707120 PubMed]
+!style="width: 20%"|Comparator
-#Jones DV Jr, Winn RJ, Brown BW, Levy LB, Pugh RP, Wade JL 3rd, Gross HM, Pendergrass KB, Levin B, Abbruzzese JL. Randomized phase III study of 5-fluorouracil plus high dose folinic acid versus 5-fluorouracil plus folinic acid plus methyl-lomustine for patients with advanced colorectal cancer. Cancer. 1995 Nov 15;76(10):1709-14. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19951115)76:10%3C1709::AID-CNCR2820761006%3E3.0.CO;2-5 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8625038 PubMed]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-#Heys SD, Eremin O, Ruggeri EM, Pein F, Rainer H, Oskam R, de Peuter RA, Palmer PA, Franks CR. A phase III study of recombinant interleukin-2, 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in patients with unresectable or metastatic colorectal carcinoma. Eur J Cancer. 1995;31A(1):19-25. [https://www.ejcancer.com/article/0959-8049(94)00360-H/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7695972 PubMed]
-#Jäger E, Heike M, Bernhard H, Klein O, Bernhard G, Lautz D, Michaelis J, Meyer zum Büschenfelde KH, Knuth Al; Study Group for Palliative Treatment of Metastatic Colorectal Cancer 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]
-#Kosmidis PA, Tsavaris N, Skarlos D, Theocharis D, Samantas E, Pavlidis N, Briassoulis E, Fountzilas G; Hellenic Cooperative Oncology Group. Fluorouracil and leucovorin with or without interferon alfa-2b in advanced colorectal cancer: analysis of a prospective randomized phase III trial. J Clin Oncol. 1996 Oct;14(10):2682-7. [https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.10.2682 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8874327 PubMed]
-#'''FFCD 9101:''' de Gramont A, Bosset JF, Milan C, Rougier P, Bouché O, Etienne PL, Morvan F, Louvet C, Guillot T, François E, Bedenne L. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol. 1997 Feb;15(2):808-15. [https://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]
-#Goldberg RM, Hatfield AK, Kahn M, Sargent DJ, Knost JA, O'Connell MJ, Krook JE, Maillard JA, Wiesenfeld M, Schaefer PL, Tirona MT, Moertel CG. Prospectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. J Clin Oncol. 1997 Nov;15(11):3320-9. [https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.11.3320 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9363861 PubMed]
-#Borner MM, Castiglione M, Bacchi M, Weber W, Herrmann R, Fey MF, Pagani O, Leyvraz S, Morant R, Pestalozzi B, Hanselmann S, Goldhirsch A; Swiss Group for Clinical Cancer Research (SAKK). The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: results of a phase III trial. Ann Oncol. 1998 May;9(5):535-41. [https://academic.oup.com/annonc/article/9/5/535/142141 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9653495 PubMed]
-#Aranda E, Díaz-Rubio E, Cervantes A, Antón-Torres A, Carrato A, Massutí T, Tabernero JM, Sastre J, Trés A, Aparicio J, López-Vega JM, Barneto I, García-Conde J. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol. 1998 Jul;9(7):727-31. [https://academic.oup.com/annonc/article/9/7/727/274760 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9739438 PubMed]
-#Hausmaninger H, Moser R, Samonigg H, Mlineritsch B, Schmidt H, Pecherstorfer M, Fridrik M, Kopf C, Nitsche D, Kaider A, Ludwig H. Biochemical modulation of 5-fluorouracil by leucovorin with or without interferon-alpha-2c in patients with advanced colorectal cancer: final results of a randomised phase III study. Eur J Cancer. 1999 Mar;35(3):380-5. [https://www.ejcancer.com/article/S0959-8049(98)00397-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10448286 PubMed]
-#Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet P, Llory JF, Letourneau Y, Coudert B, Bertheaut-Cvitkovic F, Larregain-Fournier D, Le Rol A, Walter S, Adam R, Misset JL, Lévi F. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2000 Jan;18(1):136-47. [https://ascopubs.org/doi/full/10.1200/JCO.2000.18.1.136 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10623704 PubMed]
-#Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext link to original article] '''contains verified protocol''' [https://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]
-#Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. [https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 link to original article] '''contains verified protocol''' [https://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]
-#Blanke CD, Shultz J, Cox J, Modiano M, Isaacs R, Kasimis B, Schilsky R, Fleagle J, Moore M, Kemeny N, Carlin D, Hammershaimb L, Haller D. A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer. Ann Oncol. 2002 Jan;13(1):87-91. [https://academic.oup.com/annonc/article/13/1/87/143714 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11863117 PubMed]
-#'''FUMA3008:''' Schilsky RL, Levin J, West WH, Wong A, Colwell B, Thirlwell MP, Ansari RH, Bell WN, White RL, Yates BB, McGuirt PV, Pazdur R. Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. J Clin Oncol. 2002 Mar 15;20(6):1519-26. [https://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. [https://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. [https://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]
-#'''EORTC 40952:''' Köhne CH, Wils J, Lorenz M, Schöffski P, Voigtmann R, Bokemeyer C, Lutz M, Kleeberg C, Ridwelski K, Souchon R, El-Serafi M, Weiss U, Burkhard O, Rückle H, Lichnitser M, Langenbuch T, Scheithauer W, Baron B, Couvreur ML, Schmoll HJ; European Organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952. Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952. J Clin Oncol. 2003 Oct 15;21(20):3721-8. Epub 2003 Sep 8. [https://ascopubs.org/doi/full/10.1200/JCO.2003.11.122 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12963704 PubMed]
-#Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003 Oct 15;21(20):3737-43. [https://ascopubs.org/doi/full/10.1200/JCO.2003.04.187 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14551293 PubMed]
-#Chong G, Bhatnagar A, Cunningham D, Cosgriff TM, Harper PG, Steward W, Bridgewater J, Moore M, Cassidy J, Coleman R, Coxon F, Redfern CH, Jones JJ, Hawkins R, Northfelt D, Sreedharan S, Valone F, Carmichael J. Phase III trial of 5-fluorouracil and leucovorin plus either 3H1 anti-idiotype monoclonal antibody or placebo in patients with advanced colorectal cancer. Ann Oncol. 2006 Mar;17(3):437-42. Epub 2005 Nov 25. [https://academic.oup.com/annonc/article/17/3/437/146088 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16311275 PubMed]
-#Hospers GA, Schaapveld M, Nortier JW, Wils J, van Bochove A, de Jong RS, Creemers GJ, Erjavec Z, de Gooyer DJ, Slee PH, Gerrits CJ, Smit JM, Mulder NH. Randomised Phase III study of biweekly 24-h infusion of high-dose 5FU with folinic acid and oxaliplatin versus monthly plus 5-FU/folinic acid in first-line treatment of advanced colorectal cancer. Ann Oncol. 2006 Mar;17(3):443-9. [https://academic.oup.com/annonc/article/17/3/443/146259 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16500914 PubMed]
-#'''FFCD 9601:''' Ducreux M, Bouche O, Pignon JP, Mousseau M, Raoul JL, Cassan P, Leduc B, Berger C, Dunant A, Fournet J, Bedenne L; FFCD 9601 Collaborative Group. Randomised trial comparing three different schedules of infusional 5FU and raltitrexed alone as first-line therapy in metastatic colorectal cancer: final results of the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 trial. Oncology. 2006;70(3):222-30. Epub 2006 Jun 30. [https://www.karger.com/Article/Abstract/94357 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16816536 PubMed]
-#'''MRC FOCUS:''' Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, Smith DB, Shepherd S, Maraveyas A, Ferry DR, Meade AM, Thompson L, Griffiths GO, Parmar MK, Stephens RJ; FOCUS Trial Investigators; National Cancer Research Institute Colorectal Clinical Studies Group. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007 Jul 14;370(9582):143-52. Erratum in: Lancet. 2007 Aug 18;370(9587):566. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61087-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17630037 PubMed]
-#Gamelin E, Delva R, Jacob J, Merrouche Y, Raoul JL, Pezet D, Dorval E, Piot G, Morel A, Boisdron-Celle M. Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer. J Clin Oncol. 2008 May 1;26(13):2099-105. Erratum in: J Clin Oncol. 2013 Oct 1;31(28):3612. [https://ascopubs.org/doi/full/10.1200/JCO.2007.13.3934 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18445839 PubMed]
-#Cunningham D, Sirohi B, Pluzanska A, Utracka-Hutka B, Zaluski J, Glynne-Jones R, Koralewski P, Bridgewater J, Mainwaring P, Wasan H, Wang JY, Szczylik C, Clingan P, Chan RT, Tabah-Fisch I, Cassidy J. Two different first-line 5-fluorouracil regimens with or without oxaliplatin in patients with metastatic colorectal cancer. Ann Oncol. 2009 Feb;20(2):244-50. Epub 2008 Oct 14. [https://academic.oup.com/annonc/article/20/2/244/165904 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18854549 PubMed]
-#'''MRC FOCUS2:''' Seymour MT, Thompson LC, Wasan HS, Middleton G, Brewster AE, Shepherd SF, O'Mahony MS, Maughan TS, Parmar M, Langley RE; FOCUS2 Investigators; National Cancer Research Institute Colorectal Cancer Clinical Studies Group. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. Lancet. 2011 May 21;377(9779):1749-59. Epub 2011 May 11. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60399-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109515/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21570111 PubMed]
-#'''FFCD 2000-05:''' Ducreux M, Malka D, Mendiboure J, Etienne PL, Texereau P, Auby D, Rougier P, Gasmi M, Castaing M, Abbas M, Michel P, Gargot D, Azzedine A, Lombard-Bohas C, Geoffroy P, Denis B, Pignon JP, Bedenne L, Bouché O; Fédération Francophone de Cancérologie Digestive (FFCD) 2000–05 Collaborative Group. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol. 2011 Oct;12(11):1032-44. Epub 2011 Sep 6. [https://www.thelancet.com/journals/lancetonc/article/PIIS1470204511701991/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21903473 PubMed]
-#'''FFCD 2001-02:''' Aparicio T, Lavau-Denes S, Phelip JM, Maillard E, Jouve JL, Gargot D, Gasmi M, Locher C, Adhoute X, Michel P, Khemissa F, Lecomte T, Provençal J, Breysacher G, Legoux JL, Lepère C, Charneau J, Cretin J, Chone L, Azzedine A, Bouché O, Sobhani I, Bedenne L, Mitry E; FFCD investigators. Randomized phase III trial in elderly patients comparing LV5FU2 with or without irinotecan for first-line treatment of metastatic colorectal cancer (FFCD 2001-02). Ann Oncol. 2016 Jan;27(1):121-7. Epub 2015 Oct 20. [https://academic.oup.com/annonc/article/27/1/121/2196319 link to original article] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/26487578 PubMed]
-==Fluorouracil & Levoleucovorin {{#subobject:e9bgg2|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143094/ Yoshida et al. 2014 (ACTS-CC)]
-|}
+|2008-04 to 2009-06
-===Variant #1, 1870/50 {{#subobject:138u06|Variant=1}}===
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-{| class="wikitable" style="width: 100%; text-align:center;"
+|[[#Tegafur.2C_Uracil.2C_Folinic_acid|UFT + LV]]
-! style="width: 25%" |Study
+| 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%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/8/2/169/214080 Labianca et al. 1997]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Fluorouracil_.26_Levoleucovorin_2|FULV]]; HDLV
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 370 mg/m<sup>2</sup> IV over 15 minutes once per day on days 1 to 5
-*[[Levoleucovorin (Fusilev)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 5
-'''28-day cycles'''
-===Variant #2, 1875/500 {{#subobject:13cd06|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819990201%2985%3A3%3C535%3A%3AAID-CNCR4%3E3.0.CO%3B2-7 Colucci et al. 1999]
-| style="background-color:#1a9851" |Phase III (C)
-|5-FU, LV, IFN alfa-2b
-| style="background-color:#ffffbf" |Did not meet primary efficacy endpoints
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 375 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second'''
-*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given first'''
-'''21-day cycles'''
-===Variant #3, 2800/350 ("modified de Gramont regimen") {{#subobject:a9juza|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376131/ Cheeseman et al. 2002]
-| style="background-color:#91cf61" |Non-randomized
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61087-3/fulltext Seymour et al. 2007 (MRC FOCUS)]
-| style="background-color:#1a9851" |Phase III (C)
-|-
-|}
-''Note: it is not completely clear from the abstract whether this was the protocol used in MRC FOCUS, although it is alluded to in the Cheeseman et al. 2002 publication. Also, efficacy results for MRC FOCUS are complex and will be added in the future (to be completed).''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>), '''given second'''
-*[[Levoleucovorin (Fusilev)]] 175 mg IV over 2 hours once on day 1, '''given first'''
-====Supportive medications====
-*No routine prophylactic [[:Category:Emesis_prevention|antiemetics]] and [[:Category:Anti-diarrheals|antidiarrheal]] medications were used, but patients could use [[Metoclopramide (Reglan)]] prn nausea and [[Loperamide (Imodium)]] prn diarrhea.
-'''14-day cycles'''
-===References===
-#Labianca R, Cascinu S, Frontini L, Barni S, Fiorentini G, Comella G, Zaniboni A, Gottardi O, Arnoldi E, Oliani C, Duro M, Pavanato G, Martignoni G, Raina A, Piazza E, Dallavalle G, Valsecchi R, Pancera G, Luporini G; Italian Group for the Study of Digestive Tract Cancer. High-versus low-dose levo-leucovorin as a modulator of 5-fluorouracil in advanced colorectal cancer: a 'GISCAD' phase III study. Ann Oncol. 1997 Feb;8(2):169-74. [https://academic.oup.com/annonc/article/8/2/169/214080 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9093726 PubMed]
-#Colucci G, Maiello E, Gebbia V, Giuliani F, Serravezza G, Lelli G, Leo S, Filippelli G, Nicolella G, Brandi M. 5-fluorouracil and levofolinic acid with or without recombinant interferon-2b in patients with advanced colorectal carcinoma: a randomized multicenter study with stratification for tumor burden and liver involvement by the Southern Italy Oncology Group. Cancer. 1999 Feb 1;85(3):535-45. [https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819990201%2985%3A3%3C535%3A%3AAID-CNCR4%3E3.0.CO%3B2-7 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10091727 PubMed]
-#Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12;87(4):393-9. [https://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]
-#'''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]
-==FOLFIRI {{#subobject:ebcf30|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
-<br>FUFIRI: 5-'''<u>FU</u>''' (Fluorouracil), '''<u>F</u>'''olinic acid, '''<u>IRI</u>'''notecan
-===Example orders===
-*[[Example orders for FOLFIRI in colon cancer]]
-===Variant #1, 400/2000/180, bi-weekly ("Lv5FU2-Iri") {{#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#Comparative_efficacy|Comparative 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-RT-esc)
-|[[#Fluorouracil_.26_Folinic_acid_3|5-FU & LV]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361370/ Souglakos et al. 2006]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFIRINOX|FOLFOXIRI]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://academic.oup.com/annonc/article/19/5/920/167346 Köhne et al. 2007 (EORTC 40015)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#CAPIRI|CAPIRI]]
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
-|-
-|[https://academic.oup.com/annonc/article/19/5/909/168102 Glimelius et al. 2008]
-| style="background-color:#1a9851" |Phase III (C)
-|FLIRI
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|[https://academic.oup.com/annonc/article/20/2/251/164564 Aranda et al. 2008]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FUIRI|FUIRI]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR (*)
-|-
-|[https://academic.oup.com/annonc/article/26/6/1201/161806 Passardi et al. 2015 (ITACa)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-''Note: EORTC 40015 was closed prematurely. Aranda et al. 2008 is described by the authors as a non-inferiority trial but the statistics used are superiority-based.''
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 120 minutes once per day on days 1 & 2, '''given second'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given third''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first'''
-'''14-day cycles'''
-===Variant #2, 400/2800/180 {{#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#Comparative_efficacy|Comparative 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-switch-ic)
-|1. [[#CAPIRI|CapeIRI]]
-| style="background-color:#91cf60" |Seems to have superior PFS
-|-
-|2. [[#IFL|mIFL]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa0805019 Van Cutsem et al. 2009 (CRYSTAL)]
-| 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 first, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first, with leucovorin'''
-'''14-day cycles'''
-===Variant #3, 500/2000/80, 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2005.05.546 Köhne et al. 2005 (EORTC 40986)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Fluorouracil_.26_Folinic_acid_3|5-FU & LV]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|[https://www.sciencedirect.com/science/article/pii/S0959804910009068 Fischer von Weikersthal et al. 2011]
-| style="background-color:#1a9851" |Phase III (C)
-|mIROX
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
-*[[Fluorouracil (5-FU)]] 2000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36
-*[[Irinotecan (Camptosar)]] 80 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36
-'''7-week cycles'''
-===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#Comparative_efficacy|Comparative 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-RT-esc)
-|[[#Fluorouracil_.26_Folinic_acid_3|5-FU & LV]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[https://academic.oup.com/annonc/article/26/6/1201/161806 Passardi et al. 2015 (ITACa)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 500 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 2300 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
-*[[Irinotecan (Camptosar)]] 80 mg/m<sup>2</sup> IV once on day 1
-'''7-day cycles'''
-===References===
-#Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2902034-1/fulltext link to original article] '''contains verified protocol''' [https://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. [https://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]
-#Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, Kakolyris S, Tsousis S, Kouroussis Ch, Vamvakas L, Kalykaki A, Samonis G, Mavroudis D, Georgoulias V. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-805. [https://www.nature.com/articles/6603011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361370/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16508637 PubMed]
-<!-- Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006, and at the American Society of Clinical Oncology 2006 Gastrointestinal Cancers Symposium, San Francisco, CA, January 24-27, 2006. -->
-#Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6. [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]
-#'''EORTC 40015:''' Köhne CH, De Greve J, Hartmann JT, Lang I, Vergauwe P, Becker K, Braumann D, Joosens E, Müller L, Janssens J, Bokemeyer C, Reimer P, Link H, Späth-Schwalbe E, Wilke HJ, Bleiberg H, Van Den Brande J, Debois M, Bethe U, Van Cutsem E. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer: EORTC study 40015. Ann Oncol. 2008 May;19(5):920-6. Epub 2007 Dec 6. [https://academic.oup.com/annonc/article/19/5/920/167346 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18065406 PubMed]
