Colorectal cancer

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Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. 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!
*See the colon cancer page for adjuvant regimens specific to colon cancer.
**See the RAS wild-type colon cancer page for biomarker-specific adjuvant regimens specific to colon cancer.
*See the rectal cancer page for (neo-)adjuvant regimens specific to rectal cancer.
*See the BRAF-mutated CRC page for biomarker-specific regimens.
*See the HER2+ CRC page for biomarker-specific regimens.
*See the KRAS-mutated CRC page for biomarker-specific regimens.
*See the MSI-H/dMMR CRC page for biomarker-specific regimens.
*See the RAS wild-type CRC page for biomarker-specific regimens.
Last updated on 2024-12-02:101 regimens on this page
180 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.
==AIOM==
*2017: Salvatore et al. Management of metastatic colorectal cancer patients: guidelines of the Italian Medical Oncology Association (AIOM) EuroPMC
==ASCO==
*2022: Morris et al. Treatment of Metastatic Colorectal Cancer: ASCO Guideline link to PMC article EuroPMC
*2020: Chiorean et al. Treatment of Patients With Late-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline EuroPMC
*2019: Costas-Chavarri et al. Treatment of Patients With Early-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline EuroPMC
*2013: Meyerhardt et al. Follow-up care, surveillance protocol, and secondary prevention measures for survivors of colorectal cancer: American Society of Clinical Oncology clinical practice guideline endorsement EuroPMC
==ESMO==
*2023: Yoshino et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with metastatic colorectal cancer EuroPMC
*2022: Cervantes et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up EuroPMC
**2016: van Cutsem et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer EuroPMC
**2014: van Cutsem et al. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2010: van Cutsem et al. Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment EuroPMC
**2009: van Cutsem & Oliveira. Advanced colorectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2008: van Cutsem & Oliveira. Advanced colorectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2007: van Cutsem. Advanced colorectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2005: van Cutsem et al. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of advanced colorectal cancer EuroPMC
**2001: ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of advanced colorectal cancer EuroPMC
*2019: Stjepanovic et al. Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2013: Balmaña et al. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines EuroPMC
**2009: Vasen et al. Familial colorectal cancer risk: ESMO clinical recommendations EuroPMC
==French Intergroup==
*2019: Phelip et al. Metastatic colorectal cancer (mCRC): French intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR) EuroPMC
==Japanese Society for Cancer of the Colon and Rectum (JSCCR)==
*2016: Watanabe et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer link to PMC article EuroPMC
==NCCN==
*NCCN Guidelines - Colon Cancer
**2010: Burt et al. NCCN clinical practice guidelines in oncology. Colorectal cancer screening. EuroPMC
**2005: Authors not listed. Guidelines update: colon and rectal cancers. EuroPMC
**2004: Authors not listed. NCCN guideline updates: colon and rectal cancers, version 1.2004. EuroPMC
*NCCN Guidelines - Genetic/Familial High-Risk Assessment: Colorectal
==SEOM-GEMCAD-TTD==
*2023: Fernández Montes et al. SEOM-GEMCAD-TTD clinical guidelines for the systemic treatment of metastatic colorectal cancer (2022) EuroPMC
==SIOG==
*2014: Papamichael et al. Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013 EuroPMC
=Adjuvant therapy=
==Capecitabine monotherapy==
===Regimen variant #1, no BSA cap===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Hamaguchi et al. 2017 (JCOG0910)	2010-2013 	Phase 3 (C)	S-1 	Inconclusive whether non-inferior DFS (primary endpoint)DFS36: 82% vs 77.9%(HR 0.81, 99.05% CI 0.59-1.12)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 8 cycles
===Regimen variant #2, capped BSA===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kerr et al. 2016 (QUASAR 2)	2005-2010 	Phase 3 (C)	Capecitabine & Bevacizumab	Did not meet primary endpoint of DFS36DFS36: 78.4% vs 75.4%(HR 0.94, 95% CI 0.80-1.12)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Capecitabine (Xeloda) 1250 mg/m2 (maximum dose of 2500 mg) PO twice per day on days 1 to 14
21-day cycle for 8 cycles
===References===
#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. Epub 2016 Sep 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN45133151
#JCOG0910: Hamaguchi T, Shimada Y, Mizusawa J, Kinugasa Y, Kanemitsu Y, Ohue M, Fujii S, Takiguchi N, Yatsuoka T, Takii Y, Ojima H, Masuko H, Kubo Y, Mishima H, Yamaguchi T, Bando H, Sato T, Kato T, Nakamura K, Fukuda H, Moriya Y. Capecitabine versus S-1 as adjuvant chemotherapy for patients with stage III colorectal cancer (JCOG0910): an open-label, non-inferiority, randomised, phase 3, multicentre trial. Lancet Gastroenterol Hepatol. 2018 Jan;3(1):47-56. Epub 2017 Oct 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000003272
==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
Iveson et al. 2018 (SCOT)	2008-2013 	Phase 3 (E-de-esc)	1a. CapeOx x 6 mo1b. mFOLFOX6 x 6 mo	Seems to have non-inferior DFS (primary endpoint)DFS36: 76.7% vs 77.1%(HR 1.01, 95% CI 0.91-1.11)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
21-day cycle for 4 cycles
===Regimen variant #2, 6 months===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Pectasides et al. 2015 	2005-2008 	Phase 3 (E-switch-ic)	mFOLFOX6 	Did not meet primary endpoint of DFS
Snoeren et al. 2017 (HEPATICA)	Not reported 	Phase 3 (C) 	CapeOx & Bevacizumab 	Did not meet primary endpoint of DFSDFS12: 68% vs 79%
Iveson et al. 2018 (SCOT) 	2008-2013 	Phase 3 (C) 	1a. CapeOx x 3 mo1b. mFOLFOX6 x 3 mo	Seems to have non-inferior DFSDFS36: 77.1% vs 76.7%(HR 0.99, 95% CI 0.90-1.10)
1Reported efficacy for XELOXA is based on the 2015 update.
Note: HEPATICA enrolled patients with resected colorectal liver metastases.
====Preceding treatment====
*Surgery
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
**Alternative dosing: 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===
#Pectasides D, Karavasilis V, Papaxoinis G, Gourgioti G, Makatsoris T, Raptou G, Vrettou E, Sgouros J, Samantas E, Basdanis G, Papakostas P, Bafaloukos D, Kotoula V, Kalofonos HP, Scopa CD, Pentheroudakis G, Fountzilas G. Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or stage III colorectal cancer. BMC Cancer. 2015 May 10;15:384. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC ANZCTR 12610000509066
#HEPATICA: Snoeren N, van Hillegersberg R, Schouten SB, Bergman AM, van Werkhoven E, Dalesio O, Tollenaar RA, Verheul HM, van der Sijp J, Borel Rinkes IH, Voest EE; Hepatica study group. Randomized phase III study to assess efficacy and safety of adjuvant CAPOX with or without bevacizumab in patients after resection of colorectal liver metastases: HEPATICA study. Neoplasia. 2017 Feb;19(2):93-99. Epub 2017 Jan 12. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
#SCOT: Iveson TJ, Kerr RS, Saunders MP, Cassidy J, Hollander NH, Tabernero J, Haydon A, Glimelius B, Harkin A, Allan K, McQueen J, Scudder C, Boyd KA, Briggs A, Waterston A, Medley L, Wilson C, Ellis R, Essapen S, Dhadda AS, Harrison M, Falk S, Raouf S, Rees C, Olesen RK, Propper D, Bridgewater J, Azzabi A, Farrugia D, Webb A, Cunningham D, Hickish T, Weaver A, Gollins S, Wasan HS, Paul J. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2018 Apr;19(4):562-578. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00749450
#COLOPEC: Klaver CEL, Wisselink DD, Punt CJA, Snaebjornsson P, Crezee J, Aalbers AGJ, Brandt A, Bremers AJA, Burger JWA, Fabry HFJ, Ferenschild F, Festen S, van Grevenstein WMU, Hemmer PHJ, de Hingh IHJT, Kok NFM, Musters GD, Schoonderwoerd L, Tuynman JB, van de Ven AWH, van Westreenen HL, Wiezer MJ, Zimmerman DDE, van Zweeden AA, Dijkgraaf MGW, Tanis PJ; COLOPEC collaborators group. Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial. Lancet Gastroenterol Hepatol. 2019 Oct;4(10):761-770. Epub 2019 Jul 29. link to original article does not contain dosing details in manuscript EuroPMC NCT02231086
==mFOLFOX6==
mFOLFOX6: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin
===Example orders===
*Example orders for mFOLFOX 6 in colon cancer
===Regimen variant #1, 3 months===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Iveson et al. 2018 (SCOT)	2008-2013 	Phase 3 (E-de-esc)	1a. CapeOx x 6 mo1b. mFOLFOX6 x 6 mo	Seems to have non-inferior DFS (primary endpoint)DFS36: 76.7% vs 77.1%(HR 1.01, 95% CI 0.91-1.11)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Leucovorin (Folinic acid) 350 mg/m2 IV over 2 hours once on day 1, given first, with oxaliplatin
*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)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first, with folinic acid
14-day cycle for 6 cycles
===Regimen variant #2, 6 months (LCV 200 mg/m2)===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Pectasides et al. 2015	2005-2008 	Phase 3 (C)	CAPOX 	Did not meet primary endpoint of DFS
====Preceding treatment====
*Surgery, within 10 weeks
====Chemotherapy====
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once on day 1, given first, with oxaliplatin
*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)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first, with folinic acid
14-day cycle for 12 cycles
===Regimen variant #3, 6 months (LCV 350 mg/m2)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Iveson et al. 2018 (SCOT)	2008-2013 	Phase 3 (C)	1a. CapeOx x 3 mo1b. mFOLFOX6 x 3 mo	Seems to have non-inferior DFSDFS36: 77.1% vs 76.7%(HR 0.99, 95% CI 0.90-1.10)
====Preceding treatment====
*Surgery, within 10 weeks
====Chemotherapy====
*Leucovorin (Folinic acid) 350 mg/m2 IV over 2 hours once on day 1, given first, with oxaliplatin
*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)
*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===
#Pectasides D, Karavasilis V, Papaxoinis G, Gourgioti G, Makatsoris T, Raptou G, Vrettou E, Sgouros J, Samantas E, Basdanis G, Papakostas P, Bafaloukos D, Kotoula V, Kalofonos HP, Scopa CD, Pentheroudakis G, Fountzilas G. Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or stage III colorectal cancer. BMC Cancer. 2015 May 10;15:384. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC ANZCTR 12610000509066
#SCOT: Iveson TJ, Kerr RS, Saunders MP, Cassidy J, Hollander NH, Tabernero J, Haydon A, Glimelius B, Harkin A, Allan K, McQueen J, Scudder C, Boyd KA, Briggs A, Waterston A, Medley L, Wilson C, Ellis R, Essapen S, Dhadda AS, Harrison M, Falk S, Raouf S, Rees C, Olesen RK, Propper D, Bridgewater J, Azzabi A, Farrugia D, Webb A, Cunningham D, Hickish T, Weaver A, Gollins S, Wasan HS, Paul J. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2018 Apr;19(4):562-578. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00749450
#JCOG0603: Kanemitsu Y, Shimizu Y, Mizusawa J, Inaba Y, Hamaguchi T, Shida D, Ohue M, Komori K, Shiomi A, Shiozawa M, Watanabe J, Suto T, Kinugasa Y, Takii Y, Bando H, Kobatake T, Inomata M, Shimada Y, Katayama H, Fukuda H; JCOG Colorectal Cancer Study Group. Hepatectomy Followed by mFOLFOX6 Versus Hepatectomy Alone for Liver-Only Metastatic Colorectal Cancer (JCOG0603): A Phase II or III Randomized Controlled Trial. J Clin Oncol. 2021 Dec 1;39(34):3789-3799. Epub 2021 Sep 14. link to original article EuroPMC UMIN000000653
==mFOLFOX6 (L-Leucovorin)==
mFOLFOX6: modified FOLinic acid (L-Leucovorin), Fluorouracil, OXaliplatin
===Example orders===
*Example orders for mFOLFOX 6 in colon cancer
===Regimen variant #1, 3 months, 175 mg/m2 L-LCV===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Iveson et al. 2018 (SCOT)	2008-2013 	Phase 3 (E-de-esc)	1a. CapeOx x 6 mo1b. mFOLFOX6 x 6 mo	Seems to have non-inferior DFS (primary endpoint)DFS36: 76.7% vs 77.1%(HR 1.01, 95% CI 0.91-1.11)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Levoleucovorin (Fusilev) 175 mg/m2 IV over 2 hours once on day 1, given first, with oxaliplatin
*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)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first, with L-folinic acid
14-day cycle for 6 cycles
===Regimen variant #2, 6 months, 175 mg/m2 L-LCV===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Iveson et al. 2018 (SCOT)	2008-2013 	Phase 3 (C)	1a. CapeOx x 3 mo1b. mFOLFOX6 x 3 mo	Seems to have non-inferior DFSDFS36: 77.1% vs 76.7%(HR 0.99, 95% CI 0.90-1.10)
====Preceding treatment====
*Surgery, within 10 weeks
====Chemotherapy====
*Levoleucovorin (Fusilev) 175 mg/m2 IV over 2 hours once on day 1, given first, with oxaliplatin
*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)
*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===
#SCOT: Iveson TJ, Kerr RS, Saunders MP, Cassidy J, Hollander NH, Tabernero J, Haydon A, Glimelius B, Harkin A, Allan K, McQueen J, Scudder C, Boyd KA, Briggs A, Waterston A, Medley L, Wilson C, Ellis R, Essapen S, Dhadda AS, Harrison M, Falk S, Raouf S, Rees C, Olesen RK, Propper D, Bridgewater J, Azzabi A, Farrugia D, Webb A, Cunningham D, Hickish T, Weaver A, Gollins S, Wasan HS, Paul J. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2018 Apr;19(4):562-578. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00749450
==FULV==
FULV: 5-FU & LeucoVorin (Folinic acid)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Ychou et al. 2009	2001-2006 	Phase 3 (C)	FOLFIRI 	Did not meet primary endpoint of DFSMedian DFS: 21.6 vs 24.7 mo(HR 0.90, 95% CI 0.67-1.20)
====Preceding treatment====
*Complete surgical resection of colorectal liver metastases
====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)
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given first
14-day cycle for 12 cycles
===References===
#Ychou M, Hohenberger W, Thezenas S, Navarro M, Maurel J, Bokemeyer C, Shacham-Shmueli E, Rivera F, Kwok-Keung Choi C, Santoro A. A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer. Ann Oncol. 2009 Dec;20(12):1964-70. Epub 2009 Jun 30. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==FULV (L-Leucovorin)==
FULV (L-Leucovorin): 5-FU & LevoLeucoVorin
===Regimen variant #1, 370/25, weekly===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Gray et al. 2000 (QUASAR)	1994-1997 	Phase 3 (C)	1. FULV; HDLV 	Did not meet primary endpoint of OS
Gray et al. 2000 (QUASAR)	1994-1997 	Phase 3 (C)	2. FULV & Levamisole; LDLV 3. FULV & Levamisole; HDLV	Might have longer OS
====Preceding treatment====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 370 mg/m2 IV bolus once on day 1
*Levoleucovorin (Fusilev) 25 mg/m2 IV bolus once on day 1
7-day cycle for 30 cycles
===Regimen variant #2, 1850/125, q4wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Gray et al. 2000 (QUASAR)	1994-1997 	Phase 3 (C)	1. FULV; HDLV 	Did not meet primary endpoint of OS
Gray et al. 2000 (QUASAR)	1994-1997 	Phase 3 (C)	2. FULV & Levamisole; LDLV 3. FULV & Levamisole; HDLV	Might have longer OS
====Preceding treatment====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 370 mg/m2 IV bolus once per day on days 1 to 5
*Levoleucovorin (Fusilev) 25 mg/m2 IV bolus once per day on days 1 to 5
28-day cycle for 6 cycles
===Regimen variant #3, q8wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Shimada et al. 2014 (JCOG0205)	2003-2006 	Phase 3 (C)	Tegafur, Uracil, Folinic acid	Non-inferior DFS (primary endpoint)br>(HR 0.98, 91.3% CI 0.81-1.19)
====Preceding treatment====
*Surgery with D2/D3 lymph node dissection
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV bolus once per day on days 1, 8, 15, 22, 29, 36, given halfway through levoleucovorin infusion
*Levoleucovorin (Fusilev) 250 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
8-week cycle for 3 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00005586
#QUASAR part 2: Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ; Quasar Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007 Dec 15;370(9604):2020-9. link to original article EuroPMC NCT00005586
#JCOG0205: Shimada Y, Hamaguchi T, Mizusawa J, Saito N, Kanemitsu Y, Takiguchi N, Ohue M, Kato T, Takii Y, Sato T, Tomita N, Yamaguchi S, Akaike M, Mishima H, Kubo Y, Nakamura K, Fukuda H, Moriya Y. Randomised phase III trial of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients with stage III colorectal cancer who have undergone Japanese D2/D3 lymph node dissection: final results of JCOG0205. Eur J Cancer. 2014 Sep;50(13):2231-40. Epub 2014 Jun 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00190515
==Tegafur, Uracil, Folinic acid==
UFT + LV: UFT (Tegafur and uracil) & LeucoVorin
===Regimen variant #1, 300/75===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Shimada et al. 2014 (JCOG0205) 	2003-2006 	Phase 3 (E-switch-ic)	FULV (L-Leucovorin)	Non-inferior DFS (primary endpoint)(HR 1.02, 91.3% CI 0.84-1.23)
Hasegawa et al. 2016 	2004-2010 	Phase 3 (E-esc) 	Observation 	Longer RFS (primary endpoint)Median RFS: 1.45 vs 0.7 yrs(HR 0.56, 95% CI 0.38-0.83)
Miyake et al. 2018 (MCSGO-CCTG-0501)	2006-2010 	Phase 3 (C) 	UFT/PSK 	Inconclusive whether non-inferior DFS36 (primary endpoint)DFS36: 82.3% vs 71.1%
Note: Miyake et al. 2018 does not contain treatment details in the abstract.
====Preceding treatment====
*JCOG0205: Surgery with D2/D3 lymph node dissection
*Hasegawa et al. 2016: Surgical resection of colorectal cancer liver metastases, within 8 weeks
====Chemotherapy====
*Tegafur and uracil (UFT) 100 mg/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
===References===
#JCOG0205: Shimada Y, Hamaguchi T, Mizusawa J, Saito N, Kanemitsu Y, Takiguchi N, Ohue M, Kato T, Takii Y, Sato T, Tomita N, Yamaguchi S, Akaike M, Mishima H, Kubo Y, Nakamura K, Fukuda H, Moriya Y. Randomised phase III trial of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients with stage III colorectal cancer who have undergone Japanese D2/D3 lymph node dissection: final results of JCOG0205. Eur J Cancer. 2014 Sep;50(13):2231-40. Epub 2014 Jun 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00190515
#Hasegawa K, Saiura A, Takayama T, Miyagawa S, Yamamoto J, Ijichi M, Teruya M, Yoshimi F, Kawasaki S, Koyama H, Oba M, Takahashi M, Mizunuma N, Matsuyama Y, Watanabe T, Makuuchi M, Kokudo N. Adjuvant oral uracil-tegafur with leucovorin for colorectal cancer liver metastases: A randomized controlled trial. PLoS One. 2016 Sep 2;11(9):e0162400. eCollection 2016. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN C000000013
##Update: Kokudo T, 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, Ishihara S, Makuuchi M, Kokudo N, Hasegawa K. Adjuvant chemotherapy can prolong recurrence-free survival but did not influence the type of recurrence or subsequent treatment in patients with colorectal liver metastases. Surgery. 2021 Oct;170(4):1151-1154. Epub 2021 May 22. link to original article EuroPMC
#MCSGO-CCTG-0501: Miyake Y, Nishimura J, Kato T, Ikeda M, Tsujie M, Hata T, Takemasa I, Mizushima T, Yamamoto H, Sekimoto M, Nezu R, Doki Y, Mori M; Multi-center Clinical Study Group of Osaka, Colorectal Cancer Treatment Group (MCSGO). Phase III trial comparing UFT + PSK to UFT + LV in stage IIB, III colorectal cancer (MCSGO-CCTG). Surg Today. 2018 Jan;48(1):66-72. Epub 2017 Jun 20. link to original article EuroPMC NCT00385970
=Therapy for oligometastatic disease, including perioperative therapy and hyperthermic intra-peritoneal chemotherapy=
==FOLFIRI==
FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Fiorentini et al. 2012	2006-2008 	Phase 3 (C)	DEBIRI 	Seems to have shorter OS (primary endpoint)Median OS: 15 vs 22 mo(HR not reported)
====Chemotherapy====
*Leucovorin (Folinic acid) 100 mg/m2 IV over 120 minutes once on day 1, given first, with irinotecan
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given second on day 1 (total dose per cycle: 2000 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 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. link to original article EuroPMC
==FOLFOX4==
FOLFOX4: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Nordlinger et al. 2008 (EORTC 40983)	2000-2004 	Phase 3 (E-esc)	Observation 	Might have longer PFS (primary endpoint)PFS36: 35.4% vs 28.1%(HR 0.79, 95.66% CI 0.62-1.02)
Hebbar et al. 2014 (MIROX) 	2004-2010 	Phase 3 (C) 	FOLFOX7-FOLFIRI	Did not meet primary endpoint of DFS24
Note: this is the regimen as described by de Gramont et al. 2000; EORTC 40983 refers to this protocol. In MIROX, the treatment could be given perioperatively or postoperatively.
====Preceding treatment====
*Surgical resection of oligometastatic disease
====Chemotherapy====
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, given first, with oxaliplatin on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given second (total dose per cycle: 2000 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first, 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; Australasian Gastro-Intestinal Trials Group; Fédération Francophone de Cancérologie Digestive. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008 Mar 22;371(9617):1007-16. link to original article link to PMC article does not contain dosing details EuroPMC NCT00006479
##Update: Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Mauer M, Tanis E, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und–tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie; Australasian Gastro-Intestinal Trials Group; Fédération Francophone de Cancérologie Digestive. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectalcancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1208-15. Epub 2013 Oct 11. link to original article EuroPMC
#MIROX: Hebbar M, Chibaudel B, André T, Mineur L, Smith D, Louvet C, Dutel JL, Ychou M, Legoux JL, Mabro M, Faroux R, Auby D, Brusquant D, Khalil A, Truant S, Hadengue A, Dalban C, Gayet B, Paye F, Pruvot FR, Bonnetain F, Landi B, Flesch M, Carola E, Martin P, Vaillant E, de Gramont A; Group Coopérateur Multidisciplinaire en Oncologie. FOLFOX4 versus sequential dose-dense FOLFOX7 followed by FOLFIRI in patients with resectable metastatic colorectal cancer (MIROX): a pragmatic approach to chemotherapy timing with perioperative or postoperative chemotherapy from an open-label, randomized phase III trial. Ann Oncol. 2015 Feb;26(2):340-7. Epub 2014 Nov 17. Erratum in: Ann Oncol. 2015 May;26(5):1040. Taieb, J [removed]; Brucker, P [removed]. link to original article EuroPMC NCT00268398
##HRQoL analysis: Hamidou Z, Chibaudel B, Hebbar M, Hug de Larauze M, André T, Louvet C, Brusquant D, Garcia-Larnicol ML, de Gramont A, Bonnetain F. Time to Definitive Health-Related Quality of Life Score Deterioration in Patients with Resectable Metastatic Colorectal Cancer Treated with FOLFOX4 versus Sequential Dose-Dense FOLFOX7 followed by FOLFIRI: The MIROX Randomized Phase III Trial. PLoS One. 2016;11(6):e0157067. link to original article link to EuroPMC
==mFOLFOX6==
mFOLFOX6: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Tang et al. 2020 (BECOME)	2013-2017 	Phase 3 (C)	mFOLFOX6-B	Seems to have shorter OSMedian OS: 20.5 vs 25.7 mo(HR 1.41)
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV once on day 1
14-day cycles
===References===
#BECOME: Tang W, Ren L, Liu T, Ye Q, Wei Y, He G, Lin Q, Wang X, Wang M, Liang F, Cui Y, Xu J. Bevacizumab Plus mFOLFOX6 Versus mFOLFOX6 Alone as First-Line Treatment for RAS Mutant Unresectable Colorectal Liver-Limited Metastases: The BECOME Randomized Controlled Trial. J Clin Oncol. 2020 Sep 20;38(27):3175-3184. Epub 2020 Aug 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01972490
==mFOLFOX6 (L-Leucovorin)==
mFOLFOX6: modified FOLinic acid (L-Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cashin et al. 2016 (SPS-1)	2004-2011 	Randomized (C)	IP 5-FU & LV	Seems to have shorter OS (primary endpoint)Median OS: 18 vs 25 mo(HR 1.96, 95% CI 1.04-3.70)
====Chemotherapy====
*Levoleucovorin (Fusilev) 100 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin (Eloxatin) 100 mg/m2 IV once on day 1
14-day cycle for 12 cycles
===References===
#SPS-1: Cashin PH, Mahteme H, Spång N, Syk I, Frödin JE, Torkzad M, Glimelius B, Graf W. Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: a randomised trial. Eur J Cancer. 2016 Jan;53:155-62. Epub 2016 Jan 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01524094
==mFOLFOX6-B==
mFOLFOX6-B: modified FOLinic acid, Fluorouracil, OXaliplatin, Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Tang et al. 2020 (BECOME)	2013-2017 	Phase 3 (E-esc)	mFOLFOX6 	Seems to have longer OS (secondary endpoint)Median OS: 25.7 vs 20.5 mo(HR 0.71)
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once on day 1, given first
14-day cycles
===References===
#BECOME: Tang W, Ren L, Liu T, Ye Q, Wei Y, He G, Lin Q, Wang X, Wang M, Liang F, Cui Y, Xu J. Bevacizumab Plus mFOLFOX6 Versus mFOLFOX6 Alone as First-Line Treatment for RAS Mutant Unresectable Colorectal Liver-Limited Metastases: The BECOME Randomized Controlled Trial. J Clin Oncol. 2020 Sep 20;38(27):3175-3184. Epub 2020 Aug 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01972490
==FULV==
FULV: 5-FU & LeucoVorin
===Regimen variant #1, 2000/1000===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Portier et al. 2006 (FFCD 9002)	1991-2001 	Phase 3 (E-esc)	Observation	Seems to have longer DFS (primary endpoint)DFS60: 33.5% vs 26.7%(OR 0.66, 95% CI 0.46-0.96)Might have longer PFS1 (secondary endpoint)
1Reported efficacy is based on the 2008 pooled update.