-#Glimelius B, Sørbye H, Balteskard L, Byström P, Pfeiffer P, Tveit K, Heikkilä R, Keldsen N, Albertsson M, Starkhammar H, Garmo H, Berglund A. A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer. Ann Oncol. 2008 May;19(5):909-14. Epub 2008 Jan 21. [https://academic.oup.com/annonc/article/19/5/909/168102 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18209013 PubMed]
-#Aranda E, Valladares M, Martinez-Villacampa M, Benavides M, Gomez A, Massutti B, Marcuello E, Constenla M, Cámara JC, Carrato A, Dueñas R, Reboredo M, Navarro M, Díaz-Rubio E. Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study. Ann Oncol. 2009 Feb;20(2):251-7. Epub 2008 Aug 20. [https://academic.oup.com/annonc/article/20/2/251/164564 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18718892 PubMed]
-#'''CRYSTAL:''' Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. [https://www.nejm.org/doi/full/10.1056/NEJMoa0805019 link to original article] '''contains verified protocol''' [https://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, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://www.ejcancer.com/article/S0959-8049(12)00209-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22446022 PubMed]
-##'''Biomarker analysis:''' Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. [https://ascopubs.org/doi/full/10.1200/JCO.2014.59.4812 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25605843 PubMed]
-#Fischer von Weikersthal L, Schalhorn A, Stauch M, Quietzsch D, Maubach PA, Lambertz H, Oruzio D, Schlag R, Weigang-Köhler K, Vehling-Kaiser U, Schulze M, Truckenbrodt J, Goebeler M, Mittermüller J, Bosse D, Szukics B, Grundeis M, Zwingers T, Giessen C, Heinemann V. Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer. Eur J Cancer. 2011 Jan;47(2):206-14. [https://www.sciencedirect.com/science/article/pii/S0959804910009068 link to SD article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20971632 PubMed]
-#'''ITACa:''' Passardi A, Nanni O, Tassinari D, Turci D, Cavanna L, Fontana A, Ruscelli S, Mucciarini C, Lorusso V, Ragazzini A, Frassineti GL, Amadori D. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015 Jun;26(6):1201-7. Epub 2015 Mar 3. [https://academic.oup.com/annonc/article/26/6/1201/161806 link to original article] '''refers to Douillard et al. 2000''' [https://www.ncbi.nlm.nih.gov/pubmed/25735317 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 (L-Leucovorin) {{#subobject:e98yb0|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
-===Variant #1, 200/2000/150 {{#subobject:ad9b82|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2005.07.113 Colucci et al. 2005 (GOIM 9901)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFOX4_3|FOLFOX4]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|}
-''Note: this variant was intended for patients between 70 to 75 years old.''
-====Chemotherapy====
-*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given second'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given third''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given first'''
-'''14-day cycles'''
-===Variant #2, 200/2000/180 {{#subobject:87b4fe|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2005.07.113 Colucci et al. 2005 (GOIM 9901)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFOX4_3|FOLFOX4]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|[https://academic.oup.com/annonc/article/22/5/1236/178870 Labianca et al. 2010]
-| style="background-color:#1a9851" |Phase III (C)
-|Intermittent FOLFIRI
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Chemotherapy====
-*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given second'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given third''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given first'''
-'''14-day cycles'''
-===Variant #3, 200/2800/180 {{#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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://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://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" |Did not meet primary endpoint of PFS
-|-
-|}
-''Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.''
-====Chemotherapy====
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1, '''given first, with levoleucovorin'''
-'''14-day cycles'''
-===References===
-#'''GOIM 9901:''' Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N, Cartenì G, Agostara B, Pezzella G, Manzione L, Borsellino N, Misino A, Romito S, Durini E, Cordio S, Di Seri M, Lopez M, Maiello E, Montemurro S, Cramarossa A, Lorusso V, Di Bisceglie M, Chiarenza M, Valerio MR, Guida T, Leonardi V, Pisconti S, Rosati G, Carrozza F, Nettis G, Valdesi M, Filippelli G, Fortunato S, Mancarella S, Brunetti C; Gruppo Oncologico Dell'Italia Meridionale. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol. 2005 Aug 1;23(22):4866-75. Epub 2005 Jun 6. [https://ascopubs.org/doi/full/10.1200/JCO.2005.07.113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15939922 PubMed]
-#'''CRYSTAL:''' Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. [https://www.nejm.org/doi/full/10.1056/NEJMoa0805019 link to original article] '''contains verified protocol''' [https://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, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://www.ejcancer.com/article/S0959-8049(12)00209-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22446022 PubMed]
-##'''Biomarker analysis:''' Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. [https://ascopubs.org/doi/full/10.1200/JCO.2014.59.4812 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25605843 PubMed]
-#Labianca R, Sobrero A, Isa L, Cortesi E, Barni S, Nicolella D, Aglietta M, Lonardi S, Corsi D, Turci D, Beretta GD, Fornarini G, Dapretto E, Floriani I, Zaniboni A; Italian Group for the Study of Gastrointestinal Cancer-GISCAD. Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised 'GISCAD' trial. Ann Oncol. 2011 May;22(5):1236-42. Epub 2010 Nov 15. [https://academic.oup.com/annonc/article/22/5/1236/178870 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21078826 PubMed]
-#'''SUN 1122:''' Carrato A, Swieboda-Sadlej A, Staszewska-Skurczynska M, Lim R, Roman L, Shparyk Y, Bondarenko I, Jonker DJ, Sun Y, De la Cruz JA, Williams JA, Korytowsky B, Christensen JG, Lin X, Tursi JM, Lechuga MJ, Van Cutsem E. Fluorouracil, leucovorin, and irinotecan plus either sunitinib or placebo in metastatic colorectal cancer: a randomized, phase III trial. J Clin Oncol. 2013 Apr 1;31(10):1341-7. Epub 2013 Jan 28. [https://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]
-==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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/25/30/4779.long Fuchs et al. 2007 (BICC-C)]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#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-switch-ic)
-|[[#mFOLFOX6_.26_Bevacizumab|mFOLFOX6 & Bevacizumab]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first, with leucovorin'''
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given second'''
-'''14-day cycles'''
-===Variant #2, lower dose leucovorin {{#subobject:1bfcd9|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://academic.oup.com/annonc/article/24/9/2335/202863 Johnsson et al. 2013 (Nordic ACT)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====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 44 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 120 minutes once on day 1
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1
-'''14-day cycle for 9 cycles'''
-====Subsequent treatment====
-*Nordic ACT: [[#Bevacizumab_monotherapy|Bevacizumab]] versus Erlotinib & Bevacizumab maintenance
-===References===
-<!-- Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA. -->
-#'''BICC-C:''' Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. [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]
-#'''Nordic ACT:''' Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. [https://academic.oup.com/annonc/article/24/9/2335/202863 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23788755 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]
-==FOLFIRI & Bevacizumab (L-Leucovorin) {{#subobject:92d6b8|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI & Bevacizumab: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Bevacizumab
-===Regimen {{#subobject:58ae38|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://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 (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===
-<!-- # Fotios Loupakis, Chiara Cremolini, Gianluca Masi, Sara Lonardi, Vittorina Zagonel, Patrizia Trenta, Gianluca Tomasello, Monica Ronzoni, Libero Ciuffreda, Alberto Zaniboni, Giuseppe Tonini, Angela Buonadonna, Chiara Valsuani, Silvana Chiara, Chiara Carlomagno, Corrado Boni, Lorenzo Marcucci, Luca Boni, Alfredo Falcone. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (MCRC): Results of the phase III randomized TRIBE trial. 2013 ASCO Gastrointestinal Cancers Symposium abstract 336. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=105744 link to abstract] [http://meetinglibrary.asco.org/presentationBySession/5250/1300 link to video presentation] -->
-#'''TRIBE:''' Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014 Oct 23;371(17):1609-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1403108 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1403108/suppl_file/nejmoa1403108_protocol.pdf link to protocol in supplementary material] '''contains verified protocol''' [https://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]
-==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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361370/ Souglakos et al. 2006]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[http://jco.ascopubs.org/content/25/13/1670.long Falcone et al. 2007]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-''Note: In contrast to Falcone et al. 2007, some guidelines list the dose of folinic acid as 400 mg/m<sup>2</sup> IV on day 1. No primary reference could be found for this.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 1600 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 3200 mg/m<sup>2</sup>)
-*[[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===
-#Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, Kakolyris S, Tsousis S, Kouroussis Ch, Vamvakas L, Kalykaki A, Samonis G, Mavroudis D, Georgoulias V. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-805. [https://www.nature.com/articles/6603011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361370/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16508637 PubMed]
-<!-- Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006, and at the American Society of Clinical Oncology 2006 Gastrointestinal Cancers Symposium, San Francisco, CA, January 24-27, 2006. -->
-#Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6. [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 (L-Leucovorin) {{#subobject:9bf7|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRINOX & Bevacizumab: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin, Bevacizumab
-<br>FOLFOXIRI & Bevacizumab: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>IRI</u>'''notecan, Bevacizumab
-===Regimen {{#subobject:19365|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1403108 Loupakis et al. 2014 (TRIBE)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#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, started on day 1, '''given fourth''' (total dose per cycle: 3200 mg/m<sup>2</sup>)
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given third, with oxaliplatin'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given third, with levoleucovorin'''
-*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given second'''
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV over 30 minutes once on day 1, '''given first'''
-'''14-day cycle for up to 12 cycles'''
-====Subsequent treatment====
-*Fluorouracil, leucovorin, bevacizumab maintenance (specific details not provided)
-===References===
-<!-- # Fotios Loupakis, Chiara Cremolini, Gianluca Masi, Sara Lonardi, Vittorina Zagonel, Patrizia Trenta, Gianluca Tomasello, Monica Ronzoni, Libero Ciuffreda, Alberto Zaniboni, Giuseppe Tonini, Angela Buonadonna, Chiara Valsuani, Silvana Chiara, Chiara Carlomagno, Corrado Boni, Lorenzo Marcucci, Luca Boni, Alfredo Falcone. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (MCRC): Results of the phase III randomized TRIBE trial. 2013 ASCO Gastrointestinal Cancers Symposium abstract 336. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=133&abstractID=105744 link to abstract] [http://meetinglibrary.asco.org/presentationBySession/5250/1300 link to video presentation] -->
-#'''TRIBE:''' Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014 Oct 23;371(17):1609-18. [https://www.nejm.org/doi/full/10.1056/NEJMoa1403108 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1403108/suppl_file/nejmoa1403108_protocol.pdf link to protocol in supplementary material] '''contains verified protocol''' [https://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]
-==FOLFOX2 {{#subobject:429ff9|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX2: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:d356da|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2006.06.1440 Giacchetti et al. 2006]
-| style="background-color:#1a9851" |Phase III (C)
-|chronoFLO4
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 600 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
-*[[Fluorouracil (5-FU)]] 1500 mg/m<sup>2</sup> IV continuous infusion over 22 hours once per day, started on days 1 & 2, '''given second''' (total dose per cycle: 3000 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''14-day cycles'''
-===References===
-#Giacchetti S, Bjarnason G, Garufi C, Genet D, Iacobelli S, Tampellini M, Smaaland R, Focan C, Coudert B, Humblet Y, Canon JL, Adenis A, Lo Re G, Carvalho C, Schueller J, Anciaux N, Lentz MA, Baron B, Gorlia T, Lévi F; European Organisation for Research and Treatment of Cancer Chronotherapy Group. Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group. J Clin Oncol. 2006 Aug 1;24(22):3562-9. [https://ascopubs.org/doi/full/10.1200/JCO.2006.06.1440 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16877722 PubMed]
-==FOLFOX4 {{#subobject:7239a0|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:ab483a|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/18/16/2938.long de Gramont et al. 2000]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Fluorouracil_.26_Folinic_acid_3|5-FU & Folinic acid]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/JCO.2004.09.046 Goldberg et al. 2003 (NCCTG N9741)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
-|1. [[#IFL|IFL]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|2. [[#IROX|IROX]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
-|-
-|[http://jco.ascopubs.org/content/24/3/394.long Tournigand et al. 2006 (OPTIMOX1)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFOX_7_.26_sLV5FU2|FOLFOX7/LV5FU2]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DDC
-|-
-| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 Cassidy et al. 2008 (NO16966)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-|2. [[#CapeOx_2|XELOX]]<br> 3. [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-| rowspan="2" |[http://jco.ascopubs.org/content/26/12/2013.long Saltz et al. 2008 (NO16966)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]<br> 2. [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|3. [[#CapeOx_2|XELOX]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2008.20.8397 Bokemeyer et al. 2008 (OPUS)]
-| style="background-color:#1a9851" |Randomized Phase II (C)
-|[[Colon_cancer,_KRAS_wild-type#FOLFOX4_.26_Cetuximab|FOLFOX4 & Cetuximab]]
-| style="background-color:#d73027" |Inferior OS (*)
-|-
-|[http://jco.ascopubs.org/content/28/31/4697.long Douillard et al. 2010 (PRIME)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[Colon_cancer,_KRAS_wild-type#FOLFOX4_.26_Panitumumab|FOLFOX4 & Panitumumab]]
-| style="background-color:#91cf60" |Seems to have superior PFS (*)
-|-
-|[https://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" |Did not meet primary endpoint of PFS
-|-
-|[http://jco.ascopubs.org/content/30/29/3596.long Hoff et al. 2012 (HORIZON II)]
-| style="background-color:#1a9851" |Phase III (C)
-|1. CAPOX & Cediranib<br> 2. FOLFOX4 & Cediranib<br> 3. mFOLFOX6 & Cediranib
-| style="background-color:#fc8d59" |Seems to have inferior PFS
-|-
-|[https://academic.oup.com/annonc/article/26/6/1201/161806 Passardi et al. 2015 (ITACa)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-''Note: in PRIME, patients with KRAS wild-type tumors receiving this regimen seem to have inferior OS, based on the 2014 update. Conversely, in KRAS mutants, this regimen seems to have superior PFS. Reported efficacy for OPUS is based on the 2012 pooled update and is only for KRAS wild-type tumors.''
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''14-day cycles'''
-===References===
-#de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. [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]
-#'''NCCTG N9741:''' Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. Epub 2003 Dec 9. [https://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. [https://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. [https://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]
-##'''Update:''' Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011 Jul;22(7):1535-46. Epub 2011 Jan 12. [https://academic.oup.com/annonc/article/22/7/1535/187254 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21228335 PubMed]
-##'''Pooled Update:''' Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://www.ejcancer.com/article/S0959-8049(12)00209-2/fulltext link to original article] [https://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]
-##'''Biomarker analysis:''' Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013 Sep 12;369(11):1023-34. [https://www.nejm.org/doi/full/10.1056/NEJMoa1305275 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24024839 PubMed]
-##'''Update:''' Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jul;25(7):1346-55. Epub 2014 Apr 8. [https://academic.oup.com/annonc/article/25/7/1346/2801199 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24718886 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. [https://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]
-#'''ITACa:''' Passardi A, Nanni O, Tassinari D, Turci D, Cavanna L, Fontana A, Ruscelli S, Mucciarini C, Lorusso V, Ragazzini A, Frassineti GL, Amadori D. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015 Jun;26(6):1201-7. Epub 2015 Mar 3. [https://academic.oup.com/annonc/article/26/6/1201/161806 link to original article] '''refers to de Gramont et al. 2000''' [https://www.ncbi.nlm.nih.gov/pubmed/25735317 PubMed]
-==FOLFOX4 (L-Leucovorin) {{#subobject:73uba0|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX4: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:0af678|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2005.07.113 Colucci et al. 2005 (GOIM 9901)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|[https://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" |Did not meet primary endpoint of PFS
-|-
-|[https://insights.ovid.com/pubmed?pmid=24316553 Correale et al. 2014 (GOLFIG-2)]
-| style="background-color:#1a9851" |Phase III (C)
-|GOLFIG
-| style="background-color:#d73027" |Inferior PFS
-|-
-|}
-====Chemotherapy====
-*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with leucovorin'''
-'''14-day cycles'''
-===References===
-#'''GOIM 9901:''' Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N, Cartenì G, Agostara B, Pezzella G, Manzione L, Borsellino N, Misino A, Romito S, Durini E, Cordio S, Di Seri M, Lopez M, Maiello E, Montemurro S, Cramarossa A, Lorusso V, Di Bisceglie M, Chiarenza M, Valerio MR, Guida T, Leonardi V, Pisconti S, Rosati G, Carrozza F, Nettis G, Valdesi M, Filippelli G, Fortunato S, Mancarella S, Brunetti C; Gruppo Oncologico Dell'Italia Meridionale. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol. 2005 Aug 1;23(22):4866-75. Epub 2005 Jun 6. [https://ascopubs.org/doi/full/10.1200/JCO.2005.07.113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15939922 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. [https://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]
-#'''GOLFIG-2:''' Correale P, Botta C, Rotundo MS, Guglielmo A, Conca R, Licchetta A, Pastina P, Bestoso E, Ciliberto D, Cusi MG, Fioravanti A, Guidelli GM, Bianco MT, Misso G, Martino E, Caraglia M, Tassone P, Mini E, Mantovani G, Ridolfi R, Pirtoli L, Tagliaferri P. Gemcitabine, oxaliplatin, levofolinate, 5-fluorouracil, granulocyte-macrophage colony-stimulating factor, and interleukin-2 (GOLFIG) versus FOLFOX chemotherapy in metastatic colorectal cancer patients: the GOLFIG-2 multicentric open-label randomized phase III trial. J Immunother. 2014 Jan;37(1):26-35. [https://insights.ovid.com/pubmed?pmid=24316553 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24316553 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2015.66.1181 van Hazel et al. 2016 (SIRFLOX)]
-| style="background-color:#1a9851" |Phase III (C)
-|mFOLFOX6 plus SIRT
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS (*)
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext Wasan et al. 2017 (FOXFIRE-Global)]
-| style="background-color:#1a9851" |Phase III (C)
-|mFOLFOX6 plus SIRT
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-''Note: Wasan et al. 2017, which is an update for SIRFLOX and the first publication for FOXFIRE-Global, describes the folinic acid as a flat 200 mg dose; van Hazel et al. 2016 reports 200 mg/m<sup>2</sup>; the authors were contacted for clarification.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 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#Comparative_efficacy|Comparative 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" |[https://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-switch-ic)
-|1. bFOL
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints
-|-
-|2. [[#CapeOx_2|CapeOx]]
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159415/ Maughan et al. 2011 (UK MRC COIN)]
-| style="background-color:#1a9851" |Phase III (C)
-|mFOLFOX6 & Cetuximab
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)
-|-
-|[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" |Did not meet primary endpoint of OS
-|-
-|}
-''Note: TREE-1 did not have any primary endpoints. Efficacy for UK MRC COIN is as reported for KRAS wild-type patients.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 350 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
-'''14-day cycles'''
-===Variant #3, LCV 400 mg/m<sup>2</sup> {{#subobject:db877a|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/30/29/3596.long Hoff et al. 2012 (HORIZON II)]
-| style="background-color:#1a9851" |Phase III (C)
-|1. CAPOX & Cediranib<br> 2. FOLFOX4 & Cediranib<br> 3. mFOLFOX6 & Cediranib
-| style="background-color:#fc8d59" |Seems to have inferior PFS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''14-day cycles'''
-===References===
-#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]
-#'''TREE-1:''' Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. [https://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]
-#'''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]
-##'''Update:''' Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, Kenny SL, Kay E, Hodgkinson E, Pope M, Rogers P, Wasan H, Falk S, Gollins S, Hickish T, Bessell EM, Propper D, Kennedy MJ, Kaplan R, Maughan TS; MRC COIN Trial Investigators. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011 Jul;12(7):642-53. Epub 2011 Jun 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70102-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159416/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21641867 PubMed]
-#'''HORIZON II:''' Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. [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]
-#'''SIRFLOX:''' van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M, Perez D, Robinson BA, Strickland AH, Ferguson T, Rodríguez J, Kröning H, Wolf I, Ganju V, Walpole E, Boucher E, Tichler T, Shacham-Shmueli E, Powell A, Eliadis P, Isaacs R, Price D, Moeslein F, Taieb J, Bower G, Gebski V, Van Buskirk M, Cade DN, Thurston K, Gibbs P. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2016 May 20;34(15):1723-31. Epub 2016 Feb 22. [https://ascopubs.org/doi/full/10.1200/JCO.2015.66.1181 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26903575 PubMed]
-##'''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]
-#'''FOXFIRE; FOXFIRE-Global:''' Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A, van Hazel G, Sharma RA; FOXFIRE/SIRFLOX/FOXFIRE-Global trial investigators. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. Epub 2017 Aug 3. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28781171 PubMed]
-==mFOLFOX6 (L-Leucovorin) {{#subobject:e46gn7|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:8c4386|Variant=1}}===
-{| class="wikitable" 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#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" |Did not meet primary endpoint of OS (*)
-|-
-|[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" |Did not meet primary endpoint of OS
-|-
-|}
-''Note: Efficacy for UK MRC COIN is as reported for KRAS wild-type patients.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Levoleucovorin (Fusilev)]] 175 mg IV over 2 hours once on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''14-day cycles'''
-===References===
-#'''UK MRC COIN:''' Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP; MRC COIN Trial Investigators. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011 Jun 18;377(9783):2103-14. Epub 2011 Jun 5. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60613-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159415/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21641636 PubMed]
-##'''Update:''' Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, Kenny SL, Kay E, Hodgkinson E, Pope M, Rogers P, Wasan H, Falk S, Gollins S, Hickish T, Bessell EM, Propper D, Kennedy MJ, Kaplan R, Maughan TS; MRC COIN Trial Investigators. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011 Jul;12(7):642-53. Epub 2011 Jun 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70102-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159416/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21641867 PubMed]
-#'''FOXFIRE; FOXFIRE-Global:''' Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A, van Hazel G, Sharma RA; FOXFIRE/SIRFLOX/FOXFIRE-Global trial investigators. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. Epub 2017 Aug 3. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext link to original article] '''contains verified protocol''' [https://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]]
-|}
-FOLFOX 7/sLV5FU2: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin alternating with '''<u>s</u>'''implified '''<u>L</u>'''euco'''<u>V</u>'''orin, '''<u>5-FU</u>''', '''<u>2</u>'''-weekly (every 2 weeks)
-===Regimen {{#subobject:b39a65|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/24/3/394.long Tournigand et al. 2006 (OPTIMOX1)]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FOLFOX4_2|FOLFOX4]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DDC
-|-
-|}
-''Note: this regimen has an unusual alternating schedule; see paper for more details.''
-====Chemotherapy, FOLFOX 7 portion====
-*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, started on day 1, '''given third'''
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
-'''14-day cycle for up to 6 cycles, then proceed to sLV5FU2:'''
-====Chemotherapy, sLV5FU2 portion====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1500 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 3000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''14-day cycle for up to 12 cycles, then resume FOLFOX 7 for 6 additional cycles as described above'''
-===References===
-#'''OPTIMOX1:''' Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, Mineur L, Carola E, Etienne PL, Rivera F, Chirivella I, Perez-Staub N, Louvet C, André T, Tabah-Fisch I, de Gramont A. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006 Jan 20;24(3):394-400. [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]
-==FOLFOX 7/sLV5FU2 (L-Leucovorin) {{#subobject:66b3db|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX 7/sLV5FU2: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin alternating with '''<u>s</u>'''implified L-'''<u>L</u>'''euco'''<u>V</u>'''orin, '''<u>5-FU</u>''', '''<u>2</u>'''-weekly (every 2 weeks)
-===Regimen {{#subobject:b39a65|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/24/3/394.long Tournigand et al. 2006 (OPTIMOX1)]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FOLFOX4_2|FOLFOX4]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DDC
-|-
-|}
-''Note: this regimen has an unusual alternating schedule; see paper for more details.''
-====Chemotherapy, FOLFOX 7 portion====
-*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, started on day 1, '''given third'''
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
-'''14-day cycle for up to 6 cycles, then proceed to sLV5FU2:'''
-====Chemotherapy, sLV5FU2 portion====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1500 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 3000 mg/m<sup>2</sup>)
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''14-day cycle for up to 12 cycles, then resume FOLFOX 7 for 6 additional cycles as described above'''
-===References===
-#'''OPTIMOX1:''' Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, Mineur L, Carola E, Etienne PL, Rivera F, Chirivella I, Perez-Staub N, Louvet C, André T, Tabah-Fisch I, de Gramont A. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006 Jan 20;24(3):394-400. [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]
-==mFOLFOX7 {{#subobject:7ff5f5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX7: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:d39fe0|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2009.23.4344 Chibaudel et al. 2009 (OPTIMOX2)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Chemotherapy, FOLFOX 7 portion====
-*[[Fluorouracil (5-FU)]] 3000 mg/m<sup>2</sup> IV continuous infusion over 46 hours, started on day 1, '''given second'''
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
-*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with leucovorin'''
-'''14-day cycle for 6 cycles'''
-====Subsequent treatment====
-*sLV5FU2 versus no further treatment
-===References===
-#'''OPTIMOX2:''' Chibaudel B, Maindrault-Goebel F, Lledo G, Mineur L, André T, Bennamoun M, Mabro M, Artru P, Carola E, Flesch M, Dupuis O, Colin P, Larsen AK, Afchain P, Tournigand C, Louvet C, de Gramont A. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol. 2009 Dec 1;27(34):5727-33. Epub 2009 Sep 28. [https://ascopubs.org/doi/full/10.1200/JCO.2009.23.4344 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19786657 PubMed]
-==mFOLFOX7 (L-Leucovorin) {{#subobject:7f8nb5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX7: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:d39g0k|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2009.23.4344 Chibaudel et al. 2009 (OPTIMOX2)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Chemotherapy, FOLFOX 7 portion====
-*[[Fluorouracil (5-FU)]] 3000 mg/m<sup>2</sup> IV continuous infusion over 46 hours, started on day 1, '''given second'''
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with oxaliplatin'''
-*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with leucovorin'''
-'''14-day cycle for 6 cycles'''
-====Subsequent treatment====
-*sLV5FU2 versus no further treatment
-===References===
-#'''OPTIMOX2:''' Chibaudel B, Maindrault-Goebel F, Lledo G, Mineur L, André T, Bennamoun M, Mabro M, Artru P, Carola E, Flesch M, Dupuis O, Colin P, Larsen AK, Afchain P, Tournigand C, Louvet C, de Gramont A. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol. 2009 Dec 1;27(34):5727-33. Epub 2009 Sep 28. [https://ascopubs.org/doi/full/10.1200/JCO.2009.23.4344 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19786657 PubMed]
-==FOLFOX4 & Bevacizumab {{#subobject:e93745|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX4 & Bevacizumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-<br>FOLFOX-B: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-===Regimen {{#subobject:c7030b|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative 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" |[https://ascopubs.org/doi/full/10.1200/jco.2007.14.9898 Cassidy et al. 2008 (NO16966)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[#FOLFOX4_3|FOLFOX4]]<br> 2. [[#CapeOx_2|XELOX]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|3. [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given first'''
-**Infusion times are 2 hours for cycle 1, 1 hour for cycle 2, then 30 minutes for cycles 3 and later
-'''14-day cycles'''
-===References===
-#Emmanouilides C, Sfakiotaki G, Androulakis N, Kalbakis K, Christophylakis C, Kalykaki A, Vamvakas L, Kotsakis A, Agelaki S, Diamandidou E, Touroutoglou N, Chatzidakis A, Georgoulias V, Mavroudis D, Souglakos J. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. BMC Cancer. 2007 May 30;7:91. [http://www.biomedcentral.com/1471-2407/7/91 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894803/ link to PMC article] [https://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. -->
-#'''NO16966:''' Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. [https://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]
-==mFOLFOX6 & Bevacizumab {{#subobject:b74416|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
-<br>FOLFOX-B: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-===Example orders===
-*[[Example orders for mFOLFOX 6 & Bevacizumab (Avastin) in colon cancer]]
-===Variant #1 {{#subobject:eeb338|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-| 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-switch-ic)
-|1. bFOL & Bevacizumab
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints
-| style="background-color:#ffffbf" |Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
-|-
-|2. [[#CapeOx_.26_Bevacizumab|CapeOx & Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints
-| style="background-color:#ffffbf" |Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
-|-
-|[https://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" |Did not meet primary endpoint of PFS12
-|
-|-
-|[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" |Inconclusive whether non-inferior PFS
-|
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70490-X/fulltext Yamada et al. 2013 (SOFT<sub>CRC</sub>)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#SOX_.26_Bevacizumab|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-switch-ic)
-|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|
-|-
-|}
-''This was the most common oxaliplatin-based reigimen used in PACCE. There is another trial by the name of SOFT in breast cancer.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[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, lower dose leucovorin {{#subobject:3c348b|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://academic.oup.com/annonc/article/24/9/2335/202863 Johnsson et al. 2013 (Nordic ACT)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====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 44 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 120 minutes 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
-'''14-day cycle for 9 cycles'''
-====Subsequent treatment====
-*Nordic ACT: [[#Bevacizumab_monotherapy|Bevacizumab]] versus Erlotinib & Bevacizumab maintenance
-===References===
-#'''TREE-2:''' Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. [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. [https://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]
-#'''Nordic ACT:''' Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. [https://academic.oup.com/annonc/article/24/9/2335/202863 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23788755 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]
-##'''Update:''' Baba H, Yamada Y, Takahari D, Matsumoto H, Yoshida K, Nakamura M, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K. S-1 and oxaliplatin (SOX) plus bevacizumab versus mFOLFOX6 plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer: updated overall survival analyses of the open-label, non-inferiority, randomised phase III: SOFT study. ESMO Open. 2017 Mar 9;2(1):e000135. [https://esmoopen.bmj.com/content/2/1/e000135 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519807/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28761727 PubMed]
-#'''SIRFLOX:''' van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M, Perez D, Robinson BA, Strickland AH, Ferguson T, Rodríguez J, Kröning H, Wolf I, Ganju V, Walpole E, Boucher E, Tichler T, Shacham-Shmueli E, Powell A, Eliadis P, Isaacs R, Price D, Moeslein F, Taieb J, Bower G, Gebski V, Van Buskirk M, Cade DN, Thurston K, Gibbs P. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2016 May 20;34(15):1723-31. Epub 2016 Feb 22. [https://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]
-==mFOLFOX6 & Bevacizumab (L-Leucovorin) {{#subobject:b7yy26|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-mFOLFOX6 & Bevacizumab: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Bevacizumab
-<br>FOLFOX-B: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-===Regimen {{#subobject:1d15de|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative 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 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV once on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given first'''
-'''14-day cycles'''
-===References===
-#'''TRICOLORE:''' Yamada Y, Denda T, Gamoh M, Iwanaga I, Yuki S, Shimodaira H, Nakamura M, Yamaguchi T, Ohori H, Kobayashi K, Tsuda M, Kobayashi Y, Miyamoto Y, Kotake M, Shimada K, Sato A, Morita S, Takahashi S, Komatsu Y, Ishioka C. S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized, open-label, phase III, noninferiority trial. Ann Oncol. 2018 Mar 1;29(3):624-631. [https://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]
-==FUIRI {{#subobject:e8ugac|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FUIRI: 5-'''<u>FU</u>''' & '''<u>IRI</u>'''notecan
-===Regimen {{#subobject:08ucb7|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/20/2/251/164564 Aranda et al. 2008]
-| style="background-color:#1a9851" |Phase III (E-de-esc)
-|[[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR (*)
-|-
-|}
-''Note: Aranda et al. 2008 is described by the authors as a non-inferiority trial but the statistics used are superiority-based.''
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 1125 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1, '''given second''' (total dose per cycle: 2250 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 80 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given first'''