====Preceding treatment====
*Surgical resection of oligometastatic disease
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 to 5, given second
*Leucovorin (Folinic acid) 200 mg/m2 IV once per day on days 1 to 5, given first
28-day cycle for 6 cycles
===Regimen variant #2, 2125/100 with dose escalation===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Kemeny et al. 2006 (CALGB 9481)	1996-2000 	Phase 3 (C)	HAI 	Shorter OS (primary endpoint)Median OS: 20 vs 24.4 mo(HR not reported)
Note: FU dose was increased only in the absence of GI or hematologic toxicity.
====Chemotherapy====
*Fluorouracil (5-FU) given second, as follows:
**Cycle 1: 425 mg/m2 IV once per day on days 1 to 5
**Cycle 2 onwards: 490 mg/m2 IV once per day on days 1 to 5
*Leucovorin (Folinic acid) 20 mg/m2 IV once per day on days 1 to 5, given first
28-day cycles
===References===
#CALGB 9481: Kemeny NE, Niedzwiecki D, Hollis DR, Lenz HJ, Warren RS, Naughton MJ, Weeks JC, Sigurdson ER, Herndon JE 2nd, Zhang C, Mayer RJ. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol. 2006 Mar 20;24(9):1395-403. Epub 2006 Feb 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002716
#FFCD 9002: Portier G, Elias D, Bouche O, Rougier P, Bosset JF, Saric J, Belghiti J, Piedbois P, Guimbaud R, Nordlinger B, Bugat R, Lazorthes F, Bedenne L. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol. 2006 Nov 1;24(31):4976-82. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Pooled update: Mitry E, Fields AL, Bleiberg H, Labianca R, Portier G, Tu D, Nitti D, Torri V, Elias D, O'Callaghan C, Langer B, Martignoni G, Bouché O, Lazorthes F, Van Cutsem E, Bedenne L, Moore MJ, Rougier P. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol. 2008 Oct 20;26(30):4906-11. Epub 2008 Sep 15. link to original article EuroPMC
==Intrahepatic floxuridine==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Allen-Mersh et al. 1994	1988-1993 	Phase 3 (E-esc)	Observation	Seems to have longer OS (co-primary endpoint)Median OS: 405 vs 226 days(HR not reported, p=0.03)
Kemeny et al. 1999 	Not reported 	Phase 3 (E-esc)	Observation	Seems to have higher OS24 (co-primary endpoint)
====Preceding treatment====
*Surgical resection of oligometastatic disease
====Local therapy====
*Floxuridine (FUDR) 0.25 mg/kg/day IA continuous infusion over 14 days, started on day 1 (total dose per cycle: 3.5 mg)
====Supportive therapy====
*Dexamethasone (Decadron) 20 mg IA, admixed with floxuridine and delivered over 14 days
*Unfractionated heparin (UFH) 50,000 units, admixed with floxuridine and delivered over 14 days
21-day cycle for 6 cycles
===References===
#Allen-Mersh TG, Earlam S, Fordy C, Abrams K, Houghton J. Quality of life and survival with continuous hepatic-artery floxuridine infusion for colorectal liver metastases. Lancet. 1994 Nov 5;344(8932):1255-60. link to original article EuroPMC
#Kemeny N, Huang Y, Cohen AM, Shi W, Conti JA, Brennan MF, Bertino JR, Turnbull AD, Sullivan D, Stockman J, Blumgart LH, Fong Y. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med. 1999 Dec 30;341(27):2039-48. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Intrahepatic floxuridine & IV 5-FU==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kemeny et al. 2002 (ECOG E9288)	1990-08 to 1997-01 	Phase 3 (E-esc)	Observation	Seems to have higher RFS48
====Preceding treatment====
*Surgical resection of oligometastatic disease
====Local therapy====
*Floxuridine (FUDR) as follows:
**Cycles 1 to 4: 0.1 mg/kg/day IA continuous infusion over 14 days, started on day 1 (total dose per cycle: 1.4 mg)
====Chemotherapy====
*Fluorouracil (5-FU) as follows:
**Cycles 1 to 4: 200 mg/m2/day IV continuous infusion over 14 days, started on day 15 (total dose per cycle: 2800 mg/m2)
**Cycles 5 to 12: 300 mg/m2/day IV continuous infusion over 14 days, started on day 15 (total dose per cycle: 4200 mg/m2)
'28-day cycle for 12 cycles
===References===
#ECOG E9288: Kemeny MM, Adak S, Gray B, Macdonald JS, Smith T, Lipsitz S, Sigurdson ER, O'Dwyer PJ, Benson AB 3rd. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy--an intergroup study. J Clin Oncol. 2002 Mar 15;20(6):1499-505. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Intraperitoneal 5-FU==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Cashin et al. 2016 (SPS-1)	2004-2011 	Randomized (E-switch-ooc)	mFOLFOX6 	Seems to have longer OS (primary endpoint)Median OS: 25 vs 18 mo(HR 0.51, 95% CI 0.27-0.96)
====Preceding treatment====
*Cytoreductive surgery
====Chemotherapy====
*Fluorouracil (5-FU) 550 mg/m2/day IP continuous infusion over 6 days, started on day 1 (total dose per cycle: 3300 mg/m2)
*Leucovorin (Folinic acid) 30 mg/m2/day IV once on day 1, given 60 minutes after start of 5-FU IP infusion
1-month cycle for 6 cycles
===References===
#SPS-1: Cashin PH, Mahteme H, Spång N, Syk I, Frödin JE, Torkzad M, Glimelius B, Graf W. Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: a randomised trial. Eur J Cancer. 2016 Jan;53:155-62. Epub 2016 Jan 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01524094
==Intraperitoneal hyperthermic mitomycin==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Verwaal et al. 2003	1998-2001 	Phase 3 (E-switch-ooc)	FULV; modified Laufman regimen	Longer OS (primary endpoint)Median OS: 22.3 vs 12.6 mo(HR 0.55, 95% CI 0.32-0.95)
====Preceding treatment====
*Cytoreductive surgery
====Chemotherapy====
*Hyperthermic Mitomycin (Mutamycin) 17.5 mg/m2 IP once, then 8.8 mg/m2 IP every 30 minutes (maximum dose of 70 mg)
One treatment
===References===
#Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003 Oct 15;21(20):3737-43. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Intraperitoneal hyperthermic oxaliplatin==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Quenet et al. 2021 (PRODIGE 7)	2008-2014 	Phase 3 (E-esc)	Cytoreductive surgery without HIPEC	Did not meet primary endpoint of OSMedian OS: 41.7 vs 41.2 mo(HR 1.00, 95.37% CI 0.63-1.58)
Patients enrolled had a peritoneal cancer index of 25 or less
====Preceding treatment====
*Cytoreductive surgery
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV once, 20 minutes prior to HIPEC
*Leucovorin (Folinic acid) 20 mg/m2 IV once, 20 minutes prior to HIPEC
*Hyperthermic Oxaliplatin 360 mg/m2 (closed) or 460 mg/m2 (open) IP once
One treatment
===References===
# PRODIGE 7: Quénet F, Elias D, Roca L, Goéré D, Ghouti L, Pocard M, Facy O, Arvieux C, Lorimier G, Pezet D, Marchal F, Loi V, Meeus P, Juzyna B, de Forges H, Paineau J, Glehen O; UNICANCER-GI Group and BIG Renape Group. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):256-266. Epub 2021 Jan 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00769405
=Advanced or metastatic disease, first-line=
==Capecitabine monotherapy==
C: Capecitabine
===Regimen variant #1, 2000 mg/m2/day===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Cunningham et al. 2013 (AVEX)	2007-2010 	Phase 3 (C)	Capecitabine & Bevacizumab	Shorter PFSMedian PFS: 5.1 vs 9.1 mo(HR 1.89, 95% CI 1.45-2.44)	
Kwakman et al. 2017 (SALTO) 	2014-01 to 2015-07 	Phase 3 (C)	S-1 	Did not meet secondary efficacy endpoints1 	Higher incidence of hand-foot syndrome
1Reported efficacy is based on the 2019 update.
Note: SALTO had a primary toxicity endpoint; this dose was intended for patients at least 70 years old.
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycles
===Regimen variant #2, 2500 mg/m2/day===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Hoff et al. 2001 (SO14695) 	1996-1998 	Phase 3 (E-RT-switch-ic)	FULV 	Higher ORR (primary endpoint) 	
Van Cutsem et al. 2001 (SO14796)	1996-1998 	Phase 3 (E-RT-switch-ic)	FULV 	Equivalent ORR (primary endpoint) 	
Koopman et al. 2007 (CAIRO) 	2003-01 to 2004-12 	Phase 3 (C) 	See link 	See link 	
Tebbutt et al. 2010 (AGITG MAX) 	2005-2007 	Phase 3 (C) 	1. Capecitabine & Bevacizumab	Shorter PFS (primary endpoint)Median PFS: 5.7 vs 8.5 mo(HR 1.59, 95% CI 1.27-2.00)	
Tebbutt et al. 2010 (AGITG MAX) 	2005-2007 	Phase 3 (C) 	2. CBM 	Shorter PFS (primary endpoint)Median PFS: 5.7 vs 8.4 mo(HR 1.69, 95% CI 1.33-2.13)	
Kwakman et al. 2017 (SALTO) 	2014-01 to 2015-07 	Phase 3 (C) 	S-1 	Did not meet secondary efficacy endpoints1 	Higher incidence of hand-foot syndrome
1Reported efficacy for SALTO is based on the 2019 update.
Note: SALTO had a primary toxicity endpoint; this dose was intended for patients less than 70 years old. 
====Chemotherapy====
*Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
21-day cycles
====Subsequent treatment====
*CAIRO, upon progression: Second-line irinotecan
===References===
#SO14695: Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001 Apr 15;19(8):2282-92. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Pooled update: Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. link to original article link to PMC article EuroPMC
#SO14796: Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P; Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001 Nov 1;19(21):4097-106. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Pooled update: Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. link to original article link to PMC article EuroPMC
#CAIRO: Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ; Dutch Colorectal Cancer Group. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00312000
#AGITG MAX: Tebbutt NC, Wilson K, Gebski VJ, Cummins MM, Zannino D, van Hazel GA, Robinson B, Broad A, Ganju V, Ackland SP, Forgeson G, Cunningham D, Saunders MP, Stockler MR, Chua Y, Zalcberg JR, Simes RJ, Price TJ. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group randomized phase III MAX study. J Clin Oncol. 2010 Jul 1;28(19):3191-8. Epub 2010 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#AVEX: Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, Jonker D, Osborne S, Andre N, Waterkamp D, Saunders MP; AVEX study investigators. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label,randomised phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1077-85. Epub 2013 Sep 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00484939
#SALTO: Kwakman JJM, Simkens LHJ, van Rooijen JM, van de Wouw AJ, Ten Tije AJ, Creemers GJM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, van Werkhoven E, Punt CJA; Dutch Colorectal Cancer Group. Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group. Ann Oncol. 2017 Jun 1;28(6):1288-1293. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01918852
##Update: Kwakman JJM, van Werkhoven E, Simkens LHJ, van Rooijen JM, van de Wouw YAJ, ten Tije AJ, Creemers GM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, Punt CJA; Dutch Colorectal Cancer Group. Updated Survival Analysis of the Randomized Phase III Trial of S-1 Versus Capecitabine in the First-Line Treatment of Metastatic Colorectal Cancer by the Dutch Colorectal Cancer Group. Clin Colorectal Cancer. 2019 Jun;18(2):e229-e230. Epub 2019 Jan 29. link to original article EuroPMC
==Capecitabine & Bevacizumab==
CB: Capecitabine & Bevacizumab
===Regimen variant #1, 1000/7.5===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cunningham et al. 2013 (AVEX)	2007-2010 	Phase 3 (E-esc)	Capecitabine	Longer PFS (primary endpoint)Median PFS: 9.1 vs 5.1 mo(HR 0.53, 95% CI 0.41-0.69)
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
===Regimen variant #2, 1250/7.5===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Tebbutt et al. 2010 (AGITG MAX)	2005-2007 	Phase 3 (E-esc)	1. Capecitabine 	Longer PFS (primary endpoint)Median PFS: 8.5 vs 5.7 mo(HR 0.63, 95% CI 0.50-0.79)
Tebbutt et al. 2010 (AGITG MAX)	2005-2007 	Phase 3 (E-esc)	2. CBM 	Not reported
André et al. 2022 (SOLSTICE) 	2019-03-21 to 2020-09-14	Phase 3 (C) 	Trifluridine-tipiracil & Bevacizumab	Might have shorter PFS (primary endpoint)Median PFS: 9.3 vs 9.4 mo(HR 1.15, 95% CI 0.98-1.33)
====Chemotherapy====
*Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
===Regimen variant #3, renally adjusted===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Takashima et al. 2024 (JCOG1018)	2012-09 to 2019-03 	Phase 3 (C)	1a. CapeOx & Bevacizumab1b. FOLFOX & Bevacizumab	Did not meet primary endpoint of PFSMedian PFS: 9.4 vs 10 mo(HR 1.19, 90.5% CI 0.96-1.49)
====Eligibility criteria====
*Age 70 to 74 years old with ECOG PS of 2 OR Age 75 years and older with ECOG PS of 0 to 2
====Chemotherapy====
*Capecitabine (Xeloda) by following laboratory-based criteria:
**CrCl at least 30 up to 50 mL/min/1.73m2: 1000 mg/m2 PO twice per day on days 1 to 14
**CrCl 50 mL/min/1.73m2 or more: 1250 mg/m2 PO twice per day on days 1 to 14
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
===References===
#AGITG MAX: Tebbutt NC, Wilson K, Gebski VJ, Cummins MM, Zannino D, van Hazel GA, Robinson B, Broad A, Ganju V, Ackland SP, Forgeson G, Cunningham D, Saunders MP, Stockler MR, Chua Y, Zalcberg JR, Simes RJ, Price TJ. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group randomized phase III MAX study. J Clin Oncol. 2010 Jul 1;28(19):3191-8. Epub 2010 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#AVEX: Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, Jonker D, Osborne S, Andre N, Waterkamp D, Saunders MP; AVEX study investigators. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label,randomised phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1077-85. Epub 2013 Sep 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00484939
#XELAVIRI: Modest DP, Fischer von Weikersthal L, Decker T, Vehling-Kaiser U, Uhlig J, Schenk M, Freiberg-Richter J, Peuser B, Denzlinger C, Peveling Genannt Reddemann C, Graeven U, Schuch G, Schwaner I, Stahler A, Jung A, Kirchner T, Held S, Stintzing S, Giessen-Jung C, Heinemann V; XELAVIRI/AIO KRK0110 Investigators. Sequential Versus Combination Therapy of Metastatic Colorectal Cancer Using Fluoropyrimidines, Irinotecan, and Bevacizumab: A Randomized, Controlled Study-XELAVIRI (AIO KRK0110). J Clin Oncol. 2019 Jan 1;37(1):22-32. Epub 2018 Nov 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01249638
#SOLSTICE: André T, Falcone A, Shparyk Y, Moiseenko F, Polo-Marques E, Csöszi T, Campos-Bragagnoli A, Liposits G, Chmielowska E, Aubel P, Martín L, Fougeray R, Amellal N, Saunders MP. Trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer ineligible for intensive therapy (SOLSTICE): a randomised, open-label phase 3 study. Lancet Gastroenterol Hepatol. 2023 Feb;8(2):133-144. Epub 2022 Dec 2. link to original article EuroPMC NCT03869892
#JCOG1018: Takashima A, Hamaguchi T, Mizusawa J, Nagashima F, Ando M, Ojima H, Denda T, Watanabe J, Shinozaki K, Baba H, Asayama M, Hasegawa S, Masuishi T, Nakata K, Tsukamoto S, Katayama H, Nakamura K, Fukuda H, Kanemitsu Y, Shimada Y; Colorectal Cancer Study Group in Japan Clinical Oncology Group (JCOG). Oxaliplatin Added to Fluoropyrimidine/Bevacizumab as Initial Therapy for Unresectable Metastatic Colorectal Cancer in Older Patients: A Multicenter, Randomized, Open-Label Phase III Trial (JCOG1018). J Clin Oncol. 2024 Nov 20;42(33):3967-3976. Epub 2024 Aug 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC jRCTs031180145
==CapeOx==
CapeOX: Capecitabine & OXaliplatin
XELOX: XELoda & OXaliplatin
COX: Capecitabine & OXaliplatin
===Example orders===
*Example orders for CapeOx (XELOX) in colon cancer
===Regimen variant #1, 850/130===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hochster et al. 2008 (TREE-1)	2002-12 to 2003-11 	Phase 3 (E-switch-ic)	1. bFOL 	Did not meet secondary efficacy endpoints
Hochster et al. 2008 (TREE-1)	2002-12 to 2003-11 	Phase 3 (E-switch-ic)	2. mFOLFOX6	Did not meet secondary efficacy endpoints
Note: TREE-1 did not have any primary endpoints.
====Chemotherapy====
*Capecitabine (Xeloda) 850 mg/m2 PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
21-day cycles
===Regimen variant #2, 1000/70===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Porschen et al. 2007	2002-2004 	Phase 3 (E-switch-ic)	FUFOX 	Inconclusive whether non-inferior PFS (primary endpoint)
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 70 mg/m2 IV over 2 hours once per day on days 1 & 8
21-day cycles
===Regimen variant #3, 1000/130===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Díaz-Rubio et al. 2007 (03-TTD-01)	2002-2004 	Phase 3 (E-switch-ic)	FUOX 	Did not meet primary endpoint of TTP
Ducreux et al. 2011 	2003-05-16 to 2004-08-31	Phase 3 (E-switch-ic)	mFOLFOX6 	Non-inferior OS (secondary endpoint)Median OS: 19.9 vs 20.5 mo
Cassidy et al. 2008 (NO16966) 	2003-2005 	Phase 3 (C) 	1. FOLFOX42. FOLFOX4 & Bevacizumab 	Non-inferior PFS
Cassidy et al. 2008 (NO16966) 	2003-2005 	Phase 3 (C) 	3. XELOX & Bevacizumab 	Not reported
Saltz et al. 2008 (NO16966) 	2003-2005 	Phase 3 (C) 	1. FOLFOX4 & Bevacizumab2. XELOX & Bevacizumab 	Shorter PFS
Saltz et al. 2008 (NO16966) 	2003-2005 	Phase 3 (C) 	3. FOLFOX4 	Not reported
Maughan et al. 2011 (UK MRC COIN) 	2005-2008 	Phase 3 (C) 	1a. CapeOx & Cetuximab1b. mFOLFOX6 & Cetuximab 	Did not meet primary endpoint of OS1
Hoff et al. 2012 (HORIZON II) 	2006 to not reported 	Phase 3 (C) 	1a. CAPOX & Cediranib1b. FOLFOX4 & Cediranib1c. mFOLFOX6 & Cediranib	Seems to have shorter PFS (co-primary endpoint)Median PFS: 8.3 vs 8.6 mo(HR 1.19, 95% CI 1.02-1.37)
Hong et al. 2012 (SMC 2008-03-012)	2008-05-14 to 2009-09-23	Phase 3 (C) 	SOX 	Non-inferior PFSMedian PFS: 6.7 vs 8.5 mo(HR 1.27, 95% CI 0.96-1.67)
1Reported efficacy for UK MRC COIN is for KRAS wild-type patients.
Note: NO16966 stated 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. Although NO16966 was one study, it was published simultaneously as two manuscripts looking at different aspects of the 2 x 2 factorial design (Cassidy et al. 2008 and Saltz et al. 2008).
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
**Alternative dosing: 1000 mg/m2 PO twice per day 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 varying durations: 8 cycles (Ducreux et al. 2011, HORIZON II); 9 cycles (SMC 2008-03-012); 12 cycles (03-TTD-01); indefinitely (NO16966, UK MRC COIN) 
====Subsequent treatment====
*SMC 2008-03-012: Optional 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#03-TTD-01: Díaz-Rubio E, Tabernero J, Gómez-España A, Massutí B, Sastre J, Chaves M, Abad A, Carrato A, Queralt B, Reina JJ, Maurel J, González-Flores E, Aparicio J, Rivera F, Losa F, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol. 2007 Sep 20;25(27):4224-30. Epub 2007 Jun 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00202774
#NO16966: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00069095
##Update: Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64. Epub 2011 Jun 14. link to original article link to PMC article EuroPMC
#TREE: Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Ducreux M, Bennouna J, Hebbar M, Ychou M, Lledo G, Conroy T, Adenis A, Faroux R, Rebischung C, Bergougnoux L, Kockler L, Douillard JY; GI Group of the French Anti-Cancer Centers. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer. Int J Cancer. 2011 Feb 1;128(3):682-90. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#UK MRC COIN: Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP; MRC COIN Trial Investigators. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011 Jun 18;377(9783):2103-14. Epub 2011 Jun 5. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00182715
##Update: Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, Kenny SL, Kay E, Hodgkinson E, Pope M, Rogers P, Wasan H, Falk S, Gollins S, Hickish T, Bessell EM, Propper D, Kennedy MJ, Kaplan R, Maughan TS; MRC COIN Trial Investigators. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011 Jul;12(7):642-53. Epub 2011 Jun 5. link to original article link to PMC article EuroPMC
#HORIZON II: Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00399035
#SMC 2008-03-012: Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00677443
##Update: Kim ST, Hong YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Lee JW, Jo SJ, Park YS. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: updated results from a phase 3 trial. BMC Cancer. 2014 Nov 26;14:883. link to original article link to PMC article EuroPMC
==CapeOx & Bevacizumab==
CapeOX & Bevacizumab: Capecitabine, OXaliplatin, Bevacizumab
CAPOX-B: CAPecitabine, OXaliplatin, Bevacizumab
XELOX & Bevacizumab: XELoda, OXaliplatin, Bevacizumab
===Regimen variant #1, 850/130/7.5===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Hochster et al. 2008 (TREE-2)	2003-11 to 2004-04 	Phase 3 (E-switch-ic)	1. bFOL & Bevacizumab	Did not meet secondary efficacy endpoints	Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
Hochster et al. 2008 (TREE-2)	2003-11 to 2004-04 	Phase 3 (E-switch-ic)	2. mFOLFOX6-B 	Did not meet secondary efficacy endpoints	Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
====Chemotherapy====
*Capecitabine (Xeloda) by the following renal function-based criteria:
**CrCl more than 50 mL/min/1.73 m2: 850 mg/m2 PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
**CrCl 30 to 50 mL/min/1.73 m2: 650 mg/m2 PO twice per day 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
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
===Regimen variant #2, 1000/85/5 x 12, "modified CapeOx"===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Avallone et al. 2021 (OBELICS)	2012-2014 	Phase 3 (C)	1a. mFOLFOX6-B; early bevacizumab1b. CapeOx & Bevacizumab; early bevacizumab	Did not meet primary endpoint of ORR (primary endpoint)ORR: 57.4% vs 56.5%
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 10
*Oxaliplatin (Eloxatin) 85 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once on day 1
14-day cycle for 12 cycles
===Regimen variant #3, 1000/130/7.5 x 6===
Study 	Dates of enrollment	Evidence
Díaz-Rubio et al. 2012 (MACRO) 	2006-2008 	Non-randomized part of phase 3 RCT
Johnsson et al. 2013 (Nordic ACT)	2007-2009 	Non-randomized part of phase 3 RCT
Simkens et al. 2015 (CAIRO3) 	2007-2012 	Non-randomized part of phase 3 RCT
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycle for 6 cycles
====Subsequent treatment====
*MACRO: Bevacizumab versus XELOX & Bevacizumab maintenance
*Nordic ACT: Bevacizumab versus Erlotinib & Bevacizumab maintenance
*CAIRO3: Capecitabine & Bevacizumab maintenance versus Observation
===Regimen variant #4, 1000/130/7.5 x 6, followed by cape/bev maintenance===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Tol et al. 2009 (CAIRO2) 	2005-06 to 2006-12 	Phase 3 (C)	CapeOx, Bevacizumab, Cetuximab 	Seems to have longer PFS (primary endpoint)Median PFS: 10.7 vs 9.4 mo(HR 0.82, 95% CI 0.70-0.96)
Pan et al. 2024 (B2019-023-01)	2019-03-20 to 2022-04-07	Phase 3 (C)	CapeOx, Bevacizumab, PD1-T cells	Shorter PFS (primary endpoint)Median PFS: 9.9 vs 14.8 mo(HR 1.67, 95% CI 1.14-2.50)
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) as follows:
**Cycles 1 to 6: 130 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
===Regimen variant #5, 1000/130/7.5, indefinite===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cassidy et al. 2008 (NO16966) 	2003-2005 	Phase 3 (E-RT-esc) 	1. FOLFOX42. FOLFOX4 & Bevacizumab	Non-inferior PFS (primary endpoint)
Cassidy et al. 2008 (NO16966) 	2003-2005 	Phase 3 (E-RT-esc) 	3. XELOX 	Not reported
Saltz et al. 2008 (NO16966) 	2003-2005 	Phase 3 (E-RT-esc) 	1. FOLFOX42. XELOX 	Longer PFS (primary endpoint)Median PFS: 9.4 vs 8 mo(HR 0.83, 97.5% CI 0.72-0.95)
Saltz et al. 2008 (NO16966) 	2003-2005 	Phase 3 (E-RT-esc) 	3. FOLFOX4 & Bevacizumab 	Not reported
Yamada et al. 2018 (TRICOLORE)	2012-2014 	Phase 3 (C) 	IRIS & Bevacizumab 	Non-inferior PFSMedian PFS: 10.8 vs 14 mo(HR 1.19, 95% CI 0.98-1.43)
Nakayama 2018 (CCOG-1201) 	2012-2016 	Randomized Phase 2 (C)	CAPIRI & Bevacizumab 	Did not meet primary endpoint of ORR
Note: NO16966 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. Although this was one study, it was published simultaneously as two manuscripts looking at different aspects of the 2 x 2 factorial design (Cassidy et al. 2008 and Saltz et al. 2008).