-'''7-day cycles'''
-===References===
-#Aranda E, Valladares M, Martinez-Villacampa M, Benavides M, Gomez A, Massutti B, Marcuello E, Constenla M, Cámara JC, Carrato A, Dueñas R, Reboredo M, Navarro M, Díaz-Rubio E. Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study. Ann Oncol. 2009 Feb;20(2):251-7. Epub 2008 Aug 20. [https://academic.oup.com/annonc/article/20/2/251/164564 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18718892 PubMed]
-==FUOX {{#subobject:b4j3b5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FUOX: 5-'''<u>FU</u>''' & '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:975a54|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/25/27/4224.long Díaz-Rubio et al. 2007]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#CapeOx_2|CapeOx]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
-|-
-|}
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 1125 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on days 1 & 8 (total dose per cycle: 4500 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''14-day cycle for 18 cycles'''
-===References===
-<!-- Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2005, Atlanta, GA; and the Annual Meeting of the European Society for Medical Oncology, Istanbul, Turkey, September 29-October 3, 2006. -->
-#Díaz-Rubio E, Tabernero J, Gómez-España A, Massutí B, Sastre J, Chaves M, Abad A, Carrato A, Queralt B, Reina JJ, Maurel J, González-Flores E, Aparicio J, Rivera F, Losa F, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors 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]
-==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)
-===Variant #1, q3wk {{#subobject:2354b5|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.karger.com/Article/FullText/320520 Stathopoulos et al. 2010]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#IFL_.26_Bevacizumab|IFL & Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS36
-|-
-|}
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 135 mg/m<sup>2</sup> IV once on day 1
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycles'''
-===Variant #2, 4 out of 6 weeks {{#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#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 Saltz et al. 2000]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-esc)
-|1. [[#Fluorouracil_.26_Folinic_acid_3|FULV]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|2. [[#Irinotecan_monotherapy|Irinotecan]]
-| style="background-color:#d9ef8b" |Might have superior OS
-|-
-| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/JCO.2004.09.046 Goldberg et al. 2003 (NCCTG N9741)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. [[#FOLFOX4_3|FOLFOX4]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|2. [[#IROX|IROX]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa032691 Hurwitz et al. 2004 (AVF2107g)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|1. FULV & Bevacizumab
-| style="background-color:#d3d3d3" |Not reported
-|-
-|2. [[#IFL_.26_Bevacizumab|IFL & Bevacizumab]]
-| style="background-color:#d73027" |Inferior OS
-|-
-| rowspan="2" |[http://jco.ascopubs.org/content/25/30/4779.long Fuchs et al. 2007 (BICC-C)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. [[#CAPIRI|CapeIRI]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|2. [[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012268/ Guan et al. 2011 (ARTIST<sub>CRC</sub>)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#IFL_.26_Bevacizumab|mIFL & Bevacizumab]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-''Note: 5-FU in ARTIST was given over 6 to 8 hours. ARTIST should not be confused for the trial with the same name in gastric cancer.''
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22, '''given first'''
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22
-'''42-day cycles'''
-===References===
-#Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. [https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11006366 PubMed]
-#'''NCCTG N9741:''' Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. Epub 2003 Dec 9. [https://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]
-#'''AVF2107g:''' Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa032691 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15175435 PubMed]
-##'''Update:''' Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, Hambleton J, Novotny WF, Kabbinavar F. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol. 2005 May 20;23(15):3502-8. [https://ascopubs.org/doi/full/10.1200/JCO.2005.10.017 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15908660 PubMed]
-<!-- Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA. -->
-#'''BICC-C:''' Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. [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]
-#Stathopoulos GP, Batziou C, Trafalis D, Koutantos J, Batzios S, Stathopoulos J, Legakis J, Armakolas A. Treatment of colorectal cancer with and without bevacizumab: a phase III study. Oncology. 2010;78(5-6):376-81. Epub 2010 Aug 27. [https://www.karger.com/Article/FullText/320520 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20798560 PubMed]
-#'''ARTIST:''' Guan ZZ, Xu JM, Luo RC, Feng FY, Wang LW, Shen L, Yu SY, Ba Y, Liang J, Wang D, Qin SK, Wang JJ, He J, Qi C, Xu RH. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer. 2011 Oct;30(10):682-9. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012268/ link to PMC article] '''contains verified protocol''' [https://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#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa032691 Hurwitz et al. 2004 (AVF2107g)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-esc)
-|1. FL & Bevacizumab
-| style="background-color:#d3d3d3" |Not reported
-|-
-|2. [[#IFL|IFL]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|[http://jco.ascopubs.org/content/25/30/4779.long Fuchs et al. 2007 (BICC-C)]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI+Bev]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 8
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8
-*[[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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012268/ Guan et al. 2011 (ARTIST<sub>CRC</sub>)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#IFL|mIFL]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-''Note: this trial should not be confused for the trial with the same name in gastric cancer.''
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22, '''given first'''
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV over 6 to 8 hours once per day on days 1, 8, 15, 22
-*[[Folinic acid (Leucovorin)]] 20 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1, 15, 29
-'''42-day cycles'''
-===References===
-#'''AVF2107g:''' Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. [https://www.nejm.org/doi/full/10.1056/NEJMoa032691 link to original article] [https://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#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 Saltz et al. 2000]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-de-esc)
-|1. [[#Fluorouracil_.26_Folinic_acid_3|5-FU & LV]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|2. [[#IFL|IFL]]
-| style="background-color:#fee08b" |Might have inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22
-'''42-day cycles'''
-===References===
-#Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. [https://www.nejm.org/doi/full/10.1056/NEJM200009283431302 link to original article] '''contains verified protocol''' [https://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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/29/3/624/4779925 Yamada et al. 2018 (TRICOLORE)]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. [[#CapeOx_.26_Bevacizumab|CapeOx & Bevacizumab]]<br> 2. [[#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> PO twice per day 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/29/3/624/4779925 Yamada et al. 2018 (TRICOLORE)]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|1. [[#CapeOx_.26_Bevacizumab|CapeOx & Bevacizumab]]<br> 2. [[#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> PO twice per day 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://ascopubs.org/doi/full/10.1200/JCO.2004.09.046 Goldberg et al. 2003 (NCCTG N9741)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
-|1. [[#FOLFOX4_3|FOLFOX4]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
-|-
-|2. [[#IFL|IFL]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV once on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycles'''
-===References===
-#'''NCCTG N9741:''' Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. Epub 2003 Dec 9. [https://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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://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" |
-|-
-|[https://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" |Did not meet primary endpoint of PFS
-|-
-|}
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, '''given second'''
-*[[Folinic acid (Leucovorin)]] 60 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, '''given third, 30 minutes after 5-FU'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first'''
-'''14-day cycle for 8 cycles (NORDIC-VII) or indefinitely (Sørbye et al. 2004)'''
-===References===
-#Sørbye H, Glimelius B, Berglund A, Fokstuen T, Tveit KM, Braendengen M, Øgreid D, Dahl O. Multicenter phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):31-8. [https://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]
-#'''NORDIC-VII:''' Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, Sigurdsson F, Kure E, Ikdahl T, Skovlund E, Fokstuen T, Hansen F, Hofsli E, Birkemeyer E, Johnsson A, Starkhammar H, Yilmaz MK, Keldsen N, Erdal AB, Dajani O, Dahl O, Christoffersen T. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012 May 20;30(15):1755-62. Epub 2012 Apr 2. [https://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]
-==OXAFAFU {{#subobject:a38b7e|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-OXAFAFU: '''<u>OXA</u>'''liplatin, '''<u>F</u>'''olinic '''<u>A</u>'''cid (Leucovorin), 5-'''<u>FU</u>''' (Fluorouracil)
-===Regimen {{#subobject:3dcd8b|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/16/6/878/193940 Comella et al. 2005]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|IRIFAFU
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-====Chemotherapy====
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
-*[[Folinic acid (Leucovorin)]] 250 mg/m<sup>2</sup> IV once on day 2
-*[[Fluorouracil (5-FU)]] 850 mg/m<sup>2</sup> IV once on day 2
-'''14-day cycles'''
-===References===
-#Comella P, Massidda B, Filippelli G, Palmeri S, Natale D, Farris A, De Vita F, Buzzi F, Tafuto S, Maiorino L, Mancarella S, Leo S, Lorusso V, De Lucia L, Roselli M. Oxaliplatin plus high-dose folinic acid and 5-fluorouracil IV bolus (OXAFAFU) versus irinotecan plus high-dose folinic acid and 5-fluorouracil IV bolus (IRIFAFU) in patients with metastatic colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase III trial. Ann Oncol. 2005 Jun;16(6):878-86. Epub 2005 Apr 18. [https://academic.oup.com/annonc/article/16/6/878/193940 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15837702 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%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-|[https://academic.oup.com/annonc/article-abstract/28/6/1288/3102942 Kwakman et al. 2017 (SALTO)]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Capecitabine_monotherapy_2|Capecitabine]]
-| style="background-color:#ffffbf" |Did not meet secondary efficacy endpoints (*)
-| style="background-color:#1a9850" |Lower incidence of hand-foot syndrome
-|-
-|}
-''Note: this trial had a primary toxicity endpoint; reported efficacy is based on the 2019 update.''
-====Chemotherapy====
-*[[Tegafur, gimeracil, oteracil (S-1)]] 30 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-'''21-day cycles'''
-===References===
-#'''SALTO:''' Kwakman JJM, Simkens LHJ, van Rooijen JM, van de Wouw AJ, Ten Tije AJ, Creemers GJM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, van Werkhoven E, Punt CJA. 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]
-##'''Update:''' Kwakman JJM, van Werkhoven E, Simkens LHJ, van Rooijen JM, van de Wouw YAJ, Tije AJT, Creemers GM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, Punt CJA. Updated Survival Analysis of the Randomized Phase III Trial of S-1 Versus Capecitabine in the First-Line Treatment of Metastatic Colorectal Cancer by the Dutch Colorectal Cancer Group. Clin Colorectal Cancer. 2019 Jun;18(2):e229-e230. Epub 2019 Jan 29. [https://www.clinical-colorectal-cancer.com/article/S1533-0028(18)30531-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30782413 PubMed]
-==SOX {{#subobject:693823|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-SOX: '''<u>S</u>'''-1 & '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:c54d08|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext Hong et al. 2012 (SMC 2008-03-012)]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#CapeOx_2|CapeOX]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|}
-====Chemotherapy====
-*[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycle for up to 9 cycles'''
-====Subsequent treatment====
-*Patients were allowed to continue [[#S-1_monotherapy_2|S-1 maintenance]]
-===References===
-#'''SMC 2008-03-012:''' Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23062232 PubMed]
-##'''Update:''' Kim ST, Hong YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Lee JW, Jo SJ, Park YS. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: updated results from a phase 3 trial. BMC Cancer. 2014 Nov 26;14:883. [https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-14-883 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289339/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25424120 PubMed]
-==SOX & Bevacizumab {{#subobject:6c92b3|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-SOX & Bevacizumab: '''<u>S</u>'''-1, '''<u>OX</u>'''aliplatin, Bevacizumab
-===Regimen {{#subobject:cjcn88|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70490-X/fulltext Yamada et al. 2013 (SOFT<sub>CRC</sub>)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#mFOLFOX6_.26_Bevacizumab|mFOLFOX6 & Bevacizumab]]
-| style="background-color:#eeee01" |Seems to have non-inferior PFS
-|-
-|}
-''Note: S-1 is given starting on the evening of day 1, completing after breakfast on day 15.''
-====Chemotherapy====
-*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:
-**BSA less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14 (see note)
-**BSA between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14 (see note)
-**BSA 1.5 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 14 (see note)
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1, '''given second'''
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1, '''given first'''
-'''21-day cycles'''
-===References===
-#'''SOFT:''' Yamada Y, Takahari D, Matsumoto H, Baba H, Nakamura M, Yoshida K, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1278-86. Epub 2013 Nov 11. Erratum in: Lancet Oncol. 2014 Jan;15(1):e4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70490-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24225157 PubMed]
-##'''Update:''' Baba H, Yamada Y, Takahari D, Matsumoto H, Yoshida K, Nakamura M, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K. S-1 and oxaliplatin (SOX) plus bevacizumab versus mFOLFOX6 plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer: updated overall survival analyses of the open-label, non-inferiority, randomised phase III: SOFT study. ESMO Open. 2017 Mar 9;2(1):e000135. [https://esmoopen.bmj.com/content/2/1/e000135 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519807/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28761727 PubMed]
-=Maintenance after first-line therapy=
-==Bevacizumab monotherapy {{#subobject:caff58|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:ab34c1|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/24/9/2335/202863 Johnsson et al. 2013 (Nordic ACT)]
-| style="background-color:#1a9851" |Phase III (C)
-|Erlotinib & Bevacizumab
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|[https://academic.oup.com/annonc/article/26/4/709/204652 Koeberle et al. 2015 (SAKK 41/06)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Observation_3|No further treatment]]
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior TTP
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00042-X/fulltext Hegewisch-Becker et al. 2015 (AIO KRK 0207)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[#Observation_3|No further treatment]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-|2. Fluoropyrimidine & Bevacizumab
-| style="background-color:#eeee01" |Non-inferior TTF
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00216-8/fulltext Tournigand et al. 2015 (OPTIMOX3)]
-| style="background-color:#1a9851" |Phase III (C)
-|Erlotinib & Bevacizumab
-| style="background-color:#fee08b" |Might have inferior PFS
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2017.75.2931 Aparicio et al. 2018 (PRODIGE 9)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Observation_3|No further treatment]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of TCD
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-*Nordic ACT: [[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]] x 9 or [[#mFOLFOX6_.26_Bevacizumab|mFOLFOX6 & Bevacizumab]] x 9 or [[#CAPIRI-Bev|XELIRI & Bevacizumab]] x 6 or [[#CapeOx_.26_Bevacizumab|XELOX & Bevacizumab]] x 6
+</div>
-*AIO KRK 0207 & OPTIMOX3: Bevacizumab-containing chemotherapy
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
+**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 28
+**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
-'''21-day cycles'''
+**BSA greater than 1.50 m<sup>2</sup>: 60 mg PO twice per day on days 1 to 28
+'''42-day cycle for 4 cycles'''
+</div></div>
 ===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. [https://doi.org/10.1093/annonc/mdu232 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143094/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24942277/ PubMed] [https://clinicaltrials.gov/study/NCT00660894 NCT00660894]
-#'''Nordic ACT:''' Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. [https://academic.oup.com/annonc/article/24/9/2335/202863 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23788755 PubMed]
+==SOX {{#subobject:617cc1|Regimen=1}}==
-#'''SAKK 41/06:''' Koeberle D, Betticher DC, von Moos R, Dietrich D, Brauchli P, Baertschi D, Matter K, Winterhalder R, Borner M, Anchisi S, Moosmann P, Kollar A, Saletti P, Roth A, Frueh M, Kueng M, Popescu RA, Schacher S, Hess V, Herrmann R. Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06). Ann Oncol. 2015 Apr;26(4):709-14. Epub 2015 Jan 20. [https://academic.oup.com/annonc/article/26/4/709/204652 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25605741 PubMed]
+SOX: '''<u>S</u>'''-1, '''<u>OX</u>'''aliplatin
-#'''AIO KRK 0207:''' Hegewisch-Becker S, Graeven U, Lerchenmüller CA, Killing B, Depenbusch R, Steffens CC, Al-Batran SE, Lange T, Dietrich G, Stoehlmacher J, Tannapfel A, Reinacher-Schick A, Quidde J, Trarbach T, Hinke A, Schmoll HJ, Arnold D. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1355-69. Epub 2015 Sep 8. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00042-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26361971 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