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
**Alternate dosing: 1000 mg/m2 PO twice per day 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, given second
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV over 30 to 90 minutes once on day 1, given first
21-day cycles
===References===
#NO16966: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00069095
##Update: Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64. Epub 2011 Jun 14. link to original article link to PMC article EuroPMC
#TREE-2: Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00399750
#CAIRO2: Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, Erdkamp FL, Vos AH, van Groeningen CJ, Sinnige HA, Richel DJ, Voest EE, Dijkstra JR, Vink-Börger ME, Antonini NF, Mol L, van Krieken JH, Dalesio O, Punt CJ; Dutch Colorectal Cancer Group. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009 Feb 5;360(6):563-72. Erratum in: N Engl J Med. 2010 Dec 23;363(26):2573. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00208546
##Subgroup analysis: Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009 Jul 2;361(1):98-9. Erratum in: N Engl J Med. 2011 Sep 1;365(9):869. link to original article EuroPMC
##Update: Ten Hoorn S, Mol L, Sommeijer DW, Nijman L, van den Bosch T, de Back TR, Ylstra B, van Dijk E, van Noesel CJM, Reinten RJ, Nagtegaal ID, Koopman M, Punt CJA, Vermeulen L. Long-term Survival Update and Extended RAS Mutational Analysis of the CAIRO2 Trial: Addition of Cetuximab to CAPOX/Bevacizumab in Metastatic Colorectal Cancer. Clin Colorectal Cancer. 2023 Mar;22(1):67-75. Epub 2022 Dec 5. link to original article EuroPMC
#MACRO: Díaz-Rubio E, Gómez-España A, Massutí B, Sastre J, Abad A, Valladares M, Rivera F, Safont MJ, Martínez de Prado P, Gallén M, González E, Marcuello E, Benavides M, Fernández-Martos C, Losa F, Escudero P, Arrivi A, Cervantes A, Dueñas R, López-Ladrón A, Lacasta A, Llanos M, Tabernero JM, Antón A, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors. First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study. Oncologist. 2012;17(1):15-25. Epub 2012 Jan 10. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00335595
#Nordic ACT: Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00598156
#CAIRO3: Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoeven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, Honkoop AH, Mol L, Punt CJ, Koopman M; Dutch Colorectal Cancer Group. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015 May 9;385(9980):1843-52. Epub 2015 Apr 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00442637
##Update: Goey KKH, Elias SG, van Tinteren H, Laclé MM, Willems SM, Offerhaus GJA, de Leng WWJ, Strengman E, Ten Tije AJ, Creemers GM, van der Velden A, de Jongh FE, Erdkamp FLG, Tanis BC, Punt CJA, Koopman M. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann Oncol. 2017 Sep 1;28(9):2128-2134. link to original article EuroPMC
#TRICOLORE: Yamada Y, Denda T, Gamoh M, Iwanaga I, Yuki S, Shimodaira H, Nakamura M, Yamaguchi T, Ohori H, Kobayashi K, Tsuda M, Kobayashi Y, Miyamoto Y, Kotake M, Shimada K, Sato A, Morita S, Takahashi S, Komatsu Y, Ishioka C. S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized, open-label, phase III, noninferiority trial. Ann Oncol. 2018 Mar 1;29(3):624-631. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC UMIN000007834
#CCOG-1201: Nakayama G, Mitsuma A, Sunagawa Y, Ishigure K, Yokoyama H, Matsui T, Nakayama H, Nakata K, Ishiyama A, Asada T, Umeda S, Ezaka K, Hattori N, Takami H, Kobayashi D, Tanaka C, Kanda M, Yamada S, Koike M, Fujiwara M, Fujii T, Murotani K, Ando Y, Kodera Y. Randomized phase II trial of CapOX plus bevacizumab and capIRI plus bevacizumab as first-line treatment for Japanese patients with metastatic colorectal cancer (CCOG-1201 study). Oncologist. 2018 Aug;23(8):919-927. Epub 2018 Jul 26. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC UMIN000006478
#OBELICS: Avallone A, Piccirillo MC, Nasti G, Rosati G, Carlomagno C, Di Gennaro E, Romano C, Tatangelo F, Granata V, Cassata A, Silvestro L, De Stefano A, Aloj L, Vicario V, Nappi A, Leone A, Bilancia D, Arenare L, Petrillo A, Lastoria S, Gallo C, Botti G, Delrio P, Izzo F, Perrone F, Budillon A. Effect of Bevacizumab in Combination With Standard Oxaliplatin-Based Regimens in Patients With Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA Netw Open. 2021 Jul 1;4(7):e2118475. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01718873
#B2019-023-01: Pan QZ, Zhao JJ, Liu L, Zhang DS, Wang LP, Hu WW, Weng DS, Xu X, Li YZ, Tang Y, Zhang WH, Li JY, Zheng X, Wang QJ, Li YQ, Xiang T, Zhou L, Yang SN, Wu C, Huang RX, He J, Du WJ, Chen LJ, Wu YN, Xu B, Shen Q, Zhang Y, Jiang JT, Ren XB, Xia JC. XELOX (capecitabine plus oxaliplatin) plus bevacizumab (anti-VEGF-A antibody) with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer: a multicenter, open-label, randomized, controlled, phase 3 trial. Signal Transduct Target Ther. 2024 Apr 3;9(1):79. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03950154
==CAPIRI==
CapeIRI: Capecitabine and IRInotecan
CAPIRI: CAPecitabine and IRInotecan
XELIRI: XELox (Capecitabine) and IRInotecan
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Moehler et al. 2009a 	2001-2006 	Phase 2 	 	
Koopman et al. 2007 (CAIRO) 	2003-01 to 2004-12 	Phase 3 (E-switch-ic)	See link 	See link
Fuchs et al. 2007 (BICC-C) 	2003-02 to 2004-12 	Phase 3 (E-switch-ic)	1. FOLFIRI 	Seems to have shorter PFS (primary endpoint)
Fuchs et al. 2007 (BICC-C) 	2003-02 to 2004-12 	Phase 3 (E-switch-ic)	2. mIFL 	Did not meet primary endpoint of PFS
Köhne et al. 2007 (EORTC 40015)	2003-2005 	Phase 3 (E-switch-ic)	FOLFIRI +/- Celecoxib	Inconclusive whether non-inferior PFS (primary endpoint)
Note: EORTC 40015 was closed prematurely.
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Irinotecan (Camptosar) 250 mg/m2 IV over 30 to 90 minutes once on day 1
21-day cycles
====Subsequent treatment====
*CAIRO, with progression: Second-line CapeOx
===References===
#CAIRO: Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ; Dutch Colorectal Cancer Group. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00312000
#BICC-C: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article EuroPMC
#EORTC 40015: Köhne CH, De Greve J, Hartmann JT, Lang I, Vergauwe P, Becker K, Braumann D, Joosens E, Müller L, Janssens J, Bokemeyer C, Reimer P, Link H, Späth-Schwalbe E, Wilke HJ, Bleiberg H, Van Den Brande J, Debois M, Bethe U, Van Cutsem E. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer: EORTC study 40015. Ann Oncol. 2008 May;19(5):920-6. Epub 2007 Dec 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00064181
#Moehler M, Sprinzl MF, Abdelfattah M, Schimanski CC, Adami B, Godderz W, Majer K, Flieger D, Teufel A, Siebler J, Hoehler T, Galle PR, Kanzler S. Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients. World J Gastroenterol. 2009 Jan 28;15(4):449-56. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==CAPIRI-Bev==
CAPIRI-Bev: CAPecitabine, IRInotecan, Bevacizumab
XELIRI-Bev: XELoda (Capecitabine), IRInotecan, Bevacizumab
===Regimen variant #1, 750/150/7.5===
Study 	Dates of enrollment	Evidence
Johnsson et al. 2013 (Nordic ACT)	2007-2009 	Non-randomized part of phase 3 RCT
Note: This dose was recommended for patients older than 65 years.
====Chemotherapy====
*Capecitabine (Xeloda) 750 mg/m2 PO twice per day on days 1 to 14
*Irinotecan (Camptosar) 150 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycle for 6 cycles
====Subsequent treatment====
*Bevacizumab versus Erlotinib & Bevacizumab maintenance
===Regimen variant #2, 800/200/7.5===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Modest et al. 2018 (XELAVIRI)	2010-2016 	Phase 3 (E-esc)	Cape-Bev 	Inconclusive whether non-inferior TFS (primary endpoint)
====Chemotherapy====
*Capecitabine (Xeloda) 800 mg/m2 PO twice per day on days 1 to 14
*Irinotecan (Camptosar) 200 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
===Regimen variant #3, 1000/180/7.5===
Study 	Dates of enrollment	Evidence
Johnsson et al. 2013 (Nordic ACT)	2007-2009 	Non-randomized part of phase 3 RCT
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Irinotecan (Camptosar) 180 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycle for 6 cycles
====Subsequent treatment====
*Bevacizumab versus Erlotinib & Bevacizumab maintenance
===Regimen variant #4, 1000/200/7.5===
Study 	Dates of enrollment	Evidence
Moehler et al. 2009a	2001-2006 	Phase 2
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Irinotecan (Camptosar) 200 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
===Regimen variant #5, 1000/240/7.5===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Pectasides et al. 2012	2006-2008 	Phase 3 (E-switch-ic)	FOLFIRI-Bev	Did not meet primary endpoint of PFS
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Irinotecan (Camptosar) 240 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycle for 6 cycles
===References===
#Moehler M, Sprinzl MF, Abdelfattah M, Schimanski CC, Adami B, Godderz W, Majer K, Flieger D, Teufel A, Siebler J, Hoehler T, Galle PR, Kanzler S. Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients. World J Gastroenterol. 2009 Jan 28;15(4):449-56. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
#Pectasides D, Papaxoinis G, Kalogeras KT, Eleftheraki AG, Xanthakis I, Makatsoris T, Samantas E, Varthalitis I, Papakostas P, Nikitas N, Papandreou CN, Pentheroudakis G, Timotheadou E, Koutras A, Sgouros J, Bafaloukos D, Klouvas G, Economopoulos T, Syrigos KN, Fountzilas G; Hellenic Cooperative Oncology Group. XELIRI-bevacizumab versus FOLFIRI-bevacizumab as first-line treatment in patients with metastatic colorectal cancer: a Hellenic Cooperative Oncology Group phase III trial with collateral biomarker analysis. BMC Cancer. 2012 Jun 29;12:271. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC ACTRN12610000270011
#Nordic ACT: Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00598156
#XELAVIRI: Modest DP, Fischer von Weikersthal L, Decker T, Vehling-Kaiser U, Uhlig J, Schenk M, Freiberg-Richter J, Peuser B, Denzlinger C, Peveling Genannt Reddemann C, Graeven U, Schuch G, Schwaner I, Stahler A, Jung A, Kirchner T, Held S, Stintzing S, Giessen-Jung C, Heinemann V; XELAVIRI/AIO KRK0110 Investigators. Sequential Versus Combination Therapy of Metastatic Colorectal Cancer Using Fluoropyrimidines, Irinotecan, and Bevacizumab: A Randomized, Controlled Study-XELAVIRI (AIO KRK0110). J Clin Oncol. 2019 Jan 1;37(1):22-32. Epub 2018 Nov 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01249638
==Fluorouracil monotherapy==
===Regimen variant #1, 370 mg/m2 intermittent bolus===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Bobbio-Pallavicini et al. 1993	Not reported in abstract	Phase 3 (C)	FULV 	Seems to have shorter OSMedian OS: 6 vs 8 mo(HR not reported)
Note: The full manuscript was not available for review.
====Chemotherapy====
*Fluorouracil (5-FU) 370 mg/m2 IV bolus once per day on days 1 to 5
28-day cycles
===Regimen variant #2, 400 mg/m2 intermittent bolus===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Labianca et al. 1991	1987-1989 	Phase 3 (C)	FULV 	Seems to have lower ORR
Borner et al. 1998 	1991-1995 	Phase 3 (C)	FULV 	Seems to have shorter OS (primary endpoint)Median OS: 10 vs 12.4 mo(HR not reported)
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 to 5
28-day cycles
===Regimen variant #3, 450 mg/m2 intermittent bolus===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Molinaro et al. 1989	1984-06 to 1985-09 	Phase 3 (C)	Epirubicin	Higher ORR
Note: this dose was used for those who had previously been exposed to radiotherapy.
====Chemotherapy====
*Fluorouracil (5-FU) 450 mg/m2 IV bolus once per day on days 1 to 5
28-day cycles
===Regimen variant #4, 500 mg/m2 intermittent bolus===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Molinaro et al. 1989	1984-06 to 1985-09 	Phase 3 (C)	Epirubicin 	Higher ORR
Lokich et al. 1989 	1984-1986 	Phase 3 (C)	5-FU; PVI 	Lower ORR
Poon et al. 1989 	1984-1987 	Phase 3 (C)	FULV 	Seems to have shorter OS
O'Connell 1989 	Not reported 	Phase 3 (C)	1. FULV; LDLV	Seems to have shorter OS
O'Connell 1989 	Not reported 	Phase 3 (C)	2. FULV; HDLV	Did not meet primary efficacy endpoint
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV bolus once per day on days 1 to 5
4- to 5-week cycles
===Regimen variant #5, 600 mg/m2/week===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Douglass et al. 1978 (ECOG E4273)	Not reported 	Phase 2/3 (E-switch-ic)	1. 5-FU; PO2. Cyclophosphamide & 5-FU3. 5-FU & 6-TG4. Semustine	Did not meet endpoint of OS
Smyth et al. 1995 (F-trial) 	1989-1992 	Phase 3 (C) 	TCNU 	Did not meet efficacy endpoint
Note: it is not clear from ECOG E4273 whether 5-FU was a control or experimental arm; the IV formulation appears to be experimental in this trial.
====Chemotherapy====
*Fluorouracil (5-FU) 600 mg/m2 IV bolus once on day 1
7-day cycles
===Regimen variant #6, 600 mg/m2/week, 6 out of 8 weeks===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Richards et al. 1986 	1977-1980 	Phase 3 (C)	MMF 	Did not meet efficacy endpoints
Kalofonos et al. 2002	1993-1998 	Phase 3 (C)	1. 5-FU & IFN alfa2. FULV	Did not meet primary endpoint of OS
====Chemotherapy====
*Fluorouracil (5-FU) 600 mg/m2 IV bolus once per day on days 1, 8, 15, 22, 29, 36
8-week cycles
===Regimen variant #7, weekly bolus with CI lead-in===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Greco et al. 1996	1989-1992 	Phase 3 (C)	5-FU & IFN alfa-2a	Did not meet primary endpoint of ORR
Hill et al. 1995 	1990-1992 	Phase 3 (C)	5-FU & IFN alfa-2b	Did not meet efficacy endpoints
====Chemotherapy====
*Fluorouracil (5-FU) as follows:
**Cycle 1: 750 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose: 3750 mg/m2)
**Cycle 2 onwards: 750 mg/m2 IV bolus once on day 1
7-day cycle for varying durations: 52 cycles (Hill et al. 1995); indefinitely (Greco et al. 1996)
===Regimen variant #8, weekly CI===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Aranda et al. 1998	1994-1996 	Phase 3 (E-switch-ic)	FULV; Mayo Clinic regimen	Seems to have higher ORR
====Chemotherapy====
*Fluorouracil (5-FU) 1750 mg/m2/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 3500 mg/m2)
7-day cycles
===Regimen variant #9, PVI ("Lokich regimen")===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Lokich et al. 1989 	1984-1986 	Phase 3 (E-switch-ic)	5-FU; bolus 	Higher ORR
Hansen et al. 1996 (ECOG E2286)	1987-1990 	Phase 3 (E-switch-ic)	5-FU; bolus 	Longer TTP
Maughan et al. 2002 (MRC CR06) 	1996-1998 	Phase 3 (C) 	1. FULV; de Gramont regimen	Did not meet primary endpoint of OS
Maughan et al. 2002 (MRC CR06) 	1996-1998 	Phase 3 (C) 	2. Raltitrexed 	Did not meet primary endpoint of OS
====Chemotherapy====
*Fluorouracil (5-FU) 300 mg/m2/day IV continuous infusion
Continued indefinitely
===Regimen variant #10, load to toxicity===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Witte et al. 2001	1982 to not reported	Phase 3 (C)	5-FU & Levamisole	Did not meet primary endpoint of OS
====Chemotherapy====
*Fluorouracil (5-FU) as follows:
**Cycle 1: 480 mg/m2 IV once per day on days 1 to 5, then 240 mg/m2 IV every other day to toxicity or six additional doses
**Cycle 2 onwards: 480 mg/m2 IV once per day on days 1 to 5
6-week course, then 5-week cycles
===References===
#ECOG E4273: Douglass HO Jr, Lavin PT, Woll J, Conroy JF, Carbone P. Chemotherapy of advanced measurable colon and rectal carcinoma with oral 5-fluorouracil, alone or in combination with cyclophosphamide or 6-thioguanine, with intravenous 5-fluorouracil or beta-2'-deoxythioguanosine or with oral 3(4-methyl-cyclohexyl)-1(2-chlorethyl)-1-nitrosourea: a Phase II-III study of the Eastern Cooperative Oncology Group (EST 4273). Cancer. 1978 Dec;42(6):2538-45. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Richards F 2nd, Case LD, White DR, Muss HB, Spurr CL, Jackson DV, Cooper MR, Zekan P, Cruz J, Stuart JJ, Capizzi RL, McCulloch JH, McFarland JA, Kincaid WR, Harding RW, Pope E, McMahan R, Wellls HB. Combination chemotherapy (5-fluorouracil, methyl-CCNU, mitomycin C) versus 5-fluorouracil alone for advanced previously untreated colorectal carcinoma: a phase III study of the Piedmont Oncology Association. J Clin Oncol. 1986 Apr;4(4):565-70. link to original article EuroPMC
#O'Connell MJ; North Central Cancer Treatment Group. A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer: a Mayo Clinic/North Central Cancer Treatment Group study. Cancer. 1989 Mar 15;63(6 Suppl):1026-30. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Lokich JJ, Ahlgren JD, Gullo JJ, Philips JA, Fryer JG; MAOP. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol. 1989 Apr;7(4):425-32. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#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. link to original article EuroPMC
#Poon MA, O'Connell MJ, Moertel CG, Wieand HS, Cullinan SA, Everson LK, Krook JE, Mailliard JA, Laurie JA, Tschetter LK, Wiesenfeld M; NCCTG. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol. 1989 Oct;7(10):1407-18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Poon MA, O'Connell MJ, Wieand HS, Krook JE, Gerstner JB, Tschetter LK, Levitt R, Kardinal CG, Mailliard JA. Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol. 1991 Nov;9(11):1967-72. link to original article EuroPMC
#Labianca R, Pancera G, Aitini E, Barni S, Beretta A, Beretta GD, Cesana B, Comella G, Cozzaglio L, Cristoni M, Spagnolli P, Frontini L, Gottardi O, Martignoni G, Scapaticci R, Smerieri F, Vinci M, Zadro A, Zaniboni A, Luporini G; GISCAD. Folinic acid + 5-fluorouracil (5-FU) versus equidose 5-FU in advanced colorectal cancer: phase III study of 'GISCAD' (Italian Group for the Study of Digestive Tract Cancer). Ann Oncol. 1991 Oct;2(9):673-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Bobbio-Pallavicini E, Porta C, Moroni M, Spaghi A, Casagranda I, Nastasi G. Folinic acid does improve 5-fluorouracil activity in vivo: results of a phase III study comparing 5-fluorouracil to 5-fluorouracil and folinic acid in advanced colon cancer patients. J Chemother. 1993 Feb;5(1):52-5. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#Hill M, Norman A, Cunningham D, Findlay M, Nicolson V, Hill A, Iveson A, Evans C, Joffe J, Nicolson M, Hickish T. Royal Marsden phase III trial of fluorouracil with or without interferon alfa-2b in advanced colorectal cancer. J Clin Oncol. 1995 Jun;13(6):1297-302. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Smyth JF, Hardcastle JD, Denton G, Alderson D, Grace RH, Mansi JL, Yosef HM, Nordle O, Lauri H, Wählby S. Two phase III trials of tauromustine (TCNU) in advanced colorectal cancer. Ann Oncol. 1995 Nov;6(9):948-9. link to original article EuroPMC
#ECOG E2286: Hansen RM, Ryan L, Anderson T, Krzywda B, Quebbeman E, Benson A 3rd, Haller DG, Tormey DC. Phase III study of bolus versus infusion fluorouracil with or without cisplatin in advanced colorectal cancer. J Natl Cancer Inst. 1996 May 15;88(10):668-74. link to original article EuroPMC
#Greco FA, Figlin R, York M, Einhorn L, Schilsky R, Marshall EM, Buys SS, Froimtchuk MJ, Schuller J, Schuchter L, Buyse M, Ritter L, Man A, Yap AK. Phase III randomized study to compare interferon alfa-2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer. J Clin Oncol. 1996 Oct;14(10):2674-81. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Aranda E, Díaz-Rubio E, Cervantes A, Antón-Torres A, Carrato A, Massutí T, Tabernero JM, Sastre J, Trés A, Aparicio J, López-Vega JM, Barneto I, García-Conde J; Spanish Cooperative Group for Gastrointestinal Tumor Therapy. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol. 1998 Jul;9(7):727-31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Witte RS, Cnaan A, Mansour EG, Barylak E, Harris JE, Schutt AJ; ECOG. Comparison of 5-fluorouracil alone, 5-fluorouracil with levamisole, and 5-fluorouracil with hepatic irradiation in the treatment of patients with residual, nonmeasurable, intra-abdominal metastasis after undergoing resection for colorectal carcinoma. Cancer. 2001 Mar 1;91(5):1020-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Kalofonos HP, Nicolaides C, Samantas E, Mylonakis N, Aravantinos G, Dimopoulos MA, Gennatas C, Kouvatseas G, Giannoulis E, Dervenis C, Basdanis G, Pavlidis N, Androulakis I, Fountzilas G; Hellenic Cooperative Oncology Group. A phase III study of 5-fluorouracil versus 5-fluorouracil plus interferon alpha 2b versus 5-fluorouracil plus leucovorin in patients with advanced colorectal cancer: a Hellenic Cooperative Oncology Group (HeCOG) study. Am J Clin Oncol. 2002 Feb;25(1):23-30. link to original article EuroPMC
#MRC CR06: Maughan TS, James RD, Kerr DJ, Ledermann JA, McArdle C, Seymour MT, Cohen D, Hopwood P, Johnston C, Stephens RJ; British MRC Colorectal Cancer Working Party. Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2002 May 4;359(9317):1555-63. link to original article EuroPMC NCT00002893
==FOLFIRI==
FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan
FUFIRI: 5-FU (Fluorouracil), Folinic acid (Leucovorin), IRInotecan
===Example orders===
*Example orders for FOLFIRI in colon cancer
===Regimen variant #1, 400/2000/180, bi-weekly ("Lv5FU2-Iri")===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Douillard et al. 2000 	1997-05 to 1998-02 	Phase 3 (E-RT-esc)	FULV 	Longer OS (secondary endpoint)Median OS: 17.4 vs 14.1 mo(aHR 0.46, 95% CI 0.28-0.75)Higher ORR (primary endpoint)ORR: 35% vs 22%
Souglakos et al. 2006 	2000-2004 	Phase 3 (C) 	FOLFOXIRI 	Did not meet primary endpoint of OS
Glimelius et al. 2008 	2001-2004 	Phase 3 (C) 	FLIRI 	Did not meet primary endpoint of PFS
Aranda et al. 2008 	2001-2005 	Phase 3 (C) 	FUIRI 	Did not meet primary endpoint of ORR1
Köhne et al. 2007 (EORTC 40015)	2003-2005 	Phase 3 (C) 	CAPIRI 	Inconclusive whether non-inferior PFS (primary endpoint)
Passardi et al. 2015 (ITACa) 	2007-2012 	Phase 3 (C) 	1a. FOLFIRI & Bevacizumab1b. FOLFOX4 & Bevacizumab	Did not meet primary endpoint of PFS
1Aranda et al. 2008 is described by the authors as a non-inferiority trial but the statistics used are superiority-based.
Note: EORTC 40015 was closed prematurely.
====Chemotherapy====
*Leucovorin (Folinic acid) 200 mg/m2 IV over 120 minutes once per day on days 1 & 2, given second
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given third (total dose per cycle: 2000 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first
14-day cycles
===Regimen variant #2, 400/2800/180===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Falcone et al. 2007 (GONO ASL601LIOM03)	2001-2005 	Phase 3 (C) 	FOLFOXIRI 	Seems to have shorter OS
Fuchs et al. 2007 (BICC-C) 	2003-02 to 2004-12 	Phase 3 (E-switch-ic) 	1. CapeIRI 	Seems to have longer PFS (primary endpoint)
Fuchs et al. 2007 (BICC-C) 	2003-02 to 2004-12 	Phase 3 (E-switch-ic) 	2. mIFL 	Longer PFS (primary endpoint)
Van Cutsem et al. 2009 (CRYSTAL) 	2004-07 to 2005-11 	Phase 3 (C) 	FOLFIRI & Cetuximab 	Shorter OS1
Sanoff et al. 2018 (LCCC 1029) 	2011-2015 	Randomized Phase 2 (C)	FOLFIRI & Regorafenib	Might have shorter PFS
1Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given first, with irinotecan
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours, given second (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first, with leucovorin
14-day cycles
===Regimen variant #3, 500/2000/80, 6 out of 7 weeks ("AIO regimen")===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Köhne et al. 2005 (EORTC 40986) 	1999-2001 	Phase 3 (E-esc)	FULV 	Longer PFS (primary endpoint)Median PFS: 8.5 vs 6.4 mo(HR 0.65, 95% CI 0.53-0.79)
Fischer von Weikersthal et al. 2011	2000-2004 	Phase 3 (C) 	mIROX 	Did not meet primary endpoint of PFSMedian PFS: 8.2 vs 7.2 mo(HR 0.88, 95% CI 0.73-1.06)
====Chemotherapy====
*Leucovorin (Folinic acid) 500 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
*Fluorouracil (5-FU) 2000 mg/m2 IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 12,000 mg/m2)
*Irinotecan (Camptosar) 80 mg/m2 IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36, given first
7-week cycles
===Regimen variant #4, 500/2300/80, weekly===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Douillard et al. 2000 	1997-05 to 1998-02 	Phase 3 (E-RT-esc)	FULV 	Longer OS (secondary endpoint)Median OS: 17.4 vs 14.1 mo(aHR 0.46, 95% CI 0.28-0.75)Higher ORR (primary endpoint)ORR: 35% vs 22%
Passardi et al. 2015 (ITACa)	2007-2012 	Phase 3 (C) 	1a. FOLFIRI & Bevacizumab1b. FOLFOX4 & Bevacizumab	Did not meet primary endpoint of PFS
====Chemotherapy====
*Leucovorin (Folinic acid) 500 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 2300 mg/m2 IV continuous infusion over 24 hours, started on day 1
*Irinotecan (Camptosar) 80 mg/m2 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#EORTC 40986: Köhne CH, van Cutsem E, Wils J, Bokemeyer C, El-Serafi M, Lutz MP, Lorenz M, Reichardt P, Rückle-Lanz H, Frickhofen N, Fuchs R, Mergenthaler HG, Langenbuch T, Vanhoefer U, Rougier P, Voigtmann R, Müller L, Genicot B, Anak O, Nordlinger B; EORTC Gastrointestinal Group. Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol. 2005 Aug 1;23(22):4856-65. Epub 2005 Jun 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00004885
#Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, Kakolyris S, Tsousis S, Kouroussis Ch, Vamvakas L, Kalykaki A, Samonis G, Mavroudis D, Georgoulias V; Hellenic Oncology Research Group. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-805. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
#GONO ASL601LIOM03: Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01219920
#BICC-C: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article EuroPMC
#EORTC 40015: Köhne CH, De Greve J, Hartmann JT, Lang I, Vergauwe P, Becker K, Braumann D, Joosens E, Müller L, Janssens J, Bokemeyer C, Reimer P, Link H, Späth-Schwalbe E, Wilke HJ, Bleiberg H, Van Den Brande J, Debois M, Bethe U, Van Cutsem E. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer: EORTC study 40015. Ann Oncol. 2008 May;19(5):920-6. Epub 2007 Dec 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00064181
#Glimelius B, Sørbye H, Balteskard L, Byström P, Pfeiffer P, Tveit K, Heikkilä R, Keldsen N, Albertsson M, Starkhammar H, Garmo H, Berglund A. A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer. Ann Oncol. 2008 May;19(5):909-14. Epub 2008 Jan 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Aranda E, Valladares M, Martinez-Villacampa M, Benavides M, Gomez A, Massutti B, Marcuello E, Constenla M, Cámara JC, Carrato A, Dueñas R, Reboredo M, Navarro M, Díaz-Rubio E; TTD. Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study. Ann Oncol. 2009 Feb;20(2):251-7. Epub 2008 Aug 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#CRYSTAL: Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00154102
##Update: Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Pooled update: Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article EuroPMC
##Biomarker analysis: Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. link to original article EuroPMC
#Fischer von Weikersthal L, Schalhorn A, Stauch M, Quietzsch D, Maubach PA, Lambertz H, Oruzio D, Schlag R, Weigang-Köhler K, Vehling-Kaiser U, Schulze M, Truckenbrodt J, Goebeler M, Mittermüller J, Bosse D, Szukics B, Grundeis M, Zwingers T, Giessen C, Heinemann V. Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer. Eur J Cancer. 2011 Jan;47(2):206-14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#ITACa: Passardi A, Nanni O, Tassinari D, Turci D, Cavanna L, Fontana A, Ruscelli S, Mucciarini C, Lorusso V, Ragazzini A, Frassineti GL, Amadori D. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015 Jun;26(6):1201-7. Epub 2015 Mar 3. link to original article does not contain dosing details in manuscript; refers to Douillard et al. 2000 EuroPMC NCT01878422
#LCCC 1029: Sanoff HK, Goldberg RM, Ivanova A, O'Reilly S, Kasbari SS, Kim RD, McDermott R, Moore DT, Zamboni W, Grogan W, Cohn AL, Bekaii-Saab TS, Leonard G, Ryan T, Olowokure OO, Fernando NH, McCaffrey J, El-Rayes BF, Horgan AM, Sherrill GB, Yacoub GH, O'Neil BH. Multicenter, randomized, double-blind phase 2 trial of FOLFIRI with regorafenib or placebo as second-line therapy for metastatic colorectal cancer. Cancer. 2018 Aug 1;124(15):3118-3126. Epub 2018 Jun 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01298570
==FOLFIRI (L-Leucovorin)==
FOLFIRI: FOLinic acid (L-Leucovorin), Fluorouracil, IRInotecan
===Regimen variant #1, 200/2000/150===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Colucci et al. 2005 (GOIM 9901)	1999-2002 	Phase 3 (C)	FOLFOX4 	Did not meet primary endpoint of ORR
Note: this variant was intended for patients between 70 to 75 years old.
====Chemotherapy====
*Levoleucovorin (Fusilev) 100 mg/m2 IV over 2 hours once per day on days 1 & 2, given second
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given third (total dose per cycle: 2000 mg/m2)
*Irinotecan (Camptosar) 150 mg/m2 IV over 30 minutes once on day 1, given first
14-day cycles
===Regimen variant #2, 200/2000/180===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Colucci et al. 2005 (GOIM 9901)	1999-2002 	Phase 3 (C)	FOLFOX4 	Did not meet primary endpoint of ORR
Labianca et al. 2010 	2001-2005 	Phase 3 (C)	FOLFIRI; intermittent	Did not meet primary endpoint of OS
====Chemotherapy====
*Levoleucovorin (Fusilev) 100 mg/m2 IV over 2 hours once per day on days 1 & 2, given second
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given third (total dose per cycle: 2000 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 30 minutes once on day 1, given first
14-day cycles
===Regimen variant #3, 200/2800/180===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Van Cutsem et al. 2009 (CRYSTAL)	2004-07 to 2005-11 	Phase 3 (C)	FOLFIRI & Cetuximab	Shorter OS1
Carrato et al. 2013 (SUN 1122) 	2007 to not reported	Phase 3 (C)	FOLFIRI & Sunitinib	Did not meet primary endpoint of PFSMedian PFS: 8.4 vs 7.8 mo(HR 0.91, 95% CI 0.74-1.12)
1Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.
====Chemotherapy====
*Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given first, with irinotecan
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV once on day 1, given first, with levoleucovorin
14-day cycles
===References===
#GOIM 9901: Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N, Cartenì G, Agostara B, Pezzella G, Manzione L, Borsellino N, Misino A, Romito S, Durini E, Cordio S, Di Seri M, Lopez M, Maiello E, Montemurro S, Cramarossa A, Lorusso V, Di Bisceglie M, Chiarenza M, Valerio MR, Guida T, Leonardi V, Pisconti S, Rosati G, Carrozza F, Nettis G, Valdesi M, Filippelli G, Fortunato S, Mancarella S, Brunetti C; Gruppo Oncologico Dell'Italia Meridionale. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol. 2005 Aug 1;23(22):4866-75. Epub 2005 Jun 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#CRYSTAL: Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00154102
##Update: Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Pooled update: Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article EuroPMC
##Biomarker analysis: Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. link to original article EuroPMC
#Labianca R, Sobrero A, Isa L, Cortesi E, Barni S, Nicolella D, Aglietta M, Lonardi S, Corsi D, Turci D, Beretta GD, Fornarini G, Dapretto E, Floriani I, Zaniboni A; Italian Group for the Study of Gastrointestinal Cancer. Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised 'GISCAD' trial. Ann Oncol. 2011 May;22(5):1236-42. Epub 2010 Nov 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#SUN 1122: Carrato A, Swieboda-Sadlej A, Staszewska-Skurczynska M, Lim R, Roman L, Shparyk Y, Bondarenko I, Jonker DJ, Sun Y, De la Cruz JA, Williams JA, Korytowsky B, Christensen JG, Lin X, Tursi JM, Lechuga MJ, Van Cutsem E. Fluorouracil, leucovorin, and irinotecan plus either sunitinib or placebo in metastatic colorectal cancer: a randomized, phase III trial. J Clin Oncol. 2013 Apr 1;31(10):1341-7. Epub 2013 Jan 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00457691
==FOLFIRI & Bevacizumab==
FOLFIRI & Bevacizumab: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan, Bevacizumab
===Regimen variant #1, indefinite===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Fuchs et al. 2007 (BICC-C)	2003-02 to 2004-12 	Phase 3 (E-switch-ic)	mIFL & Bevacizumab	Seems to have longer OS1 (secondary endpoint)Median OS: 28 vs 19.2 mo(HR 0.56, 95% CI 0.35-0.89)
1Reported efficacy is based on the 2008 update. Note also that the primary endpoint (PFS) of this study was not met in the original publication, and is not reported in the update.
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given first, with irinotecan
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours, given third (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first, with leucovorin
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once on day 1, given second
14-day cycles
===Regimen variant #2, 400/2000/200 ("FOLFIRI-3")===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rezvani et al. 2020 (BEV.ARY.HR.94)	2016-10 to 2018-07 	Phase 3 (C)	FOLFIRI & Bevacizumab (BE1040V biosimilar)	Non-inferior PFS (primary endpoint)Median PFS: 7 vs 7.7 mo(HR 1.27, 90% CI 0.74-2.17)
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 2000 mg/m2 IV continuous infusion over 46 hours, started on day 1, given last
*Irinotecan (Camptosar) 100 mg/m2 IV over 60 minutes once per day on days 1 & 3
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once on day 1, given first
14-day cycles
===Regimen variant #3, lower dose leucovorin===
Study 	Dates of enrollment	Evidence
Johnsson et al. 2013 (Nordic ACT)	2007-2009 	Non-randomized part of phase 3 RCT
====Chemotherapy====
*Leucovorin (Folinic acid) 200 mg/m2 IV over 120 minutes once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 44 hours (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once on day 1
14-day cycle for 9 cycles
====Subsequent treatment====
*Nordic ACT: Bevacizumab versus Erlotinib & Bevacizumab maintenance
===References===
#BICC-C: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article EuroPMC
#Observational cohort: Bendell JC, Bekaii-Saab TS, Cohn AL, Hurwitz HI, Kozloff M, Tezcan H, Roach N, Mun Y, Fish S, Flick ED, Dalal D, Grothey A. Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-bevacizumab or FOLFIRI-bevacizumab: results from ARIES, a bevacizumab observational cohort study. Oncologist. 2012;17(12):1486-95. link to original article link to PMC article EuroPMC
#Nordic ACT: Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00598156
#BEV.ARY.HR.94: Rezvani H, Mortazavizadeh SM, Allahyari A, Nekuee A, Najafi SN, Vahidfar M, Ghadyani M, Khosravi A, Qarib S, Sadeghi A, Esfandbod M, Rajaeinejad M, Rezvani A, Hajiqolami A, Payandeh M, Shazad B, Anjidani N, Meskinimood S, Alikhasi A, Karbalaeian M, Salari S. Efficacy and Safety of Proposed Bevacizumab Biosimilar BE1040V in Patients With Metastatic Colorectal Cancer: A Phase III, Randomized, Double-blind, Noninferiority Clinical Trial. Clin Ther. 2020 May;42(5):848-859. Epub 2020 Apr 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03288987
==FOLFIRI & Bevacizumab (L-Leucovorin)==
FOLFIRI & Bevacizumab: FOLinic acid (L-Leucovorin), Fluorouracil, IRInotecan, Bevacizumab
===Regimen variant #1, irinotecan 150 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Yamazaki et al. 2016 (WJOG4407G)	2008-2012 	Phase 3 (E-switch-ic)	mFOLFOX6-B	Non-inferior PFS (primary endpoint)Median PFS: 12.1 vs 10.7 mo(HR 0.905, 95% CI 0.72-1.13)
====Chemotherapy====
*Levoleucovorin (Fusilev) 200 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 150 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once on day 1
14-day cycles
===Regimen variant #2, irinotecan 180 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Loupakis et al. 2014 (TRIBE)	2008-2011 	Phase 3 (C)	FOLFOXIRI & Bevacizumab (L-Leucovorin)	Shorter PFS (primary endpoint)Median PFS: 9.7 vs 12.1 mo(HR 1.33, 95% CI 1.11-1.61)Seems to have shorter OS1 (secondary endpoint)Median OS: 25.8 vs 31 mo(HR 1.27, 95% CI 1.00-1.59)
1Reported efficacy is based on the 2015 update.
Note: Loupakis et al. 2014 described folinic acid 200 mg/m2 in the body of the paper, whereas the protocol in the supplementary material stated that levoleucovorin 200 mg/m2 was used. We have contacted NEJM regarding this suspected error.
====Chemotherapy====
*Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 60 minutes once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV over 30 minutes once on day 1
14-day cycle for up to 12 cycles
====Subsequent treatment====
*FULV & Bevacizumab maintenance
===References===
#TRIBE: Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014 Oct 23;371(17):1609-18. link to original article link to protocol in supplementary material dosing details in manuscript have been reviewed by our editors EuroPMC NCT00719797
##Update: Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, Mezi S, Tomasello G, Ronzoni M, Zaniboni A, Tonini G, Carlomagno C, Allegrini G, Chiara S, D'Amico M, Granetto C, Cazzaniga M, Boni L, Fontanini G, Falcone A. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015 Oct;16(13):1306-15. Epub 2015 Aug 31. link to original article EuroPMC
#WJOG4407G: Yamazaki K, Nagase M, Tamagawa H, Ueda S, Tamura T, Murata K, Eguchi Nakajima T, Baba E, Tsuda M, Moriwaki T, Esaki T, Tsuji Y, Muro K, Taira K, Denda T, Funai S, Shinozaki K, Yamashita H, Sugimoto N, Okuno T, Nishina T, Umeki M, Kurimoto T, Takayama T, Tsuji A, Yoshida M, Hosokawa A, Shibata Y, Suyama K, Okabe M, Suzuki K, Seki N, Kawakami K, Sato M, Fujikawa K, Hirashima T, Shimura T, Taku K, Otsuji T, Tamura F, Shinozaki E, Nakashima K, Hara H, Tsushima T, Ando M, Morita S, Boku N, Hyodo I. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol. 2016 Aug;27(8):1539-46. Epub 2016 May 13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000001396
==FOLFIRINOX==
FOLFIRINOX: FOLinic acid (Leucovorin), Fluorouracil, IRINotecan, OXaliplatin
FOLFOXIRI: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, IRInotecan
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Souglakos et al. 2006 	2000-2004 	Phase 3 (E-esc)	FOLFIRI 	Did not meet primary endpoint of OS
Falcone et al. 2007 (GONO ASL601LIOM03)	2001-2005 	Phase 3 (E-esc)	FOLFIRI 	Seems to have longer OS (secondary endpoint)Median OS: 22.6 vs 16.7 mo(HR 0.70, 95% CI 0.50-0.96)Higher RR (primary endpoint)
Note: In contrast to GONO ASL601LIOM03, some guidelines list the dose of folinic acid as 400 mg/m2 IV on day 1. No primary reference could be found for this.
====Chemotherapy====
*Leucovorin (Folinic acid) 200 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 1600 mg/m2/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 3200 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV once on day 1
*Irinotecan (Camptosar) 165 mg/m2 IV once on day 1
14-day cycles
===References===
#Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, Kakolyris S, Tsousis S, Kouroussis Ch, Vamvakas L, Kalykaki A, Samonis G, Mavroudis D, Georgoulias V; Hellenic Oncology Research Group. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-805. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
#GONO ASL601LIOM03: Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01219920
==FOLFIRINOX & Bevacizumab==
FOLFIRINOX & Bevacizumab: FOLinic acid (Leucovorin), Fluorouracil, IRINotecan, OXaliplatin, Bevacizumab
FOLFOXIRI & Bevacizumab: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, IRInotecan, Bevacizumab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Aranda et al. 2020 (VISNU-1)	2012-2016 	Phase 3 (E-esc)	mFOLFOX6-B 	Longer PFS (primary endpoint)Median PFS: 12.4 vs 9.3 mo(HR 0.64, 95% CI 0.49-0.82)
Bond et al. 2023 (CAIRO5) 	2014-11-13 to 2022-01-31	Phase 3 (E-esc)	1a. mFOLFOX6-B1b. FOLFIRI & Bevacizumab	Seems to have longer PFS (primary endpoint)Median PFS: 10.6 vs 9 mo(sHR 0.76, 95% CI 0.60-0.98)
Note: CAIRO5 had other treatment arms for left-sided and RAS and BRAF p.V600E wild-type tumors; see paper for details.
====Biomarker eligibility criteria====
*CAIRO5: Right-sided tumor OR RAS-mutated OR BRAF p.V600E
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given third
*Fluorouracil (5-FU) 1600 mg/m2/day IV continuous infusion over 46 to 48 hours, started on day 1, given fourth (total dose per cycle: 3200 mg/m2)
*Irinotecan (Camptosar) 165 mg/m2 IV over 30 to 90 minutes once on day 1, given second
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given third
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV over 15 to 90 minutes once on day 1, given first
14-day cycle for varying durations: 12 cycles (CAIRO5); indefinitely (VISNU-1)
===References===
#VISNU-1: Aranda E, Viéitez JM, Gómez-España A, Gil Calle S, Salud-Salvia A, Graña B, Garcia-Alfonso P, Rivera F, Quintero-Aldana GA, Reina-Zoilo JJ, González-Flores E, Salgado Fernández M, Guillén-Ponce C, Garcia-Carbonero R, Safont MJ, La Casta Munoa A, García-Paredes B, López López R, Sastre J, Díaz-Rubio E; Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD). FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab for patients with metastatic colorectal cancer and ≥3 circulating tumour cells: the randomised phase III VISNÚ-1 trial. ESMO Open. 2020 Nov;5(6):e000944. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01640405
#CAIRO5: Bond MJG, Bolhuis K, Loosveld OJL, de Groot JWB, Droogendijk H, Helgason HH, Hendriks MP, Klaase JM, Kazemier G, Liem MSL, Rijken AM, Verhoef C, de Wilt JHW, de Jong KP, Gerhards MF, van Amerongen MJ, Engelbrecht MRW, van Lienden KP, Molenaar IQ, de Valk B, Haberkorn BCM, Kerver ED, Erdkamp F, van Alphen RJ, Mathijssen-van Stein D, Komurcu A, Lopez-Yurda M, Swijnenburg RJ, Punt CJA; Dutch Colorectal Cancer Study Group. First-line systemic treatment strategies in patients with initially unresectable colorectal cancer liver metastases (CAIRO5): an open-label, multicentre, randomised, controlled, phase 3 study from the Dutch Colorectal Cancer Group. Lancet Oncol. 2023 Jul;24(7):757-771. Epub 2023 Jun 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02162563
==FOLFIRINOX & Bevacizumab (L-Leucovorin)==
FOLFIRINOX & Bevacizumab: FOLinic acid (L-Leucovorin), Fluorouracil, IRINotecan, OXaliplatin, Bevacizumab
FOLFOXIRI & Bevacizumab: FOLinic acid (L-Leucovorin), Fluorouracil, OXaliplatin, IRInotecan, Bevacizumab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Masi et al. 2010 (FOIB) 	2007-2008 	Phase 2 	 	
Loupakis et al. 2014 (TRIBE) 	2008-2011 	Phase 3 (E-esc) 	FOLFIRI & Bevacizumab (L-Leucovorin) 	Longer PFS (primary endpoint)Median PFS: 12.1 vs 9.7 mo(HR 0.75, 95% CI 0.62-0.90)Seems to have longer OS1 (secondary endpoint)Median OS: 31 vs 25.8 mo(HR 0.79, 95% CI 0.63-1.00)
Cremolini et al. 2020 (TRIBE2)	2015-02-26 to 2017-05-15	Phase 3 (E-switch-ic)	mFOLFOX-B, then FOLFIRI & Bevacizumab	Longer PFS-2 (primary endpoint)Median PFS-2: 19.2 vs 16.4 mo(HR 0.74, 95% CI 0.63-0.88)
1Reported efficacy for OS in TRIBE is based on the 2015 update.
Note: Loupakis et al. 2014 listed folinic acid 200 mg/m2 in the body of the paper, whereas the protocol in the supplementary material stated that levoleucovorin 200 mg/m2 was used. We have contacted NEJM regarding this suspected error. Similarly, Cremolini et al. 2020 described "leucovorin" 200 mg/m2 in the body of the paper, but the supplementary material states L-leucovorin. Some guidelines list either folinic acid 400 mg/m2 IV once on day 1 or levoleucovorin 200 mg/m2 IV once on day 1 as options.