-#'''OPTIMOX3:''' Tournigand C, Chibaudel B, Samson B, Scheithauer W, Vernerey D, Mésange P, Lledo G, Viret F, Ramée JF, Tubiana-Mathieu N, Dauba J, Dupuis O, Rinaldi Y, Mabro M, Aucoin N, Latreille J, Bonnetain F, Louvet C, Larsen AK, André T, de Gramont A. Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1493-1505. Epub 2015 Oct 22. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00216-8/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26474518 PubMed]
+===Regimen {{#subobject:c80e20|Variant=1}}===
-#'''PRODIGE 9:''' Aparicio T, Ghiringhelli F, Boige V, Le Malicot K, Taieb J, Bouché O, Phelip JM, François E, Borel C, Faroux R, Dahan L, Jacquot S, Genet D, Khemissa F, Suc E, Desseigne F, Texereau P, Lepage C, Bennouna J; PRODIGE 9 Investigators. Bevacizumab maintenance versus no maintenance during chemotherapy-free intervals in metastatic colorectal cancer: a randomized phase III trial (PRODIGE 9). J Clin Oncol. 2018 Mar 1;36(7):674-681. Epub 2018 Jan 18. [https://ascopubs.org/doi/full/10.1200/JCO.2017.75.2931 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29346040 PubMed]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
-==Capecitabine monotherapy {{#subobject:66ad1e|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/j.clcc.2019.10.002 Sunami et al. 2019 (ACTS-CC 02)]
-|}
+|2010-2014
-===Regimen {{#subobject:796f2e|Variant=1}}===
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-{| class="wikitable" style="width: 100%; text-align:center;"
+|[[Colon_cancer#Tegafur.2C_Uracil.2C_Folinic_acid|Tegafur, Uracil, Folinic Acid]]
-! style="width: 25%" |Study
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext Hong et al. 2012]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://academic.oup.com/annonc/article/27/6/1074/1741605 Luo et al. 2016]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Observation_3|Observation]]
-| style="background-color:#1a9850" |Superior PFS
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*[[Surgery#Colorectal_cancer_surgery|Surgery]]
-*Hong et al. 2012: [[#CapeOx_2|CapeOX]] x 9
+</div>
-*Luo et al. 2016: [[#mFOLFOX6_3|FOLFOX]] or [[#CapeOx_2|XELOX]]
+<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-'''21-day cycles'''
-===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]
-#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]
-==Capecitabine & Bevacizumab {{#subobject:083f75|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CAP-B: '''<u>CAP</u>'''ecitabine & '''<u>B</u>'''evacizumab
-===Regimen {{#subobject:49256d|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.karger.com/Article/FullText/355914 Yalcin et al. 2013 (Stop and Go)]
-| style="background-color:#1a9851" |Phase III (E-de-esc)
-|Continued XELOX-B
-| 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:#1a9851" |Phase III (E-esc)
-|[[#Observation_3|Observation]]
-| style="background-color:#1a9850" |Superior PFS-2
-|-
-|}
-====Preceding treatment====
-*[[#CapeOx_.26_Bevacizumab|CAPOX-B]] x 6
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day
-*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-'''21-day cycles'''
-===References===
-#'''Stop and Go:''' Yalcin S, Uslu R, Dane F, Yilmaz U, Zengin N, Buyukunal E, Buyukberber S, Camci C, Sencan O, Kilickap S, Ozdener F, Cevik D. Bevacizumab + capecitabine as maintenance therapy after initial bevacizumab + XELOX treatment in previously untreated patients with metastatic colorectal cancer: phase III 'Stop and Go' study results--a Turkish Oncology Group Trial. Oncology. 2013;85(6):328-35. Epub 2013 Nov 12. [https://www.karger.com/Article/FullText/355914 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24247559 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]
-==Observation==
-{| 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#Comparative_efficacy|Comparative 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]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Capecitabine_monotherapy|Capecitabine]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2017.75.2931 Aparicio et al. 2018 (PRODIGE 9)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Bevacizumab_monotherapy|Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of TCD
-|-
-|}
-''No further treatment after first-line induction.''
-====Preceding treatment====
-*CAIRO3: [[#CapeOx_.26_Bevacizumab|CAPOX-B]] x 6
-*Luo et al. 2016: [[#mFOLFOX6_3|FOLFOX]] or [[#CapeOx_2|XELOX]]
-===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]
-#'''PRODIGE 9:''' Aparicio T, Ghiringhelli F, Boige V, Le Malicot K, Taieb J, Bouché O, Phelip JM, François E, Borel C, Faroux R, Dahan L, Jacquot S, Genet D, Khemissa F, Suc E, Desseigne F, Texereau P, Lepage C, Bennouna J; PRODIGE 9 Investigators. Bevacizumab maintenance versus no maintenance during chemotherapy-free intervals in metastatic colorectal cancer: a randomized phase III trial (PRODIGE 9). J Clin Oncol. 2018 Mar 1;36(7):674-681. Epub 2018 Jan 18. [https://ascopubs.org/doi/full/10.1200/JCO.2017.75.2931 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29346040 PubMed]
-==S-1 monotherapy {{#subobject:b5a1dd|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:608e8f|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70363-7/fulltext Hong et al. 2012]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Preceding treatment====
-*[[#SOX_2|SOX]] x 9
 ====Chemotherapy====
 *[[Tegafur, gimeracil, oteracil (S-1)]] 40 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycles'''
+'''21-day cycle for 8 cycles'''
+</div></div>
 ===References===
+#'''ACTS-CC 02:''' Sunami E, Kusumoto T, Ota M, SakamotoY, Yoshida K, Tomita N, Maeda A, Teshima J, Okabe M, Tanaka C, Yamauchi J, Itabashi M, Kotake K, Takahashi K, Baba H, Boku N, Aiba K, Ishiguro M, Morita S, Takenaka N, Okude R, Sugihara K. S-1 and oxaliplatin versus tegafur-uracil and leucovorin as postoperative adjuvant chemotherapy in patients with high-risk stage III colon cancer (ACTS-CC 02): a randomized, open-label, multicenter, phase 3, superiority trial. Clin Colorectal Cancer. 2020 Mar;19(1):22-31.e6. Epub 2019 Oct 18. [https://doi.org/10.1016/j.clcc.2019.10.002 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31917122/ PubMed] JapicCTI-101073
+##'''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]
-#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]
+==Tegafur, Uracil, Folinic acid {{#subobject:5ed2aa|Regimen=1}}==
+UFT + LV: '''<u>UFT</u>''' (Tegafur and uracil) & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid)
-=Advanced or metastatic disease, second-line therapy=
+<div class="toccolours" style="background-color:#eeeeee">
-==CapeOx {{#subobject:6b5972|Regimen=1}}==
+===Regimen variant #1, 300/75 {{#subobject:8cc7d8|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| 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
-CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin
+| style="background-color:#1a9851" |Phase 3 (C)
-<br>XELOX: '''<u>XEL</u>'''oda, '''<u>OX</u>'''aliplatin
+|[[#Tegafur.2C_Uracil.2C_Folinic_acid|UFT + LV]]; weekly x 18 mo
-===Example orders===
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-*[[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#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext Koopman et al. 2007 (CAIRO)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143094/ Yoshida et al. 2014 (ACTS-CC)]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+|2008-04 to 2009-06
-|[[Complex_multipart_regimens#CAIRO|See link]]
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#CAIRO|See link]]
+|[[#S-1_monotherapy|S-1]]
+| style="background-color:#eeee01" |Non-inferior DFS36
 |-
-|[https://academic.oup.com/annonc/article/19/10/1720/240463 Rothenberg 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-switch-ic)
+|2010-2014
-|[[#FOLFOX4_4|FOLFOX4]]
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#eeee01" |Non-inferior PFS
+|[[#SOX|SOX]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
 |}
-====Preceding treatment====
+''Note: Miyake et al. 2018 does not contain treatment details in the abstract.''
+<div class="toccolours" style="background-color:#b3e2cd">
-*CAIRO: [[#CAPIRI|CAPIRI]], with progression
 ====Chemotherapy====
+*[[Tegafur and uracil (UFT)]] 100 mg/m<sup>2</sup> PO every 8 hours on days 1 to 28
+*[[Leucovorin (Folinic acid)]] 25 mg PO every 8 hours on days 1 to 28
+'''35-day cycle for 5 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
+===Regimen variant #2, 300/90 {{#subobject:643dbb|Variant=1}}===
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV over 2 hours once on day 1
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
-'''21-day cycles'''
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-===References===
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-#'''CAIRO:''' Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. [https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17630036 PubMed]
-#Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, Gollins S, Siu LL, Laguerre S, Cunningham D. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008 Oct;19(10):1720-6. Epub 2008 Jun 10. [https://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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815882/ Lim et al. 2015 (SMC 2009-11-017)]
-| style="background-color:#1a9851" |Phase III (C)
-|XELIRI & Simvastatin
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-'''21-day cycles'''
-===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#Comparative_efficacy|Comparative 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-switch-ic)
-|[[#FOLFIRI_3|FOLFIRI]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-'''21-day cycles'''
-===References===
-#'''SMC 2009-11-017:''' Lim SH, Kim TW, Hong YS, Han SW, Lee KH, Kang HJ, Hwang IG, Lee JY, Kim HS, Kim ST, Lee J, Park JO, Park SH, Park YS, Lim HY, Jung SH, Kang WK. A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer. Br J Cancer. 2015 Nov 17;113(10):1421-6. Epub 2015 Oct 27. [https://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#Comparative_efficacy|Comparative 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-switch-ic)
-|[[#FOLFIRI_.26_Bevacizumab_2|FOLFIRI & Bevacizumab]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-*[[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]
-==Fluorouracil monotherapy {{#subobject:8ff0ed|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:a2b84b|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext Rougier et al. 1998 (V302)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Irinotecan_monotherapy_2|Irinotecan]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|}
-''Note: this was one of three control regimens; see paper for details.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 250 to 300 mg/m<sup>2</sup>/day IV continuous infusion
-'''Continued indefinitely'''
-===References===
-#'''V302:''' Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Awad L, Herait P, Jacques C. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1407-12. Erratum in: Lancet 1998 Nov 14;352(9140):1634. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9807986 PubMed]
-==FOLFIRI {{#subobject:7325e5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
-===Example orders===
-*[[Example orders for FOLFIRI in colon cancer]]
-===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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815882/ Lim et al. 2015 (SMC 2009-11-017)]
-| style="background-color:#1a9851" |Phase III (C)
-|FOLFIRI & Simvastatin
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given first'''
-'''14-day cycles'''
-===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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2004.05.113 Tournigand et al. 2003]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#mFOLFOX6_3|mFOLFOX6]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS15
-|-
-|[http://jco.ascopubs.org/content/28/31/4706.long Peeters et al. 2010 (20050181)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[Colon_cancer,_KRAS_wild-type#FOLFIRI_.26_Panitumumab|FOLFIRI & Panitumumab]]
-| style="background-color:#fc8d59" |Seems to have inferior PFS (*)
-|-
-|[https://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. Reported efficacy for 20050181 is for wild-type KRAS, only, and is based on the 2014 update.''
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-**In Tournigand et al. 2003, if no toxicity greater than grade 1 in cycles 1 & 2, increased to: 400 mg/m<sup>2</sup> IV bolus once on day 1, then 3000 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 3400 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first, with leucovorin'''
-'''14-day cycles'''
-====Subsequent treatment====
-*Tournigand et al. 2003, upon progression: [[#mFOLFOX6_4|mFOLFOX6]]
-===References===
-#Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15;22(2):229-37. Epub 2003 Dec 2. [https://ascopubs.org/doi/full/10.1200/JCO.2004.05.113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14657227 PubMed]
-#'''20050181:''' Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010 Nov 1;28(31):4706-13. Epub 2010 Oct 4. [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]
-##'''Update:''' Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tian Y, Sidhu R. Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jan;25(1):107-16. Erratum in: Ann Oncol. 2014 Mar;25(3):757. [https://academic.oup.com/annonc/article/25/1/107/166332 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24356622 PubMed]
-#'''FFCD 2000-05:''' Ducreux M, Malka D, Mendiboure J, Etienne PL, Texereau P, Auby D, Rougier P, Gasmi M, Castaing M, Abbas M, Michel P, Gargot D, Azzedine A, Lombard-Bohas C, Geoffroy P, Denis B, Pignon JP, Bedenne L, Bouché O; Fédération Francophone de Cancérologie Digestive (FFCD) 2000–05 Collaborative Group. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol. 2011 Oct;12(11):1032-44. Epub 2011 Sep 6. [https://www.thelancet.com/journals/lancetonc/article/PIIS1470204511701991/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21903473 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. [https://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]
-##'''Subgroup analysis:''' Ruff P, Van Cutsem E, Lakomy R, Prausova J, van Hazel GA, Moiseyenko VM, Soussan-Lazard K, Dochy E, Magherini E, Macarulla T, Papamichael D. Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: An age-based analysis from the randomized placebo-controlled phase III VELOUR trial. J Geriatr Oncol. 2018 Jan;9(1):32-39. Epub 2017 Aug 12. [https://www.geriatriconcology.net/article/S1879-4068(17)30140-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28807738 PubMed]
-#'''BEBYP:''' Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-30. Epub 2015 Jan 18. [https://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]
-##'''Subgroup analysis:''' Obermannová R, Van Cutsem E, Yoshino T, Bodoky G, Prausová J, Garcia-Carbonero R, Ciuleanu T, Garcia Alfonso P, Portnoy D, Cohn A, Yamazaki K, Clingan P, Lonardi S, Kim TW, Yang L, Nasroulah F, Tabernero J. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016 Nov;27(11):2082-2090. Epub 2016 Aug 29. [https://academic.oup.com/annonc/article/27/11/2082/2467255 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091322/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27573561 PubMed]
-#'''SMC 2009-11-017:''' Lim SH, Kim TW, Hong YS, Han SW, Lee KH, Kang HJ, Hwang IG, Lee JY, Kim HS, Kim ST, Lee J, Park JO, Park SH, Park YS, Lim HY, Jung SH, Kang WK. A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer. Br J Cancer. 2015 Nov 17;113(10):1421-6. Epub 2015 Oct 27. [https://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 (L-Leucovorin) {{#subobject:7477e5|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
-===Regimen {{#subobject:db9c30|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2004.05.113 Tournigand et al. 2003]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#mFOLFOX6_3|mFOLFOX6]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS15
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#CAPIRI_2|CAPIRI]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|}
-====Chemotherapy====
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-**In Tournigand et al. 2003, if no toxicity greater than grade 1 in cycles 1 & 2, increased to: 400 mg/m<sup>2</sup> IV bolus once on day 1, then 3000 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 3400 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given first, with levoleucovorin'''
-'''14-day cycles'''
-====Subsequent treatment====
-*Tournigand et al. 2003, upon progression: [[#mFOLFOX6_4|mFOLFOX6]]
-===References===
-#Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15;22(2):229-37. Epub 2003 Dec 2. [https://ascopubs.org/doi/full/10.1200/JCO.2004.05.113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14657227 PubMed]
-#'''AXEPT:''' Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext link to original article] '''contains verified protocol''' [https://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
-===Regimen {{#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#Comparative_efficacy|Comparative 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-RT-esc)
-|[[#FOLFIRI_3|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-esc)
-|[[#FOLFIRI_3|FOLFIRI]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext Xu et al. 2018 (AXEPT)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#CAPIRI-Bev_2|mXELIRI & Bevacizumab]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|}
-''Note: the abstract of ML18147 does not specify the exact type of chemotherapy; patients had to be previously bevacizumab-exposed. BEBYP does not provide dosing details; this is the most commonly used variant of FOLFIRI.''
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given first, with leucovorin'''
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given second'''
-'''14-day cycles'''
-===References===
-#'''ML18147:''' Bennouna J, Sastre J, Arnold D, Österlund P, Greil R, Van Cutsem E, von Moos R, Viéitez JM, Bouché O, Borg C, Steffens CC, Alonso-Orduña V, Schlichting C, Reyes-Rivera I, Bendahmane B, André T, Kubicka S; ML18147 Study Investigators. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013 Jan;14(1):29-37. Epub 2012 Nov 16. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70477-1/fulltext link to original article]  [https://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 & Bevacizumab (L-Leucovorin) {{#subobject:bedg7d|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI & Bevacizumab: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Bevacizumab
-===Variant #1, 200/2800/150/5 {{#subobject:5b2542|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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478977/ Iwamoto et al. 2015 (EAGLE)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#FOLFIRI_.26_Bevacizumab_.28L-Leucovorin.29_2|FOLFIRI & Bevacizumab]]; lower-dose bevacizumab (10 mg/kg)
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-====Chemotherapy====
-*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given second, with levoleucovorin'''
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV over 30 minutes once on day 1, '''given first'''
-'''14-day cycles'''
-===Variant #2, 200/2800/180/5 {{#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#Comparative_efficacy|Comparative 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 first, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given first, with levoleucovorin'''
-*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given second'''
-'''14-day cycles'''
-===References===
-#'''EAGLE:''' Iwamoto S, Takahashi T, Tamagawa H, Nakamura M, Munemoto Y, Kato T, Hata T, Denda T, Morita Y, Inukai M, Kunieda K, Nagata N, Kurachi K, Ina K, Ooshiro M, Shimoyama T, Baba H, Oba K, Sakamoto J, Mishima H. FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study. Ann Oncol. 2015 Jul;26(7):1427-33. Epub 2015 Apr 23. [https://academic.oup.com/annonc/article/26/7/1427/165485 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478977/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25908603 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#Comparative_efficacy|Comparative 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-RT-esc)
-|[[#FOLFIRI_3|FOLFIRI]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''either given third or concurrently with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given second'''
-*[[Ramucirumab (Cyramza)]] 8 mg/kg IV over 60 minutes once on day 1, '''given first'''
-'''14-day cycles'''
-===References===
-#'''RAISE:''' Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F; RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 May;16(5):499-508. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2815%2970127-0/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25877855 PubMed]
-##'''Subgroup analysis:''' Obermannová R, Van Cutsem E, Yoshino T, Bodoky G, Prausová J, Garcia-Carbonero R, Ciuleanu T, Garcia Alfonso P, Portnoy D, Cohn A, Yamazaki K, Clingan P, Lonardi S, Kim TW, Yang L, Nasroulah F, Tabernero J. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016 Nov;27(11):2082-2090. Epub 2016 Aug 29. [https://academic.oup.com/annonc/article/27/11/2082/2467255 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091322/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27573561 PubMed]
-==FOLFIRI & Ziv-aflibercept {{#subobject:615d3f|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1200/jco.2005.04.7498 Lembersky et al. 2006 (NSABP C-06)]
-|}
+|1997-1999
-FOLFIRI & Ziv-aflibercept: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Ziv-aflibercept
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-===Regimen {{#subobject:29895|Variant=1}}===
+|[[#FULV|FULV]]
-{| class="wikitable" style="width: 100%; text-align:center;"
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of DFS/OS
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2012.42.8201 Van Cutsem et al. 2012 (VELOUR)]
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#FOLFIRI_3|FOLFIRI]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|[https://www.futuremedicine.com/doi/10.2217/fon-2017-0669 Li et al. 2018 (AFLAME)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#FOLFIRI_3|FOLFIRI]]
-| style="background-color:#1a9850" |Superior PFS
 |-
 |}
-====Chemotherapy====
+<div class="toccolours" style="background-color:#cbd5e8">
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1, '''given second'''
-*[[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. [https://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]
-##'''Subgroup analysis:''' Ruff P, Van Cutsem E, Lakomy R, Prausova J, van Hazel GA, Moiseyenko VM, Soussan-Lazard K, Dochy E, Magherini E, Macarulla T, Papamichael D. Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: An age-based analysis from the randomized placebo-controlled phase III VELOUR trial. J Geriatr Oncol. 2018 Jan;9(1):32-39. Epub 2017 Aug 12. [https://www.geriatriconcology.net/article/S1879-4068(17)30140-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28807738 PubMed]
-#'''AFLAME:''' Li J, Xu R, Qin S, Liu T, Pan H, Xu J, Bi F, Lim R, Zhang S, Ba Y, Bai Y, Fan N, Tsuji A, Yeh KH, Ma B, Wei V, Shi D, Magherini E, Shen L. Aflibercept plus FOLFIRI in Asian patients with pretreated metastatic colorectal cancer: a randomized Phase III study. Future Oncol. 2018 Aug;14(20):2031-2044. Epub 2018 Aug 17. Erratum in: Future Oncol. 2019 Feb;15(4):451. [https://www.futuremedicine.com/doi/10.2217/fon-2017-0669 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30117334 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2003.11.126 Rothenberg et al. 2003]
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|1. LV5FU2<br> 2. Oxaliplatin
-| style="background-color:#1a9850" |Superior TTP
-|-
-|[https://academic.oup.com/annonc/article/19/10/1720/240463 Rothenberg et al. 2008]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#CapeOx_3|XELOX]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''14-day cycles'''
-===References===
-#Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, Hart LL, Gupta S, Garay CA, Burger BG, Le Bail N, Haller DG. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol. 2003 Jun 1;21(11):2059-69. [https://ascopubs.org/doi/full/10.1200/JCO.2003.11.126 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12775730 PubMed]
-#Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, Gollins S, Siu LL, Laguerre S, Cunningham D. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008 Oct;19(10):1720-6. Epub 2008 Jun 10. [https://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#Comparative_efficacy|Comparative 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 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-'''14-day cycles'''
-===References===
-#'''BEBYP:''' Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-30. Epub 2015 Jan 18. [https://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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://academic.oup.com/annonc/article/26/4/724/204710 Masi et al. 2015 (BEBYP)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#mFOLFOX6_3|mFOLFOX6]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-''Note: BEBYP does not provide dosing details; this is the most commonly used variant of mFOLFOX6.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[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, 100 mg/m<sup>2</sup>, 4 weeks out of 6 {{#subobject:77bz17|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819990215%2985%3A4%3C786%3A%3AAID-CNCR5%3E3.0.CO%3B2-9 Rothenberg et al. 1999]
-| style="background-color:#91cf61" |Phase II (RT)
-|-
-|}
-''Note: this was a mid-protocol dose amendment for excess toxicity.''
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-'''42-day cycles'''
-===Variant #2, 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.4.1128 Rothenberg et al. 1996]
-| style="background-color:#91cf61" |Phase II (RT)
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.8.2910 Pitot et al. 1997]
-| style="background-color:#91cf61" |Phase II (RT)
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[http://jco.ascopubs.org/content/21/5/807.long Fuchs et al. 2003]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Irinotecan_monotherapy_2|Irinotecan]]; every 3 weeks
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS12
-|-
-|}
-''Note: In contrast to what is described here, some guidelines list irinotecan as being given on days 1 & 8 of a 21-day cycle. No primary reference could be found for this.''
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22
-'''42-day cycles'''
-===Variant #3, 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[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
-|-
-|}
-''This starting dose was intended for patients who were at least 65 years old, had prior abdomen/pelvic radiation, or had elevated bilirubin. Dose escalations in the absence of grade 2 or higher toxicities were allowed.''
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 250 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-'''21-day cycles'''
-===Variant #4, 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext Rougier et al. 1998 (V302)]
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
-|[[#Fluorouracil_monotherapy_2|CI 5-FU]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[http://jco.ascopubs.org/content/21/5/807.long Fuchs et al. 2003]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Irinotecan_monotherapy_2|Irinotecan]]; 4 weeks out of 6
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS12
-|-
-|[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" |Did not meet primary endpoint of 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
-|-
-|}
-''Note: This was the lower bound of the dosing range described by Rougier et al. 1998. In some trials, this starting dose was intended for patients who were at least 70 years old, had [[Performance status|ECOG performance status]] 2 or more, or had prior pelvic radiation. Patients in N9841 had not previously received irinotecan or oxaliplatin.''
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 300 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-'''21-day cycles'''
-===Variant #5, 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.1.251 Rougier et al. 1997]
-| style="background-color:#91cf61" |Phase II (RT)
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext Rougier et al. 1998 (V302)]
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
-|[[#Fluorouracil_monotherapy_2|CI 5-FU]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[http://jco.ascopubs.org/content/21/5/807.long Fuchs et al. 2003]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Irinotecan_monotherapy_2|Irinotecan]]; 4 weeks out of 6
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS12
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2004.01.005 Lal et al. 2004]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Irinotecan_monotherapy_2|Irinotecan]] x 8
-| style="background-color:#ffffbf" |Did not meet primary endpoint of FFS
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext Koopman et al. 2007 (CAIRO)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[Complex_multipart_regimens#CAIRO|See link]]
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#CAIRO|See link]]
-|-
-|[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" |Did not meet primary endpoint of OS
-|-
-|[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
-|-
-|}
-''Note: This was the upper bound of the dosing range described by Rougier et al. 1998. Patients in N9841 had not previously received irinotecan or oxaliplatin.''
 ====Preceding treatment====
+*A potentially curative [[Surgery#Colorectal_cancer_surgery|resection]] of stage II or stage III colon cancer
-*CAIRO: [[#Capecitabine_monotherapy_2|Capecitabine]], with progression
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Tegafur and uracil (UFT)]] 100 mg/m<sup>2</sup> PO every 8 hours on days 1 to 28
-*[[Irinotecan (Camptosar)]] 350 mg/m<sup>2</sup> IV over 90 minutes once on day 1
+*[[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.
-====Supportive medications====
+'''35-day cycle for 5 cycles'''
+</div></div>
-*(varied depending on reference):
-*"Standard regimens of [[:Category:Emesis_prevention|antiemetics]], [[Atropine (Atropen)]], and intensive [[Loperamide (Imodium)]]," but no prophylactic [[Atropine (Atropen)]] allowed on cycle 1 day 1
-'''21-day cycles'''
-====Subsequent treatment====
-*CAIRO, with progression: [[#CapeOx_4|CapeOx]]
 ===References===
+<!-- Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 13-17, 2004. -->
+#'''NSABP C-06:''' Lembersky BC, Wieand HS, Petrelli NJ, O'Connell MJ, Colangelo LH, Smith RE, Seay TE, Giguere JK, Marshall ME, Jacobs AD, Colman LK, Soran A, Yothers G, Wolmark N. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 2006 May 1;24(13):2059-64. [https://doi.org/10.1200/jco.2005.04.7498 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16648506/ PubMed] [https://clinicaltrials.gov/study/NCT00378716 NCT00378716]
+#'''ACTS-CC:''' Yoshida M, Ishiguro M, Ikejiri K, Mochizuki I, Nakamoto Y, Kinugasa Y, Takagane A, Endo T, Shinozaki H, Takii Y, Mochizuki H, Kotake K, Kameoka S, Takahashi K, Watanabe T, Watanabe M, Boku N, Tomita N, Nakatani E, Sugihara K; ACTS-CC study group. S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial). Ann Oncol. 2014 Sep;25(9):1743-9. Epub 2014 Jun 18. [https://doi.org/10.1093/annonc/mdu232 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143094/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24942277/ PubMed] [https://clinicaltrials.gov/study/NCT00660894 NCT00660894]
+#'''JFMC33-0502:''' Sadahiro S, Tsuchiya T, Sasaki K, Kondo K, Katsumata K, Nishimura G, Kakeji Y, Baba H, Sato S, Koda K, Yamaguchi Y, Morita T, Matsuoka J, Usuki H, Hamada C, Kodaira S. Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502. Ann Oncol. 2015 Nov;26(11):2274-80. Epub 2015 Sep 7. [https://doi.org/10.1093/annonc/mdv358 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621030/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26347106/ PubMed] UMIN C000000245
+#'''ACTS-CC 02:''' Sunami E, Kusumoto T, Ota M, SakamotoY, Yoshida K, Tomita N, Maeda A, Teshima J, Okabe M, Tanaka C, Yamauchi J, Itabashi M, Kotake K, Takahashi K, Baba H, Boku N, Aiba K, Ishiguro M, Morita S, Takenaka N, Okude R, Sugihara K. S-1 and oxaliplatin versus tegafur-uracil and leucovorin as postoperative adjuvant chemotherapy in patients with high-risk stage III colon cancer (ACTS-CC 02): a randomized, open-label, multicenter, phase 3, superiority trial. Clin Colorectal Cancer. 2020 Mar;19(1):22-31.e6. Epub 2019 Oct 18. [https://doi.org/10.1016/j.clcc.2019.10.002 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31917122/ PubMed] JapicCTI-101073
+##'''Update:''' Watanabe J, Sasaki S, Kusumoto T, Sakamoto Y, Yoshida K, Tomita N, Maeda A, Teshima J, Yokota M, Tanaka C, Yamauchi J, Uetake H, Itabashi M, Takahashi K, Baba H, Kotake K, Boku N, Aiba K, Morita S, Takenaka N, Sugihara K. S-1 and oxaliplatin versus tegafur-uracil and leucovorin as post-operative adjuvant chemotherapy in patients with high-risk stage III colon cancer: updated 5-year survival of the phase III ACTS-CC 02 trial. ESMO Open. 2021 Apr;6(2):100077. Epub 2021 Mar 11. [https://doi.org/10.1016/j.esmoop.2021.100077 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7966838/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33714860/ PubMed]
-#Rothenberg ML, Eckardt JR, Kuhn JG, Burris HA 3rd, Nelson J, Hilsenbeck SG, Rodriguez GI, Thurman AM, Smith LS, Eckhardt SG, Weiss GR, Elfring GL, Rinaldi DA, Schaaf LJ, Von Hoff DD. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol. 1996 Apr;14(4):1128-35. [https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.4.1128 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8648367 PubMed]
+=Advanced or metastatic disease=
-#Rougier P, Bugat R, Douillard JY, Culine S, Suc E, Brunet P, Becouarn Y, Ychou M, Marty M, Extra JM, Bonneterre J, Adenis A, Seitz JF, Ganem G, Namer M, Conroy T, Negrier S, Merrouche Y, Burki F, Mousseau M, Herait P, Mahjoubi M. Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol. 1997 Jan;15(1):251-60. [https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.1.251 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8996150 PubMed]
+''See the [[Colorectal cancer|colorectal cancer page]] for colorectal cancer regimens.''
-#Pitot HC, Wender DB, O'Connell MJ, Schroeder G, Goldberg RM, Rubin J, Mailliard JA, Knost JA, Ghosh C, Kirschling RJ, Levitt R, Windschitl HE. Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol. 1997 Aug;15(8):2910-9. [https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.8.2910 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9256135 PubMed]
-#Rothenberg ML, Cox JV, DeVore RF, Hainsworth JD, Pazdur R, Rivkin SE, Macdonald JS, Geyer CE Jr, Sandbach J, Wolf DL, Mohrland JS, Elfring GL, Miller LL, Von Hoff DD. A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer. 1999 Feb 15;85(4):786-95. [https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819990215%2985%3A4%3C786%3A%3AAID-CNCR5%3E3.0.CO%3B2-9 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10091755 PubMed]
-#'''V302:''' Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Awad L, Herait P, Jacques C. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1407-12. Erratum in: Lancet 1998 Nov 14;352(9140):1634. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03085-2/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9807986 PubMed]
-#Fuchs CS, Moore MR, Harker G, Villa L, Rinaldi D, Hecht JR. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003 Mar 1;21(5):807-14. [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]
-#Lal R, Dickson J, Cunningham D, Chau I, Norman AR, Ross PJ, Topham C, Middleton G, Hill M, Oates J. A randomized trial comparing defined-duration with continuous irinotecan until disease progression in fluoropyrimidine and thymidylate synthase inhibitor-resistant advanced colorectal cancer. J Clin Oncol. 2004 Aug 1;22(15):3023-31. [https://ascopubs.org/doi/full/10.1200/JCO.2004.01.005 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15284252 PubMed]
-#'''CAIRO:''' Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. [https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17630036 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. -->
-#'''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]
-#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]
-#'''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. [https://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]
-==IRIS {{#subobject:7f7223|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-IRIS: '''<u>IRI</u>'''notecan & '''<u>S</u>'''-1
-===Regimen {{#subobject:dd01b1|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.sciencedirect.com/science/article/pii/S1470204510701819 Muro et al. 2010 (FIRIS)]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#FOLFIRI_3|FOLFIRI]]
-| style="background-color:#eeee01" |Non-inferior OS (*)
-|-
-|}
-''Note: reported efficacy is based on the 2014 update.''
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV once per day on days 1 & 15
-*[[Tegafur, gimeracil, oteracil (S-1)]] as follows:
-**BSA less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 14
-**BSA between 1.25 and 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 14
-**BSA at least 1.5 m<sup>2</sup>: 60 mg PO twice per day on days 1 to 14
-'''28-day cycles'''
-===References===
-#'''FIRIS:''' Muro K, Boku N, Shimada Y, Tsuji A, Sameshima S, Baba H, Satoh T, Denda T, Ina K, Nishina T, Yamaguchi K, Takiuchi H, Esaki T, Tokunaga S, Kuwano H, Komatsu Y, Watanabe M, Hyodo I, Morita S, Sugihara K. Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study). Lancet Oncol. 2010 Sep;11(9):853-60. Epub 2010 Aug 12. [https://www.sciencedirect.com/science/article/pii/S1470204510701819 link to SD article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20708966 PubMed]
-##'''Update:''' Yasui H, Muro K, Shimada Y, Tsuji A, Sameshima S, Baba H, Satoh T, Denda T, Ina K, Nishina T, Yamaguchi K, Esaki T, Tokunaga S, Kuwano H, Boku N, Komatsu Y, Watanabe M, Hyodo I, Morita S, Sugihara K. A phase 3 non-inferiority study of 5-FU/l-leucovorin/irinotecan (FOLFIRI) versus irinotecan/S-1 (IRIS) as second-line chemotherapy for metastatic colorectal cancer: updated results of the FIRIS study. J Cancer Res Clin Oncol. 2015 Jan;141(1):153-60. Epub 2014 Aug 9. [https://link.springer.com/article/10.1007%2Fs00432-014-1783-3 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25106731 PubMed]
-==IROX {{#subobject:2c150d|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-IROX: '''<u>IR</u>'''inotecan & '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:78e355|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/26/28/4544.long Haller et al. 2008]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Irinotecan_monotherapy_2|Irinotecan]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|}
-====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 200 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given second'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''21-day cycles'''
-===References===
-#Haller DG, Rothenberg ML, Wong AO, Koralewski PM, Miller WH Jr, Bodoky G, Habboubi N, Garay C, Olivatto LO. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008 Oct 1;26(28):4544-50. [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]