====Chemotherapy====
*Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given third, with oxaliplatin
*Fluorouracil (5-FU) 1600 mg/m2/day IV continuous infusion over 48 hours, started on day 1, given fourth (total dose per cycle: 3200 mg/m2)
*Irinotecan (Camptosar) 165 mg/m2 IV over 60 minutes once on day 1, given second
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given third, with levoleucovorin
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV over 30 minutes once on day 1, given first
14-day cycle for varying durations: 8 cycles (TRIBE2)</span>; 12 cycles (FOIB, TRIBE)</span>
====Subsequent treatment====
*FOIB: Bevacizumab maintenance
*TRIBE & TRIBE2: FULV & Bevacizumab maintenance
===References===
# FOIB: Masi G, Loupakis F, Salvatore L, Fornaro L, Cremolini C, Cupini S, Ciarlo A, Del Monte F, Cortesi E, Amoroso D, Granetto C, Fontanini G, Sensi E, Lupi C, Andreuccetti M, Falcone A. Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Lancet Oncol. 2010 Sep;11(9):845-52. Epub 2010 Aug 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01163396
#TRIBE: Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014 Oct 23;371(17):1609-18. link to original article link to protocol in supplementary material dosing details in manuscript have been reviewed by our editors EuroPMC NCT00719797
##Update: Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, Mezi S, Tomasello G, Ronzoni M, Zaniboni A, Tonini G, Carlomagno C, Allegrini G, Chiara S, D'Amico M, Granetto C, Cazzaniga M, Boni L, Fontanini G, Falcone A. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015 Oct;16(13):1306-15. Epub 2015 Aug 31. link to original article EuroPMC
#TRIBE2: Cremolini C, Antoniotti C, Rossini D, Lonardi S, Loupakis F, Pietrantonio F, Bordonaro R, Latiano TP, Tamburini E, Santini D, Passardi A, Marmorino F, Grande R, Aprile G, Zaniboni A, Murgioni S, Granetto C, Buonadonna A, Moretto R, Corallo S, Cordio S, Antonuzzo L, Tomasello G, Masi G, Ronzoni M, Di Donato S, Carlomagno C, Clavarezza M, Ritorto G, Mambrini A, Roselli M, Cupini S, Mammoliti S, Fenocchio E, Corgna E, Zagonel V, Fontanini G, Ugolini C, Boni L, Falcone A; GONO Foundation Investigators. Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020 Apr;21(4):497-507. Epub 2020 Mar 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02339116
==FOLFOX2==
FOLFOX2: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Giacchetti et al. 2006 (EORTC 05963)	1998-2002 	Phase 3 (C)	chronoFLO4	Did not meet primary endpoint of OS
====Chemotherapy====
*Leucovorin (Folinic acid) 600 mg/m2 IV over 2 hours once per day on days 1 & 2, given first, with oxaliplatin on day 1
*Fluorouracil (5-FU) 1500 mg/m2 IV continuous infusion over 22 hours once per day, started on days 1 & 2, given second (total dose per cycle: 3000 mg/m2)
*Oxaliplatin (Eloxatin) 100 mg/m2 IV over 2 hours once on day 1, given first
14-day cycles
===References===
#EORTC 05963: Giacchetti S, Bjarnason G, Garufi C, Genet D, Iacobelli S, Tampellini M, Smaaland R, Focan C, Coudert B, Humblet Y, Canon JL, Adenis A, Lo Re G, Carvalho C, Schueller J, Anciaux N, Lentz MA, Baron B, Gorlia T, Lévi F; EORTC Chronotherapy Group. Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group. J Clin Oncol. 2006 Aug 1;24(22):3562-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003287
==FOLFOX4==
FOLFOX4: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
de Gramont et al. 2000 	1995-1997 	Phase 3 (E-esc) 	FULV 	Longer PFS (primary endpoint)Median PFS: 9 vs 6.2 mo(aHR 0.80, 95% CI not reported)
Goldberg et al. 2003 (NCCTG N9741)	1999-2001 	Phase 3 (E-RT-switch-ic)	1. IFL 	Longer OS (secondary endpoint)
Goldberg et al. 2003 (NCCTG N9741)	1999-2001 	Phase 3 (E-RT-switch-ic)	2. IROX 	Did not meet primary endpoint of TTP
Tournigand et al. 2006 (OPTIMOX1) 	2000-2002 	Phase 3 (C) 	FOLFOX7/LV5FU2 	Did not meet primary endpoint of DDC
Hecht et al. 2011 (CONFIRM 1) 	2003-02-20 to 2004-05-27	Phase 3 (C) 	FOLFOX4 & Vatalanib 	Did not meet primary endpoint of PFS
Cassidy et al. 2008 (NO16966) 	2003-2005 	Phase 3 (C) 	1. FOLFOX4 & Bevacizumab 	Not reported
Cassidy et al. 2008 (NO16966) 	2003-2005 	Phase 3 (C) 	2. XELOX 3. XELOX & Bevacizumab 	Non-inferior PFS
Saltz et al. 2008 (NO16966) 	2003-2005 	Phase 3 (C) 	1. FOLFOX4 & Bevacizumab2. XELOX & Bevacizumab 	Shorter PFS
Saltz et al. 2008 (NO16966) 	2003-2005 	Phase 3 (C) 	3. XELOX 	Not reported
Bokemeyer et al. 2008 (OPUS) 	2005-2006 	Randomized Phase 2 (C) 	FOLFOX4 & Cetuximab 	Shorter OS1
Douillard et al. 2010 (PRIME) 	2006-2008 	Phase 3 (C) 	FOLFOX4 & Panitumumab 	Seems to have longer PFS2
Hoff et al. 2012 (HORIZON II) 	2006 to not reported 	Phase 3 (C) 	1a. CAPOX & Cediranib1b. FOLFOX4 & Cediranib1c. mFOLFOX6 & Cediranib	Seems to have shorter PFS (co-primary endpoint)Median PFS: 8.3 vs 8.6 mo(HR 1.19, 95% CI 1.02-1.37)
Passardi et al. 2015 (ITACa) 	2007-2012 	Phase 3 (C) 	1a. FOLFIRI & Bevacizumab1b. FOLFOX4 & Bevacizumab 	Did not meet primary endpoint of PFS
1Reported efficacy for OPUS is based on the 2012 pooled update and is only for KRAS wild-type tumors.
2In PRIME, patients with KRAS wild-type tumors receiving this regimen seem to have shorter OS, based on the 2014 update. Conversely, in KRAS mutants, this regimen seems to have longer PFS.
Note: Although NO16966 was one study, it was published simultaneously as two manuscripts looking at different aspects of the 2 x 2 factorial design (Cassidy et al. 2008 and Saltz et al. 2008).
====Chemotherapy====
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, given first, with oxaliplatin on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given second (total dose per cycle: 2000 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first
14-day cycles
===References===
#de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#NCCTG N9741: Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. Epub 2003 Dec 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003594
##Toxicity analysis: Delaunoit T, Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Findlay BP, Thomas SP, Salim M, Schaefer PL, Stella PJ, Green E, Mailliard JA. Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup Trial N9741. Cancer. 2004 Nov 15;101(10):2170-6. link to original article EuroPMC
#OPTIMOX1: Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, Mineur L, Carola E, Etienne PL, Rivera F, Chirivella I, Perez-Staub N, Louvet C, André T, Tabah-Fisch I, de Gramont A. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006 Jan 20;24(3):394-400. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Retrospective: Goldberg RM, Tabah-Fisch I, Bleiberg H, de Gramont A, Tournigand C, Andre T, Rothenberg ML, Green E, Sargent DJ. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol. 2006 Sep 1;24(25):4085-91. link to original article EuroPMC content property of HemOnc.org
#NO16966: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00069095
##Update: Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64. Epub 2011 Jun 14. link to original article link to PMC article EuroPMC
#OPUS: Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00125034
##Update: Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011 Jul;22(7):1535-46. Epub 2011 Jan 12. link to original article EuroPMC
##Pooled update: Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article EuroPMC
#PRIME: Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010 Nov 1;28(31):4697-705. Epub 2010 Oct 4. link to original article EuroPMC NCT00364013
##Biomarker analysis: Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013 Sep 12;369(11):1023-34. link to original article EuroPMC
##Update: Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jul;25(7):1346-55. Epub 2014 Apr 8. link to original article EuroPMC
##HRQoL analysis: Siena S, Tabernero J, Bodoky G, Cunningham D, Rivera F, Ruff P, Canon JL, Koukakis R, Demonty G, Hechmati G, Douillard JY. Quality of life during first-line FOLFOX4±panitumumab in RAS wild-type metastatic colorectal carcinoma: results from a randomised controlled trial. ESMO Open. 2016 Mar 31;1(2):e000041. link to original article link to PMC article EuroPMC
#CONFIRM 1: Hecht JR, Trarbach T, Hainsworth JD, Major P, Jäger E, Wolff RA, Lloyd-Salvant K, Bodoky G, Pendergrass K, Berg W, Chen BL, Jalava T, Meinhardt G, Laurent D, Lebwohl D, Kerr D. Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):1997-2003. Epub 2011 Apr 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00056459
#HORIZON II: Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00399035
#ITACa: Passardi A, Nanni O, Tassinari D, Turci D, Cavanna L, Fontana A, Ruscelli S, Mucciarini C, Lorusso V, Ragazzini A, Frassineti GL, Amadori D. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015 Jun;26(6):1201-7. Epub 2015 Mar 3. link to original article does not contain dosing details in manuscript; refers to de Gramont et al. 2000 EuroPMC NCT01878422
==FOLFOX4 (L-Leucovorin)==
FOLFOX4: FOLinic acid (L-Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Colucci et al. 2005 (GOIM 9901)	1999-2002 	Phase 3 (E-switch-ic)	FOLFIRI 	Did not meet primary endpoint of ORR
Hecht et al. 2011 (CONFIRM 1) 	2003-02-20 to 2004-05-27	Phase 3 (C) 	FOLFOX4 & Vatalanib	Did not meet primary endpoint of PFS
Correale et al. 2014 (GOLFIG-2)	2005-2010 	Phase 3 (C) 	GOLFIG 	Shorter PFS (primary endpoint)Median PFS: 5.7 vs 9.23 mo(HR 1.92, 95% CI 1.30-2.86)
====Chemotherapy====
*Levoleucovorin (Fusilev) 100 mg/m2 IV over 2 hours once per day on days 1 & 2, given first, with oxaliplatin on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given second (total dose per cycle: 2000 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first, with leucovorin
14-day cycles
===References===
#GOIM 9901: Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N, Cartenì G, Agostara B, Pezzella G, Manzione L, Borsellino N, Misino A, Romito S, Durini E, Cordio S, Di Seri M, Lopez M, Maiello E, Montemurro S, Cramarossa A, Lorusso V, Di Bisceglie M, Chiarenza M, Valerio MR, Guida T, Leonardi V, Pisconti S, Rosati G, Carrozza F, Nettis G, Valdesi M, Filippelli G, Fortunato S, Mancarella S, Brunetti C; Gruppo Oncologico Dell'Italia Meridionale. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol. 2005 Aug 1;23(22):4866-75. Epub 2005 Jun 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#CONFIRM 1: Hecht JR, Trarbach T, Hainsworth JD, Major P, Jäger E, Wolff RA, Lloyd-Salvant K, Bodoky G, Pendergrass K, Berg W, Chen BL, Jalava T, Meinhardt G, Laurent D, Lebwohl D, Kerr D. Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):1997-2003. Epub 2011 Apr 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00056459
#GOLFIG-2: Correale P, Botta C, Rotundo MS, Guglielmo A, Conca R, Licchetta A, Pastina P, Bestoso E, Ciliberto D, Cusi MG, Fioravanti A, Guidelli GM, Bianco MT, Misso G, Martino E, Caraglia M, Tassone P, Mini E, Mantovani G, Ridolfi R, Pirtoli L, Tagliaferri P. Gemcitabine, oxaliplatin, levofolinate, 5-fluorouracil, granulocyte-macrophage colony-stimulating factor, and interleukin-2 (GOLFIG) versus FOLFOX chemotherapy in metastatic colorectal cancer patients: the GOLFIG-2 multicentric open-label randomized phase III trial. J Immunother. 2014 Jan;37(1):26-35. link to original article EuroPMC EudraCT 2005-003458-81
==FOLFOX6==
FOLFOX6: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hospers et al. 2006	1999-2002 	Phase 3 (E-esc)	FULV; Mayo Clinic regimen	Seems to have longer PFS (secondary endpoint)Median PFS: 6.7 vs 5.6 mo(HR not reported, p=0.016)Higher RR (primary endpoint)
====Chemotherapy====
*Leucovorin (Folinic acid) 200 mg/m2 IV over 60 minutes once on day 1
*Fluorouracil (5-FU) 2600 mg/m2 IV continuous infusion over 24 hours, started on day 1
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
14-day cycles
===References===
#Hospers GA, Schaapveld M, Nortier JW, Wils J, van Bochove A, de Jong RS, Creemers GJ, Erjavec Z, de Gooyer DJ, Slee PH, Gerrits CJ, Smit JM, Mulder NH. Randomised Phase III study of biweekly 24-h infusion of high-dose 5FU with folinic acid and oxaliplatin versus monthly plus 5-FU/folinic acid in first-line treatment of advanced colorectal cancer. Ann Oncol. 2006 Mar;17(3):443-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==mFOLFOX6==
mFOLFOX6: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin
OxMdG: Oxaliplatin Modified de Gramont
===Example orders===
*Example orders for mFOLFOX 6 in colon cancer
===Regimen variant #1, LCV 200 mg/m2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
van Hazel et al. 2016 (SIRFLOX) 	2006-2013 	Phase 3 (C)	mFOLFOX6 plus SIRT	Did not meet primary endpoint of PFSMedian PFS: 10.7 vs 10.2 mo(HR 1.08, 95% CI 0.89-1.30)
Wasan et al. 2017 (FOXFIRE-Global)	2013-05-20 to 2014-12-23	Phase 3 (C)	mFOLFOX6 plus SIRT	Did not meet primary endpoint of OS
Note: Wasan et al. 2017, which is an update for SIRFLOX and the first publication for FOXFIRE-Global, describes the folinic acid as a flat 200 mg dose; van Hazel et al. 2016 reports 200 mg/m2; the authors were contacted for clarification.
====Chemotherapy====
*Leucovorin (Folinic acid) 200 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
14-day cycles
===Regimen variant #2, LCV 350 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cheeseman et al. 2002 	Not reported 	Non-randomized 	 	
Hochster et al. 2008 (TREE-1) 	2002-12 to 2003-11 	Phase 3 (E-switch-ic)	1. bFOL 	Did not meet secondary efficacy endpoints
Hochster et al. 2008 (TREE-1) 	2002-12 to 2003-11 	Phase 3 (E-switch-ic)	2. CapeOx 	Did not meet secondary efficacy endpoints
Maughan et al. 2011 (UK MRC COIN)	2005-2008 	Phase 3 (C) 	1a. CapeOx & Cetuximab1b. mFOLFOX6 & Cetuximab	Did not meet primary endpoint of OS1
Wasan et al. 2017 (FOXFIRE) 	2009-2014 	Phase 3 (C) 	OxMdG plus SIRT 	Did not meet primary endpoint of OS
1Reported efficacy for UK MRC COIN is as reported for KRAS wild-type patients.
Note: TREE-1 did not have any primary endpoints.
====Chemotherapy====
*Leucovorin (Folinic acid) 350 mg/m2 IV over 2 hours once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
14-day cycles
===Regimen variant #3, LCV 400 mg/m2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Hoff et al. 2012 (HORIZON II)	2006 to not reported	Phase 3 (C)	1a. CAPOX & Cediranib1b. FOLFOX4 & Cediranib1c. mFOLFOX6 & Cediranib	Seems to have shorter PFS (co-primary endpoint)Median PFS: 8.3 vs 8.6 mo(HR 1.19, 95% CI 1.02-1.37)
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 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. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
#TREE-1: Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#UK MRC COIN: Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP; MRC COIN Trial Investigators. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011 Jun 18;377(9783):2103-14. Epub 2011 Jun 5. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00182715
##Update: Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, Kenny SL, Kay E, Hodgkinson E, Pope M, Rogers P, Wasan H, Falk S, Gollins S, Hickish T, Bessell EM, Propper D, Kennedy MJ, Kaplan R, Maughan TS; MRC COIN Trial Investigators. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011 Jul;12(7):642-53. Epub 2011 Jun 5. link to original article link to PMC article EuroPMC
#HORIZON II: Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00399035
#SIRFLOX: van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M, Perez D, Robinson BA, Strickland AH, Ferguson T, Rodríguez J, Kröning H, Wolf I, Ganju V, Walpole E, Boucher E, Tichler T, Shacham-Shmueli E, Powell A, Eliadis P, Isaacs R, Price D, Moeslein F, Taieb J, Bower G, Gebski V, Van Buskirk M, Cade DN, Thurston K, Gibbs P. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2016 May 20;34(15):1723-31. Epub 2016 Feb 22. link to original article contains partial dosing details in manuscript EuroPMC NCT00724503
##Pooled update: Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A, van Hazel G, Sharma RA; FOXFIRE/SIRFLOX/FOXFIRE-Global trial investigators. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. Epub 2017 Aug 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
#FOXFIRE: Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A, van Hazel G, Sharma RA; FOXFIRE/SIRFLOX/FOXFIRE-Global trial investigators. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. Epub 2017 Aug 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC ISRCTN83867919
#FOXFIRE-Global: Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A, van Hazel G, Sharma RA; FOXFIRE/SIRFLOX/FOXFIRE-Global trial investigators. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. Epub 2017 Aug 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01721954
#ECTX: NCT01460589
==mFOLFOX6 (L-Leucovorin)==
mFOLFOX6: modified FOLinic acid (L-Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Maughan et al. 2011 (UK MRC COIN)	2005-2008 	Phase 3 (C)	1a. CapeOx & Cetuximab1b. mFOLFOX6 & Cetuximab	Did not meet primary endpoint of OS1
Wasan et al. 2017 (FOXFIRE) 	2009-2014 	Phase 3 (C)	OxMdG plus SIRT 	Did not meet primary endpoint of OS
1Reported efficacy for UK MRC COIN is as reported for KRAS wild-type patients.
====Chemotherapy====
*Levoleucovorin (Fusilev) 175 mg IV over 2 hours once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00182715
##Update: Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, Kenny SL, Kay E, Hodgkinson E, Pope M, Rogers P, Wasan H, Falk S, Gollins S, Hickish T, Bessell EM, Propper D, Kennedy MJ, Kaplan R, Maughan TS; MRC COIN Trial Investigators. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011 Jul;12(7):642-53. Epub 2011 Jun 5. link to original article link to PMC article EuroPMC
#FOXFIRE: Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A, van Hazel G, Sharma RA; FOXFIRE/SIRFLOX/FOXFIRE-Global trial investigators. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. Epub 2017 Aug 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC ISRCTN83867919
#FOXFIRE-Global: Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A, van Hazel G, Sharma RA; FOXFIRE/SIRFLOX/FOXFIRE-Global trial investigators. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. Epub 2017 Aug 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01721954
==FOLFOX 7/sLV5FU2==
FOLFOX 7/sLV5FU2: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin alternating with simplified LeucoVorin, 5-FU, 2-weekly (every 2 weeks)
===Protocol===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Tournigand et al. 2006 (OPTIMOX1)	2000-2002 	Phase 3 (E-switch-ic)	FOLFOX4 	Did not meet primary endpoint of DDC
Note: this regimen has an unusual alternating schedule; see paper for more details.
====Chemotherapy, FOLFOX 7 portion====
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given first
*Fluorouracil (5-FU) 2400 mg/m2 IV continuous infusion over 46 hours, started on day 1, given third
*Oxaliplatin (Eloxatin) 130 mg/m2 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====
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given first
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 1500 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 3000 mg/m2)
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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==FOLFOX 7/sLV5FU2 (L-Leucovorin)==
FOLFOX 7/sLV5FU2: FOLinic acid (L-Leucovorin), Fluorouracil, OXaliplatin alternating with simplified L-LeucoVorin, 5-FU, 2-weekly (every 2 weeks)
===Protocol===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Tournigand et al. 2006 (OPTIMOX1)	2000-2002 	Phase 3 (E-switch-ic)	FOLFOX4 	Did not meet primary endpoint of DDC
Note: this regimen has an unusual alternating schedule; see paper for more details.
====Chemotherapy, FOLFOX 7 portion====
*Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given first
*Fluorouracil (5-FU) 2400 mg/m2 IV continuous infusion over 46 hours, started on day 1, given third
*Oxaliplatin (Eloxatin) 130 mg/m2 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/m2 IV bolus once on day 1, then 1500 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 3000 mg/m2)
*Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given first
14-day cycle for up to 12 cycles, then resume FOLFOX 7 for 6 additional cycles as described above
===References===
#OPTIMOX1: Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, Mineur L, Carola E, Etienne PL, Rivera F, Chirivella I, Perez-Staub N, Louvet C, André T, Tabah-Fisch I, de Gramont A. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006 Jan 20;24(3):394-400. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==mFOLFOX7==
mFOLFOX7: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence
Chibaudel et al. 2009 (OPTIMOX2)	2004-2006 	Non-randomized part of phase 3 RCT
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given first, with oxaliplatin
*Fluorouracil (5-FU) 3000 mg/m2 IV continuous infusion over 46 hours, started on day 1, given second
*Oxaliplatin (Eloxatin) 100 mg/m2 IV over 2 hours once on day 1, given first, with leucovorin
14-day cycle for 6 cycles
====Subsequent treatment====
*sLV5FU2 maintenance 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00274872
==mFOLFOX7 (L-Leucovorin)==
mFOLFOX7: modified FOLinic acid (L-Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence
Chibaudel et al. 2009 (OPTIMOX2)	2004-2006 	Non-randomized part of phase 3 RCT
====Chemotherapy====
*Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given first, with oxaliplatin
*Fluorouracil (5-FU) 3000 mg/m2 IV continuous infusion over 46 hours, started on day 1, given second
*Oxaliplatin (Eloxatin) 100 mg/m2 IV over 2 hours once on day 1, given first, with levoleucovorin
14-day cycle for 6 cycles
====Subsequent treatment====
*sLV5FU2 maintenance 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00274872
==FOLFOX4 & Bevacizumab==
FOLFOX4 & Bevacizumab: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Bevacizumab
FOLFOX-B: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Emmanouilides et al. 2007 	2004-2005 	Phase 2 	 	
Cassidy et al. 2008 (NO16966)	2003-2005 	Phase 3 (E-RT-esc)	1. FOLFOX42. XELOX 	Longer PFS (primary endpoint)
Cassidy et al. 2008 (NO16966)	2003-2005 	Phase 3 (E-RT-esc)	3. XELOX & Bevacizumab	Not reported
====Chemotherapy====
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once per day on days 1 & 2
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once on day 1, given first
**Infusion times are 2 hours for cycle 1, 1 hour for cycle 2, then 30 minutes for cycles 3 and later
14-day cycles
===References===
#Emmanouilides C, Sfakiotaki G, Androulakis N, Kalbakis K, Christophylakis C, Kalykaki A, Vamvakas L, Kotsakis A, Agelaki S, Diamandidou E, Touroutoglou N, Chatzidakis A, Georgoulias V, Mavroudis D, Souglakos J. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. BMC Cancer. 2007 May 30;7:91. link to original article link to PMC article EuroPMC
#NO16966: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00069095
##Update: Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64. Epub 2011 Jun 14. link to original article link to PMC article EuroPMC
==mFOLFOX6-B==
mFOLFOX6-B: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Bevacizumab
FOLFOX-B: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Bevacizumab
===Example orders===
*Example orders for mFOLFOX6-B in colon cancer
===Regimen variant #1, LCV 400 mg/m2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Hochster et al. 2008 (TREE-2) 	2003-11 to 2004-04 	Phase 3 (E-switch-ic)	1. bFOL & Bevacizumab 	Did not meet secondary efficacy endpoints 	Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
Hochster et al. 2008 (TREE-2) 	2003-11 to 2004-04 	Phase 3 (E-switch-ic)	2. CapeOx & Bevacizumab 	Did not meet secondary efficacy endpoints 	Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
Hecht et al. 2008 (PACCE) 	2005-03 to 2006-10 	Phase 3 (C) 	mFOLFOX6 & Bevacizumab & Panitumumab 	Longer OS (secondary endpoint)Median OS: 24.5 vs 19.4 mo(HR 0.70, 95% CI 0.55-0.90)Longer PFS (primary endpoint)Median PFS: 11.4 vs 10 mo(HR 0.79, 95% CI 0.66-0.94)	
Saltz et al. 2011 (USOR 05-041) 	2005 to not reported	Phase 3 (C) 	FOLF-CB 	Did not meet primary endpoint of PFS12 	
Schmoll et al. 2012 (HORIZON III)	2006-2009 	Phase 3 (C) 	mFOLFOX6 & Cediranib 	Inconclusive whether non-inferior PFS (primary endpoint)Median PFS: 10.3 vs 9.9 mo(HR 0.91, 95% CI 0.80-1.03) 	
Aranda et al. 2020 (VISNU-1) 	2012-2016 	Phase 3 (C) 	FOLFOXIRI & Bevacizumab 	Shorter PFSMedian PFS: 9.3 vs 12.4 mo(HR 1.56, 95% CI 1.22-2.04) 	
Wang et al. 2022 (VITALITY) 	2017-2019 	Phase 3 (C) 	1a. mFOLFOX & high-dose vitamin C1b. mFOLFOX-B & high-dose vitamin C	Might have shorter PFS 	
Tabernero et al. 2024 (AGENT) 	2018-12 to 2021-04 	Phase 3 (C) 	Arfolitixorin, 5-FU, Oxaliplatin, Bevacizumab 	Did not meet primary endpoint of ORR 	
Note: This was the most common oxaliplatin-based reigimen used in PACCE. There is another trial by the name of SOFT in breast cancer.