-=Advanced or metastatic disease, third-line therapy=
-==CapeOx {{#subobject:fed770|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin
-===Example orders===
-*[[Example orders for CapeOx (XELOX) in colon cancer]]
-===Regimen {{#subobject:09dff5|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext Koopman et al. 2007 (CAIRO)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[Complex_multipart_regimens#CAIRO|See link]]
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#CAIRO|See link]]
-|-
-|}
-====Preceding treatment====
-*[[#Irinotecan_monotherapy_2|Irinotecan]], with progression
-====Chemotherapy====
-*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycles'''
-===References===
-#'''CAIRO:''' Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. [https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17630036 PubMed]
-==FOLFIRI {{#subobject:f7001b|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
-===Example orders===
-*[[Example orders for FOLFIRI in colon cancer]]
-===Regimen {{#subobject:31fcbe|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ejcancer.com/article/S0959-8049(99)00150-1/fulltext André et al. 1999]
-| style="background-color:#91cf61" |Non-randomized
-|-
-|}
-====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
-**In André et al. 1999, the continuous infusion dose could be increased from 1200 mg/m<sup>2</sup>/day to 1500 mg/m<sup>2</sup>/day if there were no toxicities higher than grade 1
-*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first, with leucovorin'''
-'''14-day cycles'''
-===References===
-#André T, Louvet C, Maindrault-Goebel F, Couteau C, Mabro M, Lotz JP, Gilles-Amar V, Krulik M, Carola E, Izrael V, de Gramont A. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer; GERCOR. Eur J Cancer. 1999 Sep;35(9):1343-7. [https://www.ejcancer.com/article/S0959-8049(99)00150-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10658525 PubMed]
-==Regorafenib monotherapy {{#subobject:b6f523|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:7ab205|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30027-0/fulltext Eng et al. 2019 (IMblaze370)]
-| style="background-color:#1a9851" |Phase III (C)
-|1. Atezolizumab<br> 2. Atezolizumab & Cobimetinib
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-====Chemotherapy====
-*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21
-'''28-day cycles'''
-===References===
-#'''IMblaze370:''' Eng C, Kim TW, Bendell J, Argilés G, Tebbutt NC, Di Bartolomeo M, Falcone A, Fakih M, Kozloff M, Segal NH, Sobrero A, Yan Y, Chang I, Uyei A, Roberts L, Ciardiello F; IMblaze370 Investigators. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2019 Jun;20(6):849-861. Epub 2019 Apr 16. Erratum in: Lancet Oncol. 2019 Jun;20(6):e293. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30027-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31003911 PubMed]
-=Advanced or metastatic disease, subsequent lines of therapy=
-''Note: these are trials that are for lines other than first-line; trials that specify an inclusion criteria restricted to second-line or third-line therapy are to be found in the sections above.''
-==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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2898%2902309-5/fulltext Cunningham et al. 1998 (V301)]
-| 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 (20020408)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[Colon_cancer,_KRAS_wild-type#Panitumumab_monotherapy|Panitumumab]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|[https://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_2|Cetuximab]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|}
-''No treatment except for supportive care.''
-===References===
-#'''V301:''' Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1413-8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2898%2902309-5/fulltext link to original article] '''contains verified protocol''' [https://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. -->
-#'''20020408:''' 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''' -->
-#'''NCIC CTG CO.17:''' 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. [https://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:''' Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008 Oct 23;359(17):1757-65. [https://www.nejm.org/doi/10.1056/NEJMoa0804385 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18946061 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]
-==Fluorouracil monotherapy {{#subobject:8bb0ed|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:c0f84b|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2010.28.5643 Hendlisz et al. 2010]
-| style="background-color:#1a9851" |Phase III (C)
-|5-FU & Radioembolization
-| style="background-color:#fc8d59" |Seems to have inferior TTP
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 300 mg/m<sup>2</sup>/day IV continuous infusion over 14 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
-'''21-day cycles'''
-===References===
-#Hendlisz A, Van den Eynde M, Peeters M, Maleux G, Lambert B, Vannoote J, De Keukeleire K, Verslype C, Defreyne L, Van Cutsem E, Delatte P, Delaunoit T, Personeni N, Paesmans M, Van Laethem JL, Flamen P. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol. 2010 Aug 10;28(23):3687-94. Epub 2010 Jun 21. [https://ascopubs.org/doi/full/10.1200/JCO.2010.28.5643 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20567019 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
-===Regimen {{#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#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://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)
-|1. [[#FOLFOX4_.26_Bevacizumab|FOLFOX4 & Bevacizumab]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|2. Bevacizumab
-| style="background-color:#d3d3d3" |Not reported
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698019/ Kim et al. 2009 (N9841)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Irinotecan_monotherapy_2|Irinotecan]]
-| style="background-color:#eeee01" |Non-inferior OS
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2010.29.5436 Van Cutsem et al. 2011 (CONFIRM 2)]
-| style="background-color:#1a9851" |Phase III (C)
-|FOLFOX4 & Vatalanib
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-''Note: patients in N9841 had not previously received irinotecan or oxaliplatin; patients in CONFIRM 2 had not previously received oxaliplatin.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''14-day cycles'''
-===References===
-#'''ECOG E3200:''' Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd; 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. [https://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]
-#'''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. [https://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]
-#'''CONFIRM 2:''' Van Cutsem E, Bajetta E, Valle J, Köhne CH, Hecht JR, Moore M, Germond C, Berg W, Chen BL, Jalava T, Lebwohl D, Meinhardt G, Laurent D, Lin E. Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):2004-10. Epub 2011 Apr 4. [https://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]
-==FOLFOX4 (L-Leucovorin) {{#subobject:be17hb|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX4: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-===Regimen {{#subobject:16c59a|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2010.29.5436 Van Cutsem et al. 2011 (CONFIRM 2)]
-| style="background-color:#1a9851" |Phase III (C)
-|FOLFOX4 & Vatalanib
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-''Note: these patients had not previously received oxaliplatin.''
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Levoleucovorin (Fusilev)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
-'''14-day cycles'''
-===References===
-#'''CONFIRM 2:''' Van Cutsem E, Bajetta E, Valle J, Köhne CH, Hecht JR, Moore M, Germond C, Berg W, Chen BL, Jalava T, Lebwohl D, Meinhardt G, Laurent D, Lin E. Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):2004-10. Epub 2011 Apr 4. [https://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]
-==FOLFOX4 & Bevacizumab {{#subobject:8228ca|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FOLFOX4 & Bevacizumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
-===Regimen {{#subobject:2d2be1|Variant=1}}===
-{| class="wikitable" 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://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-RT-esc)
-|1. [[#FOLFOX4_5|FOLFOX4]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|2. Bevacizumab
-| style="background-color:#d3d3d3" |Not reported
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[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. [https://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]
-==FULV & Bevacizumab {{#subobject:83ygca|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FULV & Bevacizumab: 5-'''<u>FU</u>''', '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid), Bevacizumab
-===Regimen {{#subobject:2d7yqg|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2005.05.1573 Chen et al. 2006 (TRC-301)]
-| style="background-color:#91cf61" |Phase II (RT)
-|-
-|}
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]]
-*[[Folinic acid (Leucovorin)]]
-*[[Bevacizumab (Avastin)]]
-===References===
-#'''TRC-301:''' Chen HX, Mooney M, Boron M, Vena D, Mosby K, Grochow L, Jaffe C, Rubinstein L, Zwiebel J, Kaplan RS. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. J Clin Oncol. 2006 Jul 20;24(21):3354-60. [https://ascopubs.org/doi/full/10.1200/JCO.2005.05.1573 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16849749 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2898%2902309-5/fulltext Cunningham et al. 1998 (V301)]
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#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===
-#'''V301:''' Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1413-8. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2898%2902309-5/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9807987 PubMed]
-==Nivolumab monotherapy {{#subobject:ac98g4|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:91abt2|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207072/ Overman et al. 2017 (CheckMate 142)]
-| style="background-color:#91cf61" |Phase II (RT)
-|-
-|}
-'''Biomarker eligibility criteria'''
-dMMR or MSI-H colorectal cancer.
-====Immunotherapy====
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
-*
-'''14-day cycles'''
-===References===
-#'''CheckMate 142:''' Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, Desai J, Hill A, Axelson M, Moss RA, Goldberg MV, Cao ZA, Ledeine JM, Maglinte GA, Kopetz S, André T. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017 Sep;18(9):1182-1191. Epub 2017 Jul 19. Erratum in: Lancet Oncol. 2017 Sep;18(9):e510. [https://www.sciencedirect.com/science/article/pii/S1470204517304229 link to SD article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207072/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28734759 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#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2004.10.037 Rao et al. 2004]
-| style="background-color:#1a9851" |Phase III (C)
-|Tipifarnib
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[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_2|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_2|Regorafenib]]
-| style="background-color:#d73027" |Inferior OS
-|-
-|[https://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 (2014-PT026)]
-| style="background-color:#1a9851" |Phase III (C)
-|MABp1
-| style="background-color:#d73027" |Inferior primary endpoint
-|-
-|[https://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" |Did not meet primary endpoint of OS
-|-
-|[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
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158765/ Van Cutsem et al. 2018 (LUME-Colon 1)]
-| style="background-color:#1a9851" |Phase III (C)
-|Nintedanib
-| style="background-color:#d73027" |Inferior PFS
-|-
-|}
-''No active antineoplastic treatment.''
-===References===
-#Rao S, Cunningham D, de Gramont A, Scheithauer W, Smakal M, Humblet Y, Kourteva G, Iveson T, Andre T, Dostalova J, Illes A, Belly R, Perez-Ruixo JJ, Park YC, Palmer PA. Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. J Clin Oncol. 2004 Oct 1;22(19):3950-7. [https://ascopubs.org/doi/full/10.1200/JCO.2004.10.037 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15459217 PubMed]
-#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]
-##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/273 Project Data Sphere]
-#'''CONCUR:''' Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L, Yeh KH, Bi F, Cheng Y, Le AT, Lin JK, Liu T, Ma D, Kappeler C, Kalmus J, Kim TW; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):619-29. Epub 2015 May 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70156-7/fulltext link to original article] [https://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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1414325 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25970050 PubMed]
-##'''Subgroup analysis:''' Van Cutsem E, Mayer RJ, Laurent S, Winkler R, Grávalos C, Benavides M, Longo-Munoz F, Portales F, Ciardiello F, Siena S, Yamaguchi K, Muro K, Denda T, Tsuji Y, Makris L, Loehrer P, Lenz HJ, Ohtsu A; RECOURSE Study Group. The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer. Eur J Cancer. 2018 Feb;90:63-72. Epub 2017 Dec 21. [https://www.sciencedirect.com/science/article/pii/S0959804917313497 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/29274618 PubMed]
-#'''2014-PT026:''' 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. [https://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]
-#'''LUME-Colon 1:''' Van Cutsem E, Yoshino T, Lenz HJ, Lonardi S, Falcone A, Limón ML, Saunders M, Sobrero A, Park YS, Ferreiro R, Hong YS, Tomasek J, Taniguchi H, Ciardiello F, Stoehr J, Oum'Hamed Z, Vlassak S, Studeny M, Argiles G. Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study. Ann Oncol. 2018 Sep 1;29(9):1955-1963. [https://academic.oup.com/annonc/article/29/9/1955/5053583 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158765/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30010751 PubMed]
-==Regorafenib monotherapy {{#subobject:b6f696|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Variant #1, Standard Dosing {{#subobject:77bz17|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#Comparative_efficacy|Comparative 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-RT-esc)
-|[[#Placebo_2|Placebo]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70156-7/fulltext Li et al. 2015 (CONCUR)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Placebo_2|Placebo]]
-| 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'''
-===Variant #2, Dose-escalation {{#subobject:55bz17|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30272-4/fulltext Bekaii-Saab et al. 2019 (ReDOS)]
-| style="background-color:#1a9851" |Randomized Phase II (E-esc)
-|[[#Regorafenib_monotherapy_2|Regorafenib]]; standard dosing
-| style="background-color:#91cf60" |Seems to have superior OS
-| style="background-color:#1a9850" |Superior rate of patients proceeding to cycle 3
-|-
-|}
-====Chemotherapy====
-**[[Regorafenib (Stivarga)]] as follows:
-**Cycle 1: 80 mg PO once per day on days 1 to 7, then 120 mg PO once per day on days 8 to 15, then 160 mg PO once per day on days 16 to 21
-**Cycle 2 onwards: 160 mg PO once per day on days 1 to 21
-====Supportive medications====
-*Patients received 0.05% [[Clobetasol]] cream twice daily applied to palms and soles starting cycle 1 day 1 or applied when when hand-foot skin reaction developed (no difference in adverse events was found between the two clobetasol strategy groups)
-'''28-day cycles'''
-===References===
-<!-- # '''Abstract:''' Axel Grothey, Alberto F. Sobrero, Salvatore Siena, Alfredo Falcone, Marc Ychou, Heinz-Josef Lenz, Takayuki Yoshino, Frank Cihon, Andrea Wagner, Eric Van Cutsem, on behalf of the CORRECT Study Team. Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. 2012 ASCO Gastrointestinal Cancers Symposium abstract LBA385 [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=115&abstractID=87795 link to abstract] '''contains verified protocol''' -->
-#'''CORRECT:''' Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. [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]
-##'''Dataset:''' [https://www.projectdatasphere.org/projectdatasphere/html/content/273 Project Data Sphere]
-#'''CONCUR:''' Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L, Yeh KH, Bi F, Cheng Y, Le AT, Lin JK, Liu T, Ma D, Kappeler C, Kalmus J, Kim TW; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):619-29. Epub 2015 May 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70156-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25981818 PubMed]
-#'''ReDOS:''' Bekaii-Saab TS, Ou FS, Ahn DH, Boland PM, Ciombor KK, Heying EN, Dockter TJ, Jacobs NL, Pasche BC, Cleary JM, Meyers JP, Desnoyers RJ, McCune JS, Pedersen K, Barzi A, Chiorean EG, Sloan J, Lacouture ME, Lenz HJ, Grothey A. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019 Aug;20(8):1070-1082. Epub 2019 Jun 28. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30272-4/fulltext link to original article] '''contains protocol''' [https://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#Comparative_efficacy|Comparative 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-esc)
-|[[#Placebo_2|Placebo]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1414325 Mayer et al. 2015 (RECOURSE)]
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#Placebo_2|Placebo]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2017.74.3245 Xu et al. 2017 (TERRA)]
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Placebo_2|Placebo]]
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-====Chemotherapy====
-*[[Trifluridine and tipiracil (Lonsurf)]] 35 mg/m<sup>2</sup> PO twice per day, used within 1 hour after the morning and evening meals on days 1 to 5, 8 to 12
-'''28-day cycles'''
-===References===
-#Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, Tsuji A, Yamaguchi K, Muro K, Sugimoto N, Tsuji Y, Moriwaki T, Esaki T, Hamada C, Tanase T, Ohtsu A. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2012 Oct;13(10):993-1001. Epub 2012 Aug 28. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70345-5/fulltext link to original article] '''contains verified protocol''' [https://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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1414325 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25970050 PubMed]
-##'''Subgroup analysis:''' Van Cutsem E, Mayer RJ, Laurent S, Winkler R, Grávalos C, Benavides M, Longo-Munoz F, Portales F, Ciardiello F, Siena S, Yamaguchi K, Muro K, Denda T, Tsuji Y, Makris L, Loehrer P, Lenz HJ, Ohtsu A; RECOURSE Study Group. The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer. Eur J Cancer. 2018 Feb;90:63-72. Epub 2017 Dec 21. [https://www.sciencedirect.com/science/article/pii/S0959804917313497 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/29274618 PubMed]
-#'''TERRA:''' Xu J, Kim TW, Shen L, Sriuranpong V, Pan H, Xu R, Guo W, Han SW, Liu T, Park YS, Shi C, Bai Y, Bi F, Ahn JB, Qin S, Li Q, Wu C, Ma D, Lin D, Li J. Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: The TERRA study. J Clin Oncol. 2018 Feb 1;36(4):350-358. Epub 2017 Dec 7. [https://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]
 [[Category:Colon cancer regimens]]
 [[Category:Disease-specific pages]]
 [[Category:Colorectal cancers]]