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given second
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV over 30 to 90 minutes once on day 1, given first
14-day cycles
===Regimen variant #2, LCV 200 mg/m2===
Study 	Dates of enrollment	Evidence
Johnsson et al. 2013 (Nordic ACT)	2007-2009 	Non-randomized part of phase 3 RCT
====Chemotherapy====
*Leucovorin (Folinic acid) 200 mg/m2 IV over 120 minutes once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 44 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once on day 1
14-day cycle for 9 cycles
====Subsequent treatment====
*Nordic ACT: Bevacizumab 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00399750
#PACCE: Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, Marshall J, Cohn A, McCollum D, Stella P, Deeter R, Shahin S, Amado RG. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):672-80. Epub 2008 Dec 29. link to original article EuroPMC NCT00115765
#USOR 05-041: Saltz L, Badarinath S, Dakhil S, Bienvenu B, Harker WG, Birchfield G, Tokaz LK, Barrera D, Conkling PR, O'Rourke MA, Richards DA, Reidy D, Solit D, Vakiani E, Capanu M, Scales A, Zhan F, Boehm KA, Asmar L, Cohn A. Phase III trial of cetuximab, bevacizumab, and 5-fluorouracil/leucovorin vs FOLFOX-bevacizumab in colorectal cancer. Clin Colorectal Cancer. 2012 Jun;11(2):101-11. Epub 2011 Nov 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00252564
#HORIZON III: Schmoll HJ, Cunningham D, Sobrero A, Karapetis CS, Rougier P, Koski SL, Kocakova I, Bondarenko I, Bodoky G, Mainwaring P, Salazar R, Barker P, Mookerjee B, Robertson J, Van Cutsem E. Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III). J Clin Oncol. 2012 Oct 10;30(29):3588-95. Epub 2012 Sep 10. link to original article EuroPMC NCT00384176
#Observational cohort: Bendell JC, Bekaii-Saab TS, Cohn AL, Hurwitz HI, Kozloff M, Tezcan H, Roach N, Mun Y, Fish S, Flick ED, Dalal D, Grothey A. Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-bevacizumab or FOLFIRI-bevacizumab: results from ARIES, a bevacizumab observational cohort study. Oncologist. 2012;17(12):1486-95. Epub 2012 Sep 26. link to original article link to PMC article EuroPMC
#Nordic ACT: Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00598156
#SIRFLOX: van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M, Perez D, Robinson BA, Strickland AH, Ferguson T, Rodríguez J, Kröning H, Wolf I, Ganju V, Walpole E, Boucher E, Tichler T, Shacham-Shmueli E, Powell A, Eliadis P, Isaacs R, Price D, Moeslein F, Taieb J, Bower G, Gebski V, Van Buskirk M, Cade DN, Thurston K, Gibbs P. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2016 May 20;34(15):1723-31. Epub 2016 Feb 22. link to original article contains partial dosing details in manuscript EuroPMC NCT00724503
#VISNU-1: Aranda E, Viéitez JM, Gómez-España A, Gil Calle S, Salud-Salvia A, Graña B, Garcia-Alfonso P, Rivera F, Quintero-Aldana GA, Reina-Zoilo JJ, González-Flores E, Salgado Fernández M, Guillén-Ponce C, Garcia-Carbonero R, Safont MJ, La Casta Munoa A, García-Paredes B, López López R, Sastre J, Díaz-Rubio E; Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD). FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab for patients with metastatic colorectal cancer and ≥3 circulating tumour cells: the randomised phase III VISNÚ-1 trial. ESMO Open. 2020 Nov;5(6):e000944. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01640405
#VITALITY: Wang F, He MM, Xiao J, Zhang YQ, Yuan XL, Fang WJ, Zhang Y, Wang W, Hu XH, Ma ZG, Yao YC, Zhuang ZX, Zhou FX, Ying JE, Yuan Y, Zou QF, Guo ZQ, Wu XY, Jin Y, Mai ZJ, Wang ZQ, Qiu H, Guo Y, Shi SM, Chen SZ, Luo HY, Zhang DS, Wang FH, Li YH, Xu RH. A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study). Clin Cancer Res. 2022 Oct 3;28(19):4232-4239. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
#AGENT: Tabernero J, Yoshino T, Stintzing S, de Gramont A, Gibbs P, Jonker DJ, Nygren P, Papadimitriou C, Prager GW, Tell R, Lenz HJ. A Randomized Phase III Study of Arfolitixorin versus Leucovorin with 5-Fluorouracil, Oxaliplatin, and Bevacizumab for First-Line Treatment of Metastatic Colorectal Cancer: The AGENT Trial. Cancer Res Commun. 2024 Jan 4;4(1):28-37. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03750786
==mFOLFOX6-B (L-Leucovorin)==
mFOLFOX6-B: modified FOLinic acid (L-Leucovorin), Fluorouracil, OXaliplatin, Bevacizumab
FOLFOX-B: FOLinic acid (L-Leucovorin), Fluorouracil, OXaliplatin, Bevacizumab
===Regimen variant #1, 12 cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Avallone et al. 2021 (OBELICS)	2012-2014 	Phase 3 (C)	1a. mFOLFOX6-B; early bevacizumab1b. CapeOx & Bevacizumab; early bevacizumab	Did not meet primary endpoint of ORR (primary endpoint)ORR: 57.4% vs 56.5%
====Chemotherapy====
*Levoleucovorin (Fusilev) 200 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once on day 1
14-day cycle for 12 cycles
===Regimen variant #2, indefinite===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Yamazaki et al. 2016 (WJOG4407G)	2008-2012 	Phase 3 (E-switch-ic)	FOLFIRI & Bevacizumab	Non-inferior PFS (primary endpoint)
Yamada et al. 2013 (SOFTCRC) 	2009-2011 	Phase 3 (C) 	SOX & Bevacizumab 	Seems to have non-inferior PFS
Yamada et al. 2018 (TRICOLORE) 	2012-2014 	Phase 3 (C) 	IRIS & Bevacizumab 	Non-inferior PFS (primary endpoint)Median PFS: 10.8 vs 14 mo(HR 1.19, 95% CI 0.98-1.43)
====Chemotherapy====
*Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV over 30 to 90 minutes once on day 1, given first
14-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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC JapicCTI-090699
##Update: Baba H, Yamada Y, Takahari D, Matsumoto H, Yoshida K, Nakamura M, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K. S-1 and oxaliplatin (SOX) plus bevacizumab versus mFOLFOX6 plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer: updated overall survival analyses of the open-label, non-inferiority, randomised phase III: SOFT study. ESMO Open. 2017 Mar 9;2(1):e000135. 	 link to original article link to PMC article EuroPMC
#WJOG4407G: Yamazaki K, Nagase M, Tamagawa H, Ueda S, Tamura T, Murata K, Eguchi Nakajima T, Baba E, Tsuda M, Moriwaki T, Esaki T, Tsuji Y, Muro K, Taira K, Denda T, Funai S, Shinozaki K, Yamashita H, Sugimoto N, Okuno T, Nishina T, Umeki M, Kurimoto T, Takayama T, Tsuji A, Yoshida M, Hosokawa A, Shibata Y, Suyama K, Okabe M, Suzuki K, Seki N, Kawakami K, Sato M, Fujikawa K, Hirashima T, Shimura T, Taku K, Otsuji T, Tamura F, Shinozaki E, Nakashima K, Hara H, Tsushima T, Ando M, Morita S, Boku N, Hyodo I. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol. 2016 Aug;27(8):1539-46. Epub 2016 May 13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000001396
#TRICOLORE: Yamada Y, Denda T, Gamoh M, Iwanaga I, Yuki S, Shimodaira H, Nakamura M, Yamaguchi T, Ohori H, Kobayashi K, Tsuda M, Kobayashi Y, Miyamoto Y, Kotake M, Shimada K, Sato A, Morita S, Takahashi S, Komatsu Y, Ishioka C. S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized, open-label, phase III, noninferiority trial. Ann Oncol. 2018 Mar 1;29(3):624-631. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC UMIN000007834
#OBELICS: Avallone A, Piccirillo MC, Nasti G, Rosati G, Carlomagno C, Di Gennaro E, Romano C, Tatangelo F, Granata V, Cassata A, Silvestro L, De Stefano A, Aloj L, Vicario V, Nappi A, Leone A, Bilancia D, Arenare L, Petrillo A, Lastoria S, Gallo C, Botti G, Delrio P, Izzo F, Perrone F, Budillon A. Effect of Bevacizumab in Combination With Standard Oxaliplatin-Based Regimens in Patients With Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA Netw Open. 2021 Jul 1;4(7):e2118475. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01718873
==FUFOX==
FUFOX: 5-FU, Folinic acid (Leucovorin), OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Porschen et al. 2007	2002-2004 	Phase 3 (C)	CapeOx 	Inconclusive whether non-inferior PFS (primary endpoint)
====Chemotherapy====
*Fluorouracil (5-FU) 2000 mg/m2 IV continuous infusion over 22 hours, started on days 1, 8, 15, 22, given third (total dose per cycle: 8000 mg/m2)
*Leucovorin (Folinic acid) 500 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22,, given second
*Oxaliplatin (Eloxatin) 50 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, given first
35-day 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==FUIRI==
FUIRI: 5-FU & IRInotecan
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Aranda et al. 2008	2001-2005 	Phase 3 (E-de-esc)	FOLFIRI 	Did not meet primary endpoint of ORR1
1Aranda et al. 2008 is described by the authors as a non-inferiority trial but the statistics used are superiority-based.
====Chemotherapy====
*Fluorouracil (5-FU) 1125 mg/m2/day IV continuous infusion over 48 hours, started on day 1, given second (total dose per cycle: 2250 mg/m2)
*Irinotecan (Camptosar) 80 mg/m2 IV over 30 minutes once on day 1, given first
7-day cycles
===References===
#Aranda E, Valladares M, Martinez-Villacampa M, Benavides M, Gomez A, Massutti B, Marcuello E, Constenla M, Cámara JC, Carrato A, Dueñas R, Reboredo M, Navarro M, Díaz-Rubio E; TTD. Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study. Ann Oncol. 2009 Feb;20(2):251-7. Epub 2008 Aug 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==FULV==
FULV: 5-FU & LeucoVorin
LV5FU2: LeucoVorin and 5-FU, two days out of the month
sLV5FU2: simplified LeucoVorin and 5-FU, two days out of the month
===Example orders===
*Example orders for 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV) in colon cancer
*Example orders for 5-FU & high-dose Leucovorin (Roswell Park regimen/HDLV) in colon cancer
*Example orders for weekly 5-FU & Leucovorin in colon cancer
*Example orders for simplified biweekly 5-FU & leucovorin (sLV5FU2) in colon cancer
===Regimen variant #1, 400/80 ("modified Laufman regimen")===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Verwaal et al. 2003	1998-2001 	Phase 3 (C)	HIPEC 	Shorter OS (primary endpoint)Median OS: 12.6 vs 22.3 mo(HR 1.82, 95% CI 1.05-3.12)
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1
*Leucovorin (Folinic acid) 80 mg/m2 IV once on day 1
7-day cycle for up to 26 cycles (6 months)
===Regimen variant #2, 450/200===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kosmidis et al. 1996	Not reported 	Phase 3 (C)	FULV & IFN alfa-2b	Longer OS (secondary endpoint)Median OS: 10.1 vs 7.2 mo(HR not reported, p=0.00189)
====Chemotherapy====
*Fluorouracil (5-FU) 450 mg/m2 IV bolus once on day 1, given halfway through
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once on day 1
7-day cycle for up to 52 cycles (1 year)
===Regimen variant #3, 500/20===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Jäger et al. 1996	1989-1994 	Phase 3 (C)	FULV; high-dose	Did not meet primary endpoint of ORR
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV bolus once on day 1, given second, 1 hour after start of leucovorin
*Leucovorin (Folinic acid) 20 mg/m2 IV over 2 hours once on day 1, given first
7-day cycles
===Regimen variant #4, 500/200, 6 out of 8 weeks===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Blanke et al. 2002	1995-1999 	Phase 3 (C)	FULV & Trimetrexate	Did not meet primary endpoint of PFS
====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 cycles
===Regimen variant #5, 500/500 (modified "Roswell Park regimen")===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kabbinavar et al. 2005 (AVF0780g)	2000-08 to 2002-07 	Randomized Phase 2 (C)	FULV & Bevacizumab	Did not meet primary endpoint of OS
Note: the original Roswell Park regimen used a 5-FU dose of 600 mg/m2.
====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 12 cycles
===Regimen variant #6, 600/25, 6 out of 8 weeks===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Heys et al. 1995	Not reported 	Phase 3 (C)	FULV & rIL2	Might have shorter OS
====Chemotherapy====
*Fluorouracil (5-FU) 600 mg/m2 IV bolus once per day on days 1, 8, 15, 22, 29, 36
*Leucovorin (Folinic acid) 25 mg/m2 IV bolus once per day on days 1, 8, 15, 22, 29, 36
8-week cycle for up to 3 cycles
===Regimen variant #7, 600/500 (original "Roswell Park regimen")===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Petrelli et al. 1987	Not reported 	Phase 3 (E-esc)	1. 5-FU2. 5-FU & MTX 	Higher ORR
Petrelli et al. 1989	Not reported 	Phase 3 (E-esc)	1. 5-FU2. FULV; LDLV 	Might have longer OS
Buroker et al. 1994 	1988-1990 	Phase 3 (E-esc)	FULV; Mayo Clinic regimen	Did not meet primary endpoint of OS50%
Jones et al. 1995 	1988-1991 	Phase 3 (C) 	MFL 	Did not meet primary endpoint of ORR
====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 cycles
===Regimen variant #8, 1500/400===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Gamelin et al. 2008	Not reported 	Phase 3 (C)	FULV; PK-guided	Might have shorter OS
====Chemotherapy====
*Fluorouracil (5-FU) 1500 mg/m2 IV over 8 hours once on day 1
*Leucovorin (Folinic acid) 200 mg/m2 IV bolus every 4 hours on day 1, given before and 4 hours into 5-FU infusion (total dose per cycle: 400 mg/m2)
7-day cycles
===Regimen variant #9, 1850/1000===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Man et al. 1995 (Corfu-A) 	1990-01 to 1991-04 	Phase 3 (E-switch-ooc)	5-FU & IFN alfa-2a	Did not meet primary endpoint of ORR
Bobbio-Pallavicini et al. 1993	Not reported in abstract	Phase 3 (E-esc) 	5-FU 	Seems to have longer OSMedian OS: 8 vs 6 mo(HR not reported)
Note: The full manuscript for Bobbio-Pallavicini et al. 1993 was not available for review.
====Chemotherapy====
*Fluorouracil (5-FU) 370 mg/m2 IV bolus once per day on days 1 to 5, given second
*Leucovorin (Folinic acid) 200 mg/m2 IV over 10 minutes once per day on days 1 to 5, given first
28-day cycles
===Regimen variant #10, 1850/1000, with spacing out===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Goldberg et al. 1997	1990-1995 	Phase 3 (E-esc)	1. FULV; LDLV2. FULV; oral LV	Did not meet primary endpoint of OS
====Chemotherapy====
*Fluorouracil (5-FU) 370 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 2 cycles, then 35-day cycles
===Regimen variant #11, 2000/100===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Borner et al. 1998	1991-1995 	Phase 3 (E-esc)	5-FU 	Seems to have longer OS (primary endpoint)Median OS: 12.4 vs 10 mo(HR not reported)
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 to 5
*Leucovorin (Folinic acid) 20 mg/m2 IV once per day on days 1 to 5
1-month cycles
===Regimen variant #12, 2000/400 (LV5FU2 aka "de Gramont regimen")===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
de Gramont et al. 1997 (FFCD 9101) 	1991-1994 	Phase 3 (E-esc)	FULV; Mayo Clinic regimen 	Might have longer OS (primary endpoint)Median OS: 62 vs 56.8 weeks(HR not reported, p=0.067)
Kerr et al. 2003 	1994-2000 	Phase 3 (C) 	FULV; IHA LV5FU2 	Did not meet primary endpoint of OS
de Gramont et al. 2000 	1995-1997 	Phase 3 (C) 	FOLFOX4 	Shorter PFS (primary endpoint)Median PFS: 6.2 vs 9 mo(aHR 1.25, 95% CI not reported)
Maughan et al. 2002 (MRC CR06) 	1996-1998 	Phase 3 (C) 	1. Lokich regimen 	Did not meet primary endpoint of OS
Maughan et al. 2002 (MRC CR06) 	1996-1998 	Phase 3 (C) 	2. Raltitrexed 	Did not meet primary endpoint of OS
Maughan et al. 2003 	1996-2000 	Phase 3 (C) 	FULV; intermittent LV5FU2 	Did not meet primary endpoint of OS
Douillard et al. 2000 	1997-05 to 1998-02 	Phase 3 (C) 	1a. IFL1b. FOLFIRI 	Shorter OS (secondary endpoint)Median OS: 14.1 vs 17.4 mo(aHR 2.17, 95% CI 1.33-3.57)Shorter ORR (primary endpoint)ORR: 22% vs 35%
Ducreux et al. 2006 (FFCD 9601) 	1997-2001 	Phase 3 (C) 	1. FULV; ldLV5FU22. 5-FU 	Did not meet primary endpoint of PFS
Ducreux et al. 2006 (FFCD 9601) 	1997-2001 	Phase 3 (C) 	3. Raltitrexed 	Seems to have longer PFS
Cunningham et al. 2008 	2000 to not reported	Phase 3b (C) 	FOLFOX4 	Did not meet primary endpoint of OS
Aparicio et al. 2015 (FFCD 2001-02)	2003-2010 	Phase 3 (C) 	1. FOLFIRI; "classic"2. FOLFIRI; "simplified"	Did not meet primary endpoint of PFS
Aparicio et al. 2015 (FFCD 2001-02)	2003-2010 	Phase 3 (C) 	3. FULV; sLV5FU2 	Did not meet primary endpoint of PFS
Note: Maughan et al. 2003 randomized patients to 12 weeks of treatment with re-treatment upon progression, versus continuous treatment. There was no difference in outcome between the two arms. FFCD 2001-02 enrolled elderly (75 or older) patients.
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given second (total dose per cycle: 2000 mg/m2)
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, given first
14-day cycles (see note)
===Regimen variant #13, 2000/500===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Scheithauer et al. 1997	1991-1994 	Phase 3 (C)	FULV (L-Leucovorin)	Did not meet primary endpoint of OS12
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV over 2 hours once per day on days 1 to 5, given second
*Leucovorin (Folinic acid) 100 mg/m2 IV bolus once per day on days 1 to 5, given first
28-day cycle for up to 6 cycles
===Regimen variant #14, 2000/1000===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Labianca et al. 1991	1987-1989 	Phase 3 (E-esc)	5-FU 	Seems to have higher ORR
Cocconi et al. 1998 	1995-07 to 1996-02 	Phase 3 (C) 	Raltitrexed	Longer TTP (primary endpoint)Median TTP: 5.1 vs 3.9 mo(HR 0.75, 95% CI 0.62-0.92)
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV over 15 minutes once per day on days 1 to 5, given second
*Leucovorin (Folinic acid) 200 mg/m2 IV bolus once per day on days 1 to 5, given first
28-day cycles
===Regimen variant #15, 2125/100 ("Mayo Clinic regimen") variant #1===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
de Gramont et al. 1997 (FFCD 9101)	1991-1994 	Phase 3 (C)	FULV; LV5FU2 	Might have shorter OS (primary endpoint)Median OS: 56.8 vs 62 weeks(HR not reported, log-rank p=0.067)
Cunningham et al. 1995 	1993-11 to 1994-06 	Phase 3 (C)	Raltitrexed 	Did not meet primary endpoint of TTP
Douillard et al. 2002 	1995-1997 	Phase 3 (C)	UFT & Leucovorin 	Seems to have equivalent OS (primary endpoint)
Köhne et al. 2003 (EORTC 40952) 	1995-1998 	Phase 3 (C)	1. FU24h2. FU24h + LV	Did not meet primary endpoint of OS
Saltz et al. 2000 	1996-1998 	Phase 3 (C)	1. IFL 	Seems to have shorter OS
Saltz et al. 2000 	1996-1998 	Phase 3 (C)	2. Irinotecan 	Did not meet primary endpoint of PFS
Hoff et al. 2001 (SO14695) 	1996-1998 	Phase 3 (C)	Capecitabine 	Lower ORR
Van Cutsem et al. 2001 (SO14796) 	1996-1998 	Phase 3 (C)	Capecitabine 	Equivalent ORR
Schilsky et al. 2002 (FUMA3008) 	1997-1999 	Phase 3 (C)	Eniluracil & 5-FU 	Inconclusive whether non-inferior OS (primary endpoint)Median OS: 14.5 vs 13.3 mo
Chong et al. 2005 	1998-2001 	Phase 3 (C)	FULV & 3H1 	Did not meet primary endpoint of OS
Note: not all manuscripts explicitly describe the timing described here; O'Connell 1989 is the clearest.
====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 (see note)
===Regimen variant #16, 2125/100 ("Mayo Clinic regimen") variant #2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
O'Connell 1989 	Not reported 	Phase 3 (E-RT-esc)	1. 5-FU 	Seems to have longer OS
O'Connell 1989 	Not reported 	Phase 3 (E-RT-esc)	2. FULV; HDLV 	Did not meet primary efficacy endpoint
Poon et al. 1989 	1984-1987 	Phase 3 (E-RT-esc)	5-FU 	Seems to have longer OSMedian OS: 12 vs 7.7 mo
Buroker et al. 1994	1988-1990 	Phase 3 (E-de-esc)	FULV; Roswell Park regimen	Did not meet primary endpoint of OS50%
Aranda et al. 1998 	1994-1996 	Phase 3 (C) 	5-FU; high-dose 	Seems to have lower ORR
====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 2 cycles, then 35-day cycles
===Regimen variant #17, 2125/100 ("Mayo Clinic regimen") variant #3===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Hospers et al. 2006	1999-2002 	Phase 3 (C)	FOLFOX6 	Seems to have shorter PFS (secondary endpoint)Median PFS: 5.6 vs 6.7 mo(HR not reported, log-rank p=0.016)Lower RR (primary endpoint)
====Chemotherapy====
*Fluorouracil (5-FU) 425 mg/m2 IV bolus once per day on days 1 to 5
*Leucovorin (Folinic acid) 20 mg/m2 IV once per day on days 1 to 5
28-day cycles
===Regimen variant #18, 2125/100 ("Mayo Clinic regimen") variant #4===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Carmichael et al. 2002	1996-05 to 1997-07 	Phase 3 (C)	UFT & Leucovorin	Did not meet primary endpoint of TTP
====Chemotherapy====
*Fluorouracil (5-FU) 425 mg/m2 IV bolus once per day on days 1 to 5
*Leucovorin (Folinic acid) 20 mg/m2 IV once per day on days 1 to 5
35-day cycles
===Regimen variant #19, 2560/175 (reduced-dose sLV5FU2)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Seymour et al. 2011 (MRC FOCUS2)	2004-01 to 2006-07 	Phase 3 (C)	1. Capecitabine2. CapeOx 3. OxFU	Might have shorter PFS (see note)	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/m2 IV bolus once on day 1, then 2240 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2560 mg/m2)
*Leucovorin (Folinic acid) 175 mg/m2 IV over 2 hours once on day 1
14-day cycles
===Regimen variant #20, 2600/500, weekly===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Douillard et al. 2000	1997-05 to 1998-02 	Phase 3 (C)	1a. IFL1b. FOLFIRI	Shorter OS (secondary endpoint)Median OS: 14.1 vs 17.4 mo(aHR 2.17, 95% CI 1.33-3.57)Shorter ORR (primary endpoint)ORR: 22% vs 35%
====Chemotherapy====
*Fluorouracil (5-FU) 2600 mg/m2 IV continuous infusion over 24 hours, started on day 1
*Leucovorin (Folinic acid) 500 mg/m2 IV once on day 1
7-day cycles
===Regimen variant #21, 2600/500, 6 out of 8 weeks ("AIO regimen")===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Köhne et al. 2005 (EORTC 40986)	1999-2001 	Phase 3 (C)	FOLFIRI 	Shorter PFSMedian PFS: 6.4 vs 8.5 mo(HR 1.54, 95% CI 1.27-1.89)
====Chemotherapy====
*Fluorouracil (5-FU) 2600 mg/m2 IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 15,600 mg/m2)
*Leucovorin (Folinic acid) 500 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
8-week cycles
===Regimen variant #22, 2800/400 (sLV5FU2)===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Ducreux et al. 2011 (FFCD 2000-05)	2002-2006 	Phase 3 (C)	See link 	See link
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given first
14-day cycles
====Subsequent treatment====
*FFCD 2000-05, upon progression: mFOLFOX6
===Regimen variant #23, other===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hausmaninger et al. 1999	1991-1995 	Phase 3 (C)	FULV & IFN alfa-2c 	Did not meet primary endpoint of ORR
Giacchetti et al. 2000 	1994-1996 	Phase 3 (C)	Chronomodulated FOLFOX	Lower ORR (primary endpoint)ORR: 16% vs 53%
Note: See papers for details.
====Chemotherapy====
*Fluorouracil (5-FU)
*Leucovorin (Folinic acid)
===References===
#Petrelli N, Herrera L, Rustum Y, Burke P, Creaven P, Stulc J, Emrich LJ, Mittelman A. A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol. 1987 Oct;5(10):1559-65. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#O'Connell MJ; North Central Cancer Treatment Group. A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer: a Mayo Clinic/North Central Cancer Treatment Group study. Cancer. 1989 Mar 15;63(6 Suppl):1026-30. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Poon MA, O'Connell MJ, Moertel CG, Wieand HS, Cullinan SA, Everson LK, Krook JE, Mailliard JA, Laurie JA, Tschetter LK, Wiesenfeld M; NCCTG. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol. 1989 Oct;7(10):1407-18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Poon MA, O'Connell MJ, Wieand HS, Krook JE, Gerstner JB, Tschetter LK, Levitt R, Kardinal CG, Mailliard JA. Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol. 1991 Nov;9(11):1967-72. link to original article EuroPMC
#Petrelli N, Douglass HO Jr, Herrera L, Russell D, Stablein DM, Bruckner HW, Mayer RJ, Schinella R, Green MD, Muggia FM, Megibow A, Greenwald ES, Bukowski RM, Harris J, Levin B, Gaynor E, Loutfi A, Kaiser MH, Barkin JS, Benedetto P, Woolley PV, Nauta R, Weaver DW, Leichman LP; Gastrointestinal Tumor Study Group. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. J Clin Oncol. 1989 Oct;7(10):1419-26. Erratum in: J Clin Oncol 1990 Jan;8(1):185. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Labianca R, Pancera G, Aitini E, Barni S, Beretta A, Beretta GD, Cesana B, Comella G, Cozzaglio L, Cristoni M, Spagnolli P, Frontini L, Gottardi O, Martignoni G, Scapaticci R, Smerieri F, Vinci M, Zadro A, Zaniboni A, Luporini G; GISCAD. Folinic acid + 5-fluorouracil (5-FU) versus equidose 5-FU in advanced colorectal cancer: phase III study of 'GISCAD' (Italian Group for the Study of Digestive Tract Cancer). Ann Oncol. 1991 Oct;2(9):673-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Bobbio-Pallavicini E, Porta C, Moroni M, Spaghi A, Casagranda I, Nastasi G. Folinic acid does improve 5-fluorouracil activity in vivo: results of a phase III study comparing 5-fluorouracil to 5-fluorouracil and folinic acid in advanced colon cancer patients. J Chemother. 1993 Feb;5(1):52-5. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#Buroker TR, O'Connell MJ, Wieand HS, Krook JE, Gerstner JB, Mailliard JA, Schaefer PL, Levitt R, Kardinal CG, Gesme DH Jr. Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol. 1994 Jan;12(1):14-20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Corfu-A: Man A, Levi J, Weinerman B, Kjaer M, Yap AKL; Corfu-A Study Group. Phase III randomized study of two fluorouracil combinations with either interferon alfa-2a or leucovorin for advanced colorectal cancer. J Clin Oncol. 1995 Apr;13(4):921-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Jones DV Jr, Winn RJ, Brown BW, Levy LB, Pugh RP, Wade JL 3rd, Gross HM, Pendergrass KB, Levin B, Abbruzzese JL. Randomized phase III study of 5-fluorouracil plus high dose folinic acid versus 5-fluorouracil plus folinic acid plus methyl-lomustine for patients with advanced colorectal cancer. Cancer. 1995 Nov 15;76(10):1709-14. link to original article EuroPMC
#Cunningham D, Zalcberg JR, Rath U, Olver I, Van Cutsem E, Svensson C, Seitz JF, Harper P, Kerr D, Perez-Manga G, Azab M, Seymour L, Lowery K; The 'Tomudex' Colorectal Cancer Study Group. 'Tomudex' (ZD1694): results of a randomised trial in advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopenia. Eur J Cancer. 1995 Nov;31A(12):1945-54. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Cunningham D, Zalcberg JR, Rath U, Oliver I, van Cutsem E, Svensson C, Seitz JF, Harper P, Kerr D, Perez-Manga G; "Tomudex" Colorectal Cancer Study Group. Final results of a randomised trial comparing 'Tomudex' (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. Ann Oncol. 1996 Nov;7(9):961-5. Erratum in: Ann Oncol 1997 Apr;8(4):407. link to original article EuroPMC
#Heys SD, Eremin O, Ruggeri EM, Pein F, Rainer H, Oskam R, de Peuter RA, Palmer PA, Franks CR. A phase III study of recombinant interleukin-2, 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in patients with unresectable or metastatic colorectal carcinoma. Eur J Cancer. 1995;31A(1):19-25. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Jäger E, Heike M, Bernhard H, Klein O, Bernhard G, Lautz D, Michaelis J, Meyer zum Büschenfelde KH, Knuth Al; Study Group for Palliative Treatment of Metastatic Colorectal Cancer. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. J Clin Oncol. 1996 Aug;14(8):2274-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Kosmidis PA, Tsavaris N, Skarlos D, Theocharis D, Samantas E, Pavlidis N, Briassoulis E, Fountzilas G; Hellenic Cooperative Oncology Group. Fluorouracil and leucovorin with or without interferon alfa-2b in advanced colorectal cancer: analysis of a prospective randomized phase III trial. J Clin Oncol. 1996 Oct;14(10):2682-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#FFCD 9101: de Gramont A, Bosset JF, Milan C, Rougier P, Bouché O, Etienne PL, Morvan F, Louvet C, Guillot T, François E, Bedenne L. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol. 1997 Feb;15(2):808-15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Scheithauer W, Kornek G, Marczell A, Salem G, Karner J, Kovats E, Burger D, Greiner R, Pidlich J, Schneeweiss B, Raderer M, Rosen H, Depisch D. Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study. J Clin Oncol. 1997 Mar;15(3):908-14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Goldberg RM, Hatfield AK, Kahn M, Sargent DJ, Knost JA, O'Connell MJ, Krook JE, Maillard JA, Wiesenfeld M, Schaefer PL, Tirona MT, Moertel CG; North Central Cancer Treatment Group. Prospectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. J Clin Oncol. 1997 Nov;15(11):3320-9. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#Borner MM, Castiglione M, Bacchi M, Weber W, Herrmann R, Fey MF, Pagani O, Leyvraz S, Morant R, Pestalozzi B, Hanselmann S, Goldhirsch A; Swiss Group for Clinical Cancer Research. The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: results of a phase III trial. Ann Oncol. 1998 May;9(5):535-41. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#Aranda E, Díaz-Rubio E, Cervantes A, Antón-Torres A, Carrato A, Massutí T, Tabernero JM, Sastre J, Trés A, Aparicio J, López-Vega JM, Barneto I, García-Conde J; TTD. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol. 1998 Jul;9(7):727-31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Cocconi G, Cunningham D, Van Cutsem E, Francois E, Gustavsson B, van Hazel G, Kerr D, Possinger K, Hietschold SM; Tomudex Colorectal Cancer Study Group. Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. J Clin Oncol. 1998 Sep;16(9):2943-52. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Hausmaninger H, Moser R, Samonigg H, Mlineritsch B, Schmidt H, Pecherstorfer M, Fridrik M, Kopf C, Nitsche D, Kaider A, Ludwig H. Biochemical modulation of 5-fluorouracil by leucovorin with or without interferon-alpha-2c in patients with advanced colorectal cancer: final results of a randomised phase III study. Eur J Cancer. 1999 Mar;35(3):380-5. link to original article EuroPMC
#Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet P, Llory JF, Letourneau Y, Coudert B, Bertheaut-Cvitkovic F, Larregain-Fournier D, Le Rol A, Walter S, Adam R, Misset JL, Lévi F. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2000 Jan;18(1):136-47. link to original article EuroPMC
#Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#SO14695: Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001 Apr 15;19(8):2282-92. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Pooled update: Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. link to original article link to PMC article EuroPMC
#SO14796: Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P; Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001 Nov 1;19(21):4097-106. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Pooled update: Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. link to original article link to PMC article EuroPMC
#Blanke CD, Shultz J, Cox J, Modiano M, Isaacs R, Kasimis B, Schilsky R, Fleagle J, Moore M, Kemeny N, Carlin D, Hammershaimb L, Haller D. A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer. Ann Oncol. 2002 Jan;13(1):87-91. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#FUMA3008: Schilsky RL, Levin J, West WH, Wong A, Colwell B, Thirlwell MP, Ansari RH, Bell WN, White RL, Yates BB, McGuirt PV, Pazdur R. Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. J Clin Oncol. 2002 Mar 15;20(6):1519-26. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#MRC CR06: Maughan TS, James RD, Kerr DJ, Ledermann JA, McArdle C, Seymour MT, Cohen D, Hopwood P, Johnston C, Stephens RJ; British MRC Colorectal Cancer Working Party. Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2002 May 4;359(9317):1555-63. link to original article EuroPMC NCT00002893
#Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12;87(4):393-9. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
#Douillard JY, Hoff PM, Skillings JR, Eisenberg P, Davidson N, Harper P, Vincent MD, Lembersky BC, Thompson S, Maniero A, Benner SE. Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2002 Sep 1;20(17):3605-16. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#Carmichael J, Popiela T, Radstone D, Falk S, Borner M, Oza A, Skovsgaard T, Munier S, Martin C. Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2002 Sep 1;20(17):3617-27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Kerr DJ, McArdle CS, Ledermann J, Taylor I, Sherlock DJ, Schlag PM, Buckels J, Mayer D, Cain D, Stephens RJ; Medical Research Council's colorectal cancer study group; EORTC colorectal cancer study group. Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. Lancet. 2003 Feb 1;361(9355):368-73. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#Maughan TS, James RD, Kerr DJ, Ledermann JA, Seymour MT, Topham C, McArdle C, Cain D, Stephens RJ; Medical Research Council Colorectal Cancer Group. Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial. Lancet. 2003 Feb 8;361(9356):457-64. link to original article EuroPMC
#EORTC 40952: Köhne CH, Wils J, Lorenz M, Schöffski P, Voigtmann R, Bokemeyer C, Lutz M, Kleeberg C, Ridwelski K, Souchon R, El-Serafi M, Weiss U, Burkhard O, Rückle H, Lichnitser M, Langenbuch T, Scheithauer W, Baron B, Couvreur ML, Schmoll HJ; European Organization of Research and Treatment of Cancer Gastrointestinal Group. Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952. J Clin Oncol. 2003 Oct 15;21(20):3721-8. Epub 2003 Sep 8. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003 Oct 15;21(20):3737-43. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#AVF0780g: Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, Mass R, Perrou B, Nelson B, Novotny WF. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005 Jun 1;23(16):3697-705. Epub 2005 Feb 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#EORTC 40986: Köhne CH, van Cutsem E, Wils J, Bokemeyer C, El-Serafi M, Lutz MP, Lorenz M, Reichardt P, Rückle-Lanz H, Frickhofen N, Fuchs R, Mergenthaler HG, Langenbuch T, Vanhoefer U, Rougier P, Voigtmann R, Müller L, Genicot B, Anak O, Nordlinger B; EORTC Gastrointestinal Group. Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol. 2005 Aug 1;23(22):4856-65. Epub 2005 Jun 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00004885
#Chong G, Bhatnagar A, Cunningham D, Cosgriff TM, Harper PG, Steward W, Bridgewater J, Moore M, Cassidy J, Coleman R, Coxon F, Redfern CH, Jones JJ, Hawkins R, Northfelt D, Sreedharan S, Valone F, Carmichael J. Phase III trial of 5-fluorouracil and leucovorin plus either 3H1 anti-idiotype monoclonal antibody or placebo in patients with advanced colorectal cancer. Ann Oncol. 2006 Mar;17(3):437-42. Epub 2005 Nov 25. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Hospers GA, Schaapveld M, Nortier JW, Wils J, van Bochove A, de Jong RS, Creemers GJ, Erjavec Z, de Gooyer DJ, Slee PH, Gerrits CJ, Smit JM, Mulder NH. Randomised Phase III study of biweekly 24-h infusion of high-dose 5FU with folinic acid and oxaliplatin versus monthly plus 5-FU/folinic acid in first-line treatment of advanced colorectal cancer. Ann Oncol. 2006 Mar;17(3):443-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#FFCD 9601: Ducreux M, Bouche O, Pignon JP, Mousseau M, Raoul JL, Cassan P, Leduc B, Berger C, Dunant A, Fournet J, Bedenne L; FFCD. Randomised trial comparing three different schedules of infusional 5FU and raltitrexed alone as first-line therapy in metastatic colorectal cancer: final results of the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 trial. Oncology. 2006;70(3):222-30. Epub 2006 Jun 30. link to original article EuroPMC
#Gamelin E, Delva R, Jacob J, Merrouche Y, Raoul JL, Pezet D, Dorval E, Piot G, Morel A, Boisdron-Celle M. Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer. J Clin Oncol. 2008 May 1;26(13):2099-105. Erratum in: J Clin Oncol. 2013 Oct 1;31(28):3612. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Cunningham D, Sirohi B, Pluzanska A, Utracka-Hutka B, Zaluski J, Glynne-Jones R, Koralewski P, Bridgewater J, Mainwaring P, Wasan H, Wang JY, Szczylik C, Clingan P, Chan RT, Tabah-Fisch I, Cassidy J. Two different first-line 5-fluorouracil regimens with or without oxaliplatin in patients with metastatic colorectal cancer. Ann Oncol. 2009 Feb;20(2):244-50. Epub 2008 Oct 14. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#MRC FOCUS2: Seymour MT, Thompson LC, Wasan HS, Middleton G, Brewster AE, Shepherd SF, O'Mahony MS, Maughan TS, Parmar M, Langley RE; FOCUS2 Investigators; National Cancer Research Institute Colorectal Cancer Clinical Studies Group. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. Lancet. 2011 May 21;377(9779):1749-59. Epub 2011 May 11. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00070213
#FFCD 2000-05: Ducreux M, Malka D, Mendiboure J, Etienne PL, Texereau P, Auby D, Rougier P, Gasmi M, Castaing M, Abbas M, Michel P, Gargot D, Azzedine A, Lombard-Bohas C, Geoffroy P, Denis B, Pignon JP, Bedenne L, Bouché O; Fédération Francophone de Cancérologie Digestive. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol. 2011 Oct;12(11):1032-44. Epub 2011 Sep 6. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT00126256
#FFCD 2001-02: Aparicio T, Lavau-Denes S, Phelip JM, Maillard E, Jouve JL, Gargot D, Gasmi M, Locher C, Adhoute X, Michel P, Khemissa F, Lecomte T, Provençal J, Breysacher G, Legoux JL, Lepère C, Charneau J, Cretin J, Chone L, Azzedine A, Bouché O, Sobhani I, Bedenne L, Mitry E; FFCD. Randomized phase III trial in elderly patients comparing LV5FU2 with or without irinotecan for first-line treatment of metastatic colorectal cancer (FFCD 2001-02). Ann Oncol. 2016 Jan;27(1):121-7. Epub 2015 Oct 20. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT00303771
==FULV (L-Leucovorin)==
FULV (L-Leucovorin): 5-FU & L-LeucoVorin
===Regimen variant #1, 1870/50===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Labianca et al. 1997	1991-1994 	Phase 3 (C)	FULV; HDLV	Did not meet primary endpoint of ORR
====Chemotherapy====
*Fluorouracil (5-FU) 370 mg/m2 IV over 15 minutes once per day on days 1 to 5, given second
*Levoleucovorin (Fusilev) 10 mg/m2 IV bolus once per day on days 1 to 5, given first
28-day cycles
===Regimen variant #2, 1875/500===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Colucci et al. 1999	1991-1993 	Phase 3 (C)	FULV & IFN alfa-2b	Did not meet primary efficacy endpoints
====Chemotherapy====
*Fluorouracil (5-FU) 375 mg/m2 IV bolus once per day on days 1 to 5, given second
*Levoleucovorin (Fusilev) 100 mg/m2 IV over 15 minutes once per day on days 1 to 5, given first
21-day cycles
===Regimen variant #3, 3200/350 ("modified de Gramont regimen")===
Study 	Dates of enrollment 	Evidence
Cheeseman et al. 2002 	Not reported 	Non-randomized
Seymour et al. 2007 (MRC FOCUS)	2000-05-01 to 2003-12-31	Phase 3 (C)
Note: This variant used a higher total dose of 5-FU per cycle than most similar regimens. Efficacy results for MRC FOCUS are complex and will be added in the future (to be completed).
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, given second, then 2800 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 3200 mg/m2)
*Levoleucovorin (Fusilev) 175 mg IV over 2 hours once on day 1, given first
====Supportive therapy====
*No routine prophylactic antiemetics and 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Colucci G, Maiello E, Gebbia V, Giuliani F, Serravezza G, Lelli G, Leo S, Filippelli G, Nicolella G, Brandi M; SICOG. 5-fluorouracil and levofolinic acid with or without recombinant interferon-2b in patients with advanced colorectal carcinoma: a randomized multicenter study with stratification for tumor burden and liver involvement by the Southern Italy Oncology Group. Cancer. 1999 Feb 1;85(3):535-45. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12;87(4):393-9. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
#MRC FOCUS: Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, Smith DB, Shepherd S, Maraveyas A, Ferry DR, Meade AM, Thompson L, Griffiths GO, Parmar MK, Stephens RJ; FOCUS Trial Investigators; National Cancer Research Institute Colorectal Clinical Studies Group. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007 Jul 14;370(9582):143-52. Erratum in: Lancet. 2007 Aug 18;370(9587):566. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00008060
==FULV & Bevacizumab==
FULV & Bevacizumab: 5-FU, LeucoVorin, Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Kabbinavar et al. 2005 (AVF0780g)	2000-08 to 2002-07 	Randomized Phase 2 (E-RT-esc)	FULV 	Did not meet primary endpoint of OS
Note: This regimen was intended for patients who were felt to be nonoptimal candidates for first-line irinotecan.
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV bolus once per day on days 1, 8, 15, 22, 29, 36, given midway through leucovorin infusion
*Leucovorin (Folinic acid) 500 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once per day on days 1, 15, 29, 43
56-day cycle for up to 12 cycles
===References===
#AVF0780g: Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, Mass R, Perrou B, Nelson B, Novotny WF. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005 Jun 1;23(16):3697-705. Epub 2005 Feb 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==FULV & Bevacizumab (L-Leucovorin)==
FULV & Bevacizumab: 5-FU, LevoleucoVorin, Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Takashima et al. 2024 (JCOG1018)	2012-09 to 2019-03 	Phase 3 (C)	1a. CapeOx & Bevacizumab1b. FOLFOX & Bevacizumab	Did not meet primary endpoint of PFSMedian PFS: 9.4 vs 10 mo(HR 1.19, 90.5% CI 0.96-1.49)
====Eligibility criteria====
*Age 70 to 74 years old with ECOG PS of 2 OR Age 75 years and older with ECOG PS of 0 to 2
====Chemotherapy====
*Fluorouracil (5-FU) 2400 mg/m2 IV once on day 1
*Levoleucovorin (Fusilev) 200 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once on day 1
14-day cycles
===References===
#JCOG1018: Takashima A, Hamaguchi T, Mizusawa J, Nagashima F, Ando M, Ojima H, Denda T, Watanabe J, Shinozaki K, Baba H, Asayama M, Hasegawa S, Masuishi T, Nakata K, Tsukamoto S, Katayama H, Nakamura K, Fukuda H, Kanemitsu Y, Shimada Y; Colorectal Cancer Study Group in Japan Clinical Oncology Group (JCOG). Oxaliplatin Added to Fluoropyrimidine/Bevacizumab as Initial Therapy for Unresectable Metastatic Colorectal Cancer in Older Patients: A Multicenter, Randomized, Open-Label Phase III Trial (JCOG1018). J Clin Oncol. 2024 Nov 20;42(33):3967-3976. Epub 2024 Aug 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC jRCTs031180145
==FUOX==
FUOX: 5-FU & OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Díaz-Rubio et al. 2007 (03-TTD-01)	2002-2004 	Phase 3 (C)	CapeOx 	Did not meet primary endpoint of TTP
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Chemotherapy====
*Fluorouracil (5-FU) 1125 mg/m2/day IV continuous infusion over 48 hours, started on days 1 & 8 (total dose per cycle: 4500 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
14-day cycle for 18 cycles
===References===
#03-TTD-01: Díaz-Rubio E, Tabernero J, Gómez-España A, Massutí B, Sastre J, Chaves M, Abad A, Carrato A, Queralt B, Reina JJ, Maurel J, González-Flores E, Aparicio J, Rivera F, Losa F, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol. 2007 Sep 20;25(27):4224-30. Epub 2007 Jun 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00202774
==IFL==
IFL: Irinotecan, Fluorouracil, Leucovorin
mIFL: modified Irinotecan, Fluorouracil, Leucovorin
===Regimen variant #1, q3wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Stathopoulos et al. 2010	2004-2008 	Phase 3 (C)	IFL & Bevacizumab	Did not meet primary endpoint of OS36
====Chemotherapy====
*Irinotecan (Camptosar) 135 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Leucovorin (Folinic acid) 200 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #2, 4 out of 6 weeks===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Saltz et al. 2000 	1996-1998 	Phase 3 (E-RT-esc) 	1. FULV 	Seems to have longer OS
Saltz et al. 2000 	1996-1998 	Phase 3 (E-RT-esc) 	2. Irinotecan 	Might have longer OS
Goldberg et al. 2003 (NCCTG N9741)	1999-2001 	Phase 3 (C) 	1. FOLFOX4 	Shorter OS
Goldberg et al. 2003 (NCCTG N9741)	1999-2001 	Phase 3 (C) 	2. IROX 	Seems to have shorter OS
Hurwitz et al. 2004 (AVF2107g) 	2000-2002 	Phase 3 (C) 	1. FULV & Bevacizumab	Did not meet primary endpoint of OS1
Hurwitz et al. 2004 (AVF2107g) 	2000-2002 	Phase 3 (C) 	2. IFL & Bevacizumab 	Shorter OS
Fuchs et al. 2007 (BICC-C) 	2003-02 to 2004-12 	Phase 3 (E-switch-ic)	1. CapeIRI 	Did not meet primary endpoint of PFS
Fuchs et al. 2007 (BICC-C) 	2003-02 to 2004-12 	Phase 3 (E-switch-ic)	2. FOLFIRI 	Shorter PFS (primary endpoint)
Guan et al. 2011 (ARTISTCRC) 	2007-07-20 to 2008-08-07	Phase 3 (C) 	mIFL & Bevacizumab 	Shorter PFS (co-primary endpoint)Median PFS: 4.2 vs 8.3 mo(HR 2.27, 95% CI 1.59-3.23)Shorter OS (secondary endpoint)Median OS: 13.4 vs 18.7 mo(HR 1.61, 95% CI 1.05-2.44)
1Reported efficacy for this arm of AVF2107g is based on the 2005 update.
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/m2 IV over 90 minutes once per day on days 1, 8, 15, 22, given first
*Fluorouracil (5-FU) 500 mg/m2 IV bolus once per day on days 1, 8, 15, 22
*Leucovorin (Folinic acid) 20 mg/m2 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#NCCTG N9741: Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. Epub 2003 Dec 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003594
##Toxicity analysis: Delaunoit T, Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Findlay BP, Thomas SP, Salim M, Schaefer PL, Stella PJ, Green E, Mailliard JA. Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup Trial N9741. Cancer. 2004 Nov 15;101(10):2170-6. link to original article EuroPMC
#AVF2107g: Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00109070
##Update: Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, Hambleton J, Novotny WF, Kabbinavar F. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol. 2005 May 20;23(15):3502-8. link to original article EuroPMC
#BICC-C: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article EuroPMC
#Stathopoulos GP, Batziou C, Trafalis D, Koutantos J, Batzios S, Stathopoulos J, Legakis J, Armakolas A. Treatment of colorectal cancer with and without bevacizumab: a phase III study. Oncology. 2010;78(5-6):376-81. Epub 2010 Aug 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#ARTISTCRC: Guan ZZ, Xu JM, Luo RC, Feng FY, Wang LW, Shen L, Yu SY, Ba Y, Liang J, Wang D, Qin SK, Wang JJ, He J, Qi C, Xu RH. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer. 2011 Oct;30(10):682-9. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00642577
==IFL & Bevacizumab==
IFL & Bevacizumab: Irinotecan, Fluorouracil, Leucovorin, Bevacizumab
mIFL & Bevacizumab: modified Irinotecan, Fluorouracil, Leucovorin, Bevacizumab
===Regimen variant #1, IFL===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Fuchs et al. 2007 (BICC-C)	2003-02 to 2004-12 	Phase 3 (E-switch-ic)	FOLFIRI+Bev	Seems to have shorter OS (secondary endpoint)
====Chemotherapy====
*Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1 & 8
*Fluorouracil (5-FU) 500 mg/m2 IV bolus once per day on days 1 & 8
*Leucovorin (Folinic acid) 20 mg/m2 IV bolus once per day on days 1 & 8
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
===Regimen variant #2, mIFL===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Hurwitz et al. 2004 (AVF2107g)	2000-2002 	Phase 3 (E-RT-esc)	1. FL & Bevacizumab	Not reported
Hurwitz et al. 2004 (AVF2107g)	2000-2002 	Phase 3 (E-RT-esc)	2. IFL 	Longer OS (primary endpoint)Median OS: 20.3 vs 15.6 mo(HR 0.66)
Guan et al. 2011 (ARTISTCRC) 	2007-07-20 to 2008-08-07	Phase 3 (E-esc) 	mIFL 	Longer OS (secondary endpoint)Median OS: 18.7 vs 13.4 mo(HR 0.62, 95% CI 0.41-0.95)Longer PFS (co-primary endpoint)Median PFS: 8.3 vs 4.2 mo(HR 0.44, 95% CI 0.31-0.63)
Note: this trial should not be confused for the trial with the same name in gastric cancer.