Difference between revisions of "Colon cancer"

Latest revision as of 17:45, 23 June 2024

Guidelines

ASCO

ESMO

NCCN

Perioperative therapy

mFOLFOX6 (L-Leucovorin)

Neoadjuvant

Chemotherapy

Definitive

Local therapy

Adjuvant

Chemotherapy

References

Adjuvant therapy

Capecitabine monotherapy

Regimen

Preceding treatment

Chemotherapy

References

CapeOx

Example orders

Regimen variant #1, 3 months

Preceding treatment

Chemotherapy

Regimen variant #2, 6 months

Preceding treatment

Chemotherapy

References

FLOX

Example orders

Regimen

Preceding treatment

Chemotherapy

References

FOLFOX4

Regimen

Preceding treatment

Chemotherapy

References

mFOLFOX6

Example orders

Regimen

Preceding treatment

Chemotherapy

References

mFOLFOX6 (L-Leucovorin)

Example orders

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

Preceding treatment

Chemotherapy

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

Preceding treatment

Chemotherapy

References

FULV

Example orders

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

Preceding treatment

Chemotherapy

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

Preceding treatment

Chemotherapy

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

Preceding treatment

Chemotherapy

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

Preceding treatment

Chemotherapy

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

Preceding treatment

Chemotherapy

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

Preceding treatment

Chemotherapy

Regimen variant #7, 2000/1000

Preceding treatment

Chemotherapy

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

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

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