====Chemotherapy====
*Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1, 8, 15, 22, given first
*Fluorouracil (5-FU) 500 mg/m2 IV over 6 to 8 hours once per day on days 1, 8, 15, 22
*Leucovorin (Folinic acid) 20 mg/m2 IV bolus once per day on days 1, 8, 15, 22
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once per day on days 1, 15, 29
42-day cycles
===References===
#AVF2107g: Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00109070
##Update: Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, Hambleton J, Novotny WF, Kabbinavar F. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol. 2005 May 20;23(15):3502-8. link to original article EuroPMC
#BICC-C: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article EuroPMC
#ARTISTCRC: Guan ZZ, Xu JM, Luo RC, Feng FY, Wang LW, Shen L, Yu SY, Ba Y, Liang J, Wang D, Qin SK, Wang JJ, He J, Qi C, Xu RH. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer. 2011 Oct;30(10):682-9. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00642577
==Irinotecan monotherapy==
===Example orders===
*Example orders for Irinotecan (Camptosar) in colon cancer
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Saltz et al. 2000	1996-1998 	Phase 3 (E-de-esc)	1. FULV 	Did not meet primary endpoint of PFS
Saltz et al. 2000	1996-1998 	Phase 3 (E-de-esc)	2. IFL 	Might have shorter OS (secondary endpoint)
====Chemotherapy====
*Irinotecan (Camptosar) 125 mg/m2 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==IRIS & Bevacizumab==
IRIS & Bevacizumab: IRInotecan, S-1, Bevacizumab
===Regimen variant #1, q3wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Yamada et al. 2018 (TRICOLORE)	2012-2014 	Phase 3 (E-switch-ic)	1a. CapeOx & Bevacizumab1b. mFOLFOX6-B	Non-inferior PFS (primary endpoint)Median PFS: 14 vs 10.8 mo(HR 0.84, 95% CI 0.70-1.02)
====Chemotherapy====
*Irinotecan (Camptosar) 150 mg/m2 IV once on day 1, given second
*Tegafur, gimeracil, oteracil (S-1) 40 mg/m2 PO twice per day on days 1 to 15, beginning in the evening (28 doses per cycle)
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1, given first
21-day cycles
===Regimen variant #2, q4wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Yamada et al. 2018 (TRICOLORE)	2012-2014 	Phase 3 (E-switch-ic)	1a. CapeOx & Bevacizumab1b. mFOLFOX6-B	Non-inferior PFS (primary endpoint)Median PFS: 14 vs 10.8 mo(HR 0.84, 95% CI 0.70-1.02)
====Chemotherapy====
*Irinotecan (Camptosar) 100 mg/m2 IV once per day on days 1 & 15, given second
*Tegafur, gimeracil, oteracil (S-1) 40 mg/m2 PO twice per day on days 1 to 15, beginning in the evening (28 doses per cycle)
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once per day on days 1 & 15, given first
28-day cycles
===References===
#TRICOLORE: Yamada Y, Denda T, Gamoh M, Iwanaga I, Yuki S, Shimodaira H, Nakamura M, Yamaguchi T, Ohori H, Kobayashi K, Tsuda M, Kobayashi Y, Miyamoto Y, Kotake M, Shimada K, Sato A, Morita S, Takahashi S, Komatsu Y, Ishioka C. S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized, open-label, phase III, noninferiority trial. Ann Oncol. 2018 Mar 1;29(3):624-631. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC UMIN000007834
==IROX==
IROX: IRinotecan & OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Goldberg et al. 2003 (NCCTG N9741)	1999-2001 	Phase 3 (E-RT-switch-ic)	1. FOLFOX4	Did not meet primary endpoint of TTP
Goldberg et al. 2003 (NCCTG N9741)	1999-2001 	Phase 3 (E-RT-switch-ic)	2. IFL 	Seems to have longer OS (secondary endpoint)
====Chemotherapy====
*Irinotecan (Camptosar) 200 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) 85 mg/m2 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003594
##Toxicity analysis: Delaunoit T, Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Findlay BP, Thomas SP, Salim M, Schaefer PL, Stella PJ, Green E, Mailliard JA. Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup Trial N9741. Cancer. 2004 Nov 15;101(10):2170-6. link to original article EuroPMC
==Nordic FLOX==
FLOX: Fluorouracil, Leucovorin, OXaliplatin
===Example orders===
*Example orders for FLOX in colon cancer
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Sørbye et al. 2004 	2000-2001 	Phase 2 	 	
Tveit et al. 2012 (NORDIC-VII)	2005-2007 	Phase 3 (C)	Nordic FLOX & Cetuximab	Did not meet primary endpoint of PFS
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV bolus once per day on days 1 & 2, given second
*Leucovorin (Folinic acid) 60 mg/m2 IV bolus once per day on days 1 & 2, given third, 30 minutes after 5-FU
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 30 to 90 minutes once on day 1, given first
14-day cycle for varying durations: 8 cycles (NORDIC-VII); 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. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#NORDIC-VII: Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, Sigurdsson F, Kure E, Ikdahl T, Skovlund E, Fokstuen T, Hansen F, Hofsli E, Birkemeyer E, Johnsson A, Starkhammar H, Yilmaz MK, Keldsen N, Erdal AB, Dajani O, Dahl O, Christoffersen T. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012 May 20;30(15):1755-62. Epub 2012 Apr 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00145314
##Update: Guren TK, Thomsen M, Kure EH, Sorbye H, Glimelius B, Pfeiffer P, Österlund P, Sigurdsson F, Lothe IMB, Dalsgaard AM, Skovlund E, Christoffersen T, Tveit KM. Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study. Br J Cancer. 2017 May 9;116(10):1271-1278. Epub 2017 Apr 11. link to original article link to PMC article EuroPMC
==OXAFAFU==
OXAFAFU: OXAliplatin, Folinic Acid (Leucovorin), 5-FU (Fluorouracil)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Comella et al. 2005	2001-2003 	Phase 3 (E-switch-ic)	IRIFAFU 	Seems to have longer OS (secondary endpoint)Median OS: 18.9 vs 15.6 mo(HR not reported, p=0.032)
Note: This was the dosage after a mid-protocol amendment.
====Chemotherapy====
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
*Leucovorin (Folinic acid) 250 mg/m2 IV over 2 hours once on day 2
*Fluorouracil (5-FU) 850 mg/m2 IV bolus once on day 2
14-day cycle for 8 to 12 cycles
===References===
#Comella P, Massidda B, Filippelli G, Palmeri S, Natale D, Farris A, De Vita F, Buzzi F, Tafuto S, Maiorino L, Mancarella S, Leo S, Lorusso V, De Lucia L, Roselli M; SICOG. Oxaliplatin plus high-dose folinic acid and 5-fluorouracil IV bolus (OXAFAFU) versus irinotecan plus high-dose folinic acid and 5-fluorouracil IV bolus (IRIFAFU) in patients with metastatic colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase III trial. Ann Oncol. 2005 Jun;16(6):878-86. Epub 2005 Apr 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==S-1 monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Kwakman et al. 2017 (SALTO)	2014-01 to 2015-07 	Phase 3 (E-switch-ic)	Capecitabine	Did not meet secondary efficacy endpoints1	Lower incidence of hand-foot syndrome
1Reported efficacy is based on the 2019 update.
Note: this trial had a primary toxicity endpoint.
====Chemotherapy====
*Tegafur, gimeracil, oteracil (S-1) 30 mg/m2 PO twice per day on days 1 to 14
21-day cycles 
===References===
#SALTO: Kwakman JJM, Simkens LHJ, van Rooijen JM, van de Wouw AJ, Ten Tije AJ, Creemers GJM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, van Werkhoven E, Punt CJA; Dutch Colorectal Cancer Group. Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group. Ann Oncol. 2017 Jun 1;28(6):1288-1293. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01918852
##Update: Kwakman JJM, van Werkhoven E, Simkens LHJ, van Rooijen JM, van de Wouw YAJ, ten Tije AJ, Creemers GM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, Punt CJA; Dutch Colorectal Cancer Group. Updated Survival Analysis of the Randomized Phase III Trial of S-1 Versus Capecitabine in the First-Line Treatment of Metastatic Colorectal Cancer by the Dutch Colorectal Cancer Group. Clin Colorectal Cancer. 2019 Jun;18(2):e229-e230. Epub 2019 Jan 29. link to original article EuroPMC
==SOX==
SOX: S-1 & OXaliplatin
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Hong et al. 2012 (SMC 2008-03-012)	2008-05-14 to 2009-09-23	Phase 3 (E-switch-ic)	CapeOX 	Non-inferior PFS (primary endpoint)Median PFS: 8.5 vs 6.7 mo(HR 0.79, 95% CI 0.60-1.04)
====Chemotherapy====
*Tegafur, gimeracil, oteracil (S-1) 40 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
21-day cycle for up to 9 cycles 
====Subsequent treatment====
*Patients were allowed to continue 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00677443
##Update: Kim ST, Hong YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Lee JW, Jo SJ, Park YS. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: updated results from a phase 3 trial. BMC Cancer. 2014 Nov 26;14:883. link to original article link to PMC article EuroPMC
==SOX & Bevacizumab==
SOX & Bevacizumab: S-1, OXaliplatin, Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Yamada et al. 2013 (SOFTCRC)	2009-2011 	Phase 3 (E-switch-ic)	mFOLFOX6-B	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) by the following BSA-based criteria:
**Less than 1.25 m2: 40 mg PO twice per day on days 1 to 14 (see note)
**Between 1.25 m2 and 1.5 m2: 50 mg PO twice per day on days 1 to 14 (see note)
**1.5 m2 or more: 60 mg PO twice per day on days 1 to 14 (see note)
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1, given second
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV over 30 to 90 minutes once on day 1, given first
21-day cycles
===References===
#SOFT: Yamada Y, Takahari D, Matsumoto H, Baba H, Nakamura M, Yoshida K, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1278-86. Epub 2013 Nov 11. Erratum in: Lancet Oncol. 2014 Jan;15(1):e4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC JapicCTI-090699
##Update: Baba H, Yamada Y, Takahari D, Matsumoto H, Yoshida K, Nakamura M, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K. S-1 and oxaliplatin (SOX) plus bevacizumab versus mFOLFOX6 plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer: updated overall survival analyses of the open-label, non-inferiority, randomised phase III: SOFT study. ESMO Open. 2017 Mar 9;2(1):e000135. 	 link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
=Maintenance after first-line therapy=
==Bevacizumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Johnsson et al. 2013 (Nordic ACT) 	2007-2009 	Phase 3 (C) 	Erlotinib & Bevacizumab 	Did not meet primary endpoint of PFS
Tournigand et al. 2015 (OPTIMOX3) 	2007-2011 	Phase 3 (C) 	Erlotinib & Bevacizumab 	Might have shorter PFS (primary endpoint)Median PFS: 4.9 vs 5.3 mo(sHR 1.23, 95% CI 0.99-1.52)
Koeberle et al. 2015 (SAKK 41/06) 	2007-2012 	Phase 3 (E-esc)	No further treatment 	Inconclusive whether non-inferior TTP (primary endpoint)
Hegewisch-Becker et al. 2015 (AIO KRK 0207)	2009-2013 	Phase 3 (E-esc)	1. No further treatment 	Not reported
Hegewisch-Becker et al. 2015 (AIO KRK 0207)	2009-2013 	Phase 3 (E-esc)	2. Fluoropyrimidine & Bevacizumab	Non-inferior TTF (primary endpoint)
Aparicio et al. 2018 (PRODIGE 9) 	2010-2013 	Phase 3 (E-esc)	No further treatment 	Did not meet primary endpoint of TCD
====Preceding treatment====
*Nordic ACT: First-line FOLFIRI & Bevacizumab x 9 or mFOLFOX6-B x 9 or XELIRI & Bevacizumab x 6 or XELOX & Bevacizumab x 6
*AIO KRK 0207 & OPTIMOX3: First-line bevacizumab-containing chemotherapy
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
===References===
#Nordic ACT: Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, Sundberg J, De Pont Christensen R, Garm Spindler KL, Bergström D, Jakobsen A. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. Epub 2013 Jun 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00598156
#SAKK 41/06: Koeberle D, Betticher DC, von Moos R, Dietrich D, Brauchli P, Baertschi D, Matter K, Winterhalder R, Borner M, Anchisi S, Moosmann P, Kollar A, Saletti P, Roth A, Frueh M, Kueng M, Popescu RA, Schacher S, Hess V, Herrmann R. Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06). Ann Oncol. 2015 Apr;26(4):709-14. Epub 2015 Jan 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00544700
#AIO KRK 0207: Hegewisch-Becker S, Graeven U, Lerchenmüller CA, Killing B, Depenbusch R, Steffens CC, Al-Batran SE, Lange T, Dietrich G, Stoehlmacher J, Tannapfel A, Reinacher-Schick A, Quidde J, Trarbach T, Hinke A, Schmoll HJ, Arnold D. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1355-69. Epub 2015 Sep 8. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. link to original article EuroPMC NCT00973609
#OPTIMOX3: Tournigand C, Chibaudel B, Samson B, Scheithauer W, Vernerey D, Mésange P, Lledo G, Viret F, Ramée JF, Tubiana-Mathieu N, Dauba J, Dupuis O, Rinaldi Y, Mabro M, Aucoin N, Latreille J, Bonnetain F, Louvet C, Larsen AK, André T, de Gramont A. Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1493-1505. Epub 2015 Oct 22. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00265824
#PRODIGE 9: Aparicio T, Ghiringhelli F, Boige V, Le Malicot K, Taieb J, Bouché O, Phelip JM, François E, Borel C, Faroux R, Dahan L, Jacquot S, Genet D, Khemissa F, Suc E, Desseigne F, Texereau P, Lepage C, Bennouna J; PRODIGE 9 Investigators. Bevacizumab maintenance versus no maintenance during chemotherapy-free intervals in metastatic colorectal cancer: a randomized phase III trial (PRODIGE 9). J Clin Oncol. 2018 Mar 1;36(7):674-681. Epub 2018 Jan 18. link to original article EuroPMC NCT00952029
==Capecitabine monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Hong et al. 2012 (SMC 2008-03-012)	2008-05-14 to 2009-09-23	Non-randomized part of phase 3 RCT	 	
Luo et al. 2016 	2010-2013 	Phase 3 (E-esc) 	Observation	Longer PFS (primary endpoint)Median PFS: 6.4 vs 3.4 mo(HR 0.54, 95% CI 0.42-0.70)
Adams et al. 2021 (FOCUS4-N) 	2014-2020 	Phase 3 (E-esc) 	Observation	Longer PFS (primary endpoint)Median PFS: 3.9 vs 1.9 mo(HR 0.44, 95% CI 0.33-0.57)
Note: In FOCUS4-N, capecitabine was dosed "according to standard guidelines".
====Preceding treatment====
*SMC 2008-03-012: First-line CapeOX x 9
*Luo et al. 2016: First-line FOLFOX or XELOX
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycles
===References===
#SMC 2008-03-012: Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00677443
#Luo HY, Li YH, Wang W, Wang ZQ, Yuan X, Ma D, Wang FH, Zhang DS, Lin DR, Lin YC, Jia J, Hu XH, Peng JW, Xu RH. Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety. Ann Oncol. 2016 Jun;27(6):1074-81. Epub 2016 Mar 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02027363
#FOCUS4-N: Adams RA, Fisher DJ, Graham J, Seligmann JF, Seymour M, Kaplan R, Yates E, Parmar M, Richman SD, Quirke P, Butler R, Brown E, Collinson F, Falk S, Wasan H, Shiu KK, Middleton G, Samuel L, Wilson RH, Brown LC, Maughan TS; FOCUS4 Trial Investigators. Capecitabine Versus Active Monitoring in Stable or Responding Metastatic Colorectal Cancer After 16 Weeks of First-Line Therapy: Results of the Randomized FOCUS4-N Trial. J Clin Oncol. 2021 Nov 20;39(33):3693-3704. Epub 2021 Sep 13. link to original article link to PMC article EuroPMC ISRCTN90061546
==Capecitabine & Bevacizumab==
CAP-B: CAPecitabine & Bevacizumab
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Yalcin et al. 2013 (Stop and Go)	2008-04 to 2009-07 	Phase 3 (E-de-esc)	XELOX-B; continued	Longer PFS (primary endpoint)Median PFS: 11 vs 8.3 mo(HR 0.6, 95% CI 0.43-0.83)
Simkens et al. 2015 (CAIRO3) 	2007-2012 	Phase 3 (E-esc) 	Observation 	Longer PFS-2 (primary endpoint)Median PFS: 11.7 vs 8.5 mo(HR 0.67, 95% CI 0.56-0.81)
====Preceding treatment====
*First-line CAPOX-B x 6
====Chemotherapy====
*Capecitabine (Xeloda) 625 mg/m2 PO twice per day
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1
21-day cycles
===Regimen variant #2, q3wk capecitabine/q2wk bevacizumab===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Takashima et al. 2024 (LYNK-003)	2020-08 to 2022-05 	Phase 3 (C)	1. Olaparib 	Longer PFS (primary endpoint)Median PFS: 5.6 vs 3.5 mo(HR 0.47, 95% CI 0.31-0.72)
Takashima et al. 2024 (LYNK-003)	2020-08 to 2022-05 	Phase 3 (C)	2. Olaparib & Bevacizumab	Seems to have longer PFS (primary endpoint)Median PFS: 5.6 vs 3.7 mo(HR 0.66, 95% CI 0.44-0.98)
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14, 22 to 35
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once per day on days 1, 15, 29
6-week cycles
===References===
#Stop and Go: Yalcin S, Uslu R, Dane F, Yilmaz U, Zengin N, Buyukunal E, Buyukberber S, Camci C, Sencan O, Kilickap S, Ozdener F, Cevik D; Turkish Oncology Group. Bevacizumab + capecitabine as maintenance therapy after initial bevacizumab + XELOX treatment in previously untreated patients with metastatic colorectal cancer: phase III 'Stop and Go' study results--a Turkish Oncology Group trial. Oncology. 2013;85(6):328-35. Epub 2013 Nov 12. link to original article EuroPMC NCT00623805
#CAIRO3: Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoeven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, Honkoop AH, Mol L, Punt CJ, Koopman M; Dutch Colorectal Cancer Group. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015 May 9;385(9980):1843-52. Epub 2015 Apr 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00442637
##Update: Goey KKH, Elias SG, van Tinteren H, Laclé MM, Willems SM, Offerhaus GJA, de Leng WWJ, Strengman E, Ten Tije AJ, Creemers GM, van der Velden A, de Jongh FE, Erdkamp FLG, Tanis BC, Punt CJA, Koopman M. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann Oncol. 2017 Sep 1;28(9):2128-2134. link to original article EuroPMC
#LYNK-003: Takashima A, García-Alfonso P, Manneh R, Beşen AA, Hong YS, Cuyle PJ, Yanez P, Burge M, Yoshino T, Kim TW, Cui K, Li C, Jain R, Adelberg D, Taieb J. Olaparib with or without bevacizumab versus bevacizumab plus a fluoropyrimidine as maintenance therapy in advanced colorectal cancer: The randomized phase 3 LYNK-003 study. Eur J Cancer. 2024 Jul;205:114036. Epub 2024 Mar 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04456699
==Fluorouracil & Bevacizumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Takashima et al. 2024 (LYNK-003)	2020-08 to 2022-05 	Phase 3 (C)	1. Olaparib 	Longer PFS (primary endpoint)Median PFS: 5.6 vs 3.5 mo(HR 0.47, 95% CI 0.31-0.72)
Takashima et al. 2024 (LYNK-003)	2020-08 to 2022-05 	Phase 3 (C)	2. Olaparib & Bevacizumab	Seems to have longer PFS (primary endpoint)Median PFS: 5.6 vs 3.7 mo(HR 0.66, 95% CI 0.44-0.98)
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Preceding treatment====
*First-line mFOLFOX6-B
====Chemotherapy====
*Fluorouracil (5-FU) 2400 mg/m2 IV continuous infusion over 46 to 48 hours, started on day 1 (total dose per cycle: 2400 mg/m2)
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once on day 1
14-day cycles
===References===
#LYNK-003: Takashima A, García-Alfonso P, Manneh R, Beşen AA, Hong YS, Cuyle PJ, Yanez P, Burge M, Yoshino T, Kim TW, Cui K, Li C, Jain R, Adelberg D, Taieb J. Olaparib with or without bevacizumab versus bevacizumab plus a fluoropyrimidine as maintenance therapy in advanced colorectal cancer: The randomized phase 3 LYNK-003 study. Eur J Cancer. 2024 Jul;205:114036. Epub 2024 Mar 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04456699
==FULV & Bevacizumab (L-Leucovorin)==
FULV & Bevacizumab: 5-FU, LevoleucoVorin, Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence
Loupakis et al. 2014 (TRIBE)	2008-2011 	Non-randomized part of phase 3 RCT
Note: Loupakis et al. 2014 listed folinic acid 200 mg/m2 in the body of the paper, whereas the protocol in the supplementary material stated that levoleucovorin 200 mg/m2 was used. We have contacted NEJM regarding this suspected error.
====Preceding treatment====
*First-line FOLFIRI & Bevacizumab x 12 versus FOLFOXIRI & Bevacizumab x 12
====Chemotherapy====
*Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV over 30 minutes once on day 1
14-day cycles
===References===
#TRIBE: Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014 Oct 23;371(17):1609-18. link to original article link to protocol in supplementary material dosing details in manuscript have been reviewed by our editors EuroPMC NCT00719797
##Update: Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, Mezi S, Tomasello G, Ronzoni M, Zaniboni A, Tonini G, Carlomagno C, Allegrini G, Chiara S, D'Amico M, Granetto C, Cazzaniga M, Boni L, Fontanini G, Falcone A. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015 Oct;16(13):1306-15. Epub 2015 Aug 31. link to original article EuroPMC
==S-1 monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Hong et al. 2012 (SMC 2008-03-012)	2008-05-14 to 2009-09-23	Non-randomized part of phase 3 RCT
====Preceding treatment====
*First-line SOX x 9
====Chemotherapy====
*Tegafur, gimeracil, oteracil (S-1) 40 mg/m2 PO twice per day on days 1 to 14
21-day cycles 
===References===
#SMC 2008-03-012: Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. Epub 2012 Oct 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00677443
=Advanced or metastatic disease, second-line therapy=
==CapeOx==
CapeOx: Capecitabine & Oxaliplatin
XELOX: XELoda & OXaliplatin
===Example orders===
*Example orders for CapeOx (XELOX) in colon cancer
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Koopman et al. 2007 (CAIRO) 	2003-01 to 2004-12 	Phase 3 (E-switch-ic)	See link 	See link
Rothenberg et al. 2008 (NO16967)	2003-2005 	Phase 3 (E-switch-ic)	FOLFOX4 	Non-inferior PFS (primary endpoint)
====Preceding treatment====
*CAIRO: First-line CAPIRI, with progression
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
21-day cycles 
===References===
#CAIRO: Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ; Dutch Colorectal Cancer Group. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00312000
#NO16967: Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, Gollins S, Siu LL, Laguerre S, Cunningham D. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008 Oct;19(10):1720-6. Epub 2008 Jun 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00069108
==CapeOx & Erlotinib==
CapeOx & Erlotinib: Capecitabine, OXaliplatin, Erlotinib
===Regimen===
Study 	Dates of enrollment	Evidence
Meyerhardt et al. 2006	2003-2004 	Phase 2
====Chemotherapy====
*Capecitabine (Xeloda) 750 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
====Targeted therapy====
*Erlotinib (Tarceva) 150 mg PO once per day on days 1 to 21
21-day cycles 
===References===
# Meyerhardt JA, Zhu AX, Enzinger PC, Ryan DP, Clark JW, Kulke MH, Earle CC, Vincitore M, Michelini A, Sheehan S, Fuchs CS. Phase II study of capecitabine, oxaliplatin, and erlotinib in previously treated patients with metastastic colorectal cancer. J Clin Oncol. 2006 Apr 20;24(12):1892-7. link to original article EuroPMC
==CAPIRI==
CapeIRI: Capecitabine and IRInotecan
CAPIRI: CAPecitabine and IRInotecan
XELIRI: XELox (Capecitabine) and IRInotecan
mXELIRI: modified XELox (Capecitabine) and IRInotecan
===Regimen variant #1, "standard"===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Lim et al. 2015 (SMC 2009-11-017)	2010-2013 	Phase 3 (C)	1a. FOLFIRI & Simvastatin1b. XELIRI & Simvastatin	Did not meet primary endpoint of PFS
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Irinotecan (Camptosar) 250 mg/m2 IV over 90 minutes once on day 1
21-day cycles
===Regimen variant #2, "modified"===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2018 (AXEPT)	2013-2015 	Phase 3 (E-switch-ic)	1a. FOLFIRI1b. FOLFIRI & Bevacizumab	Non-inferior OS (primary endpoint)Median OS: 16.8 vs 15.4 mo(HR 0.85, 95% CI 0.71-1.02)
====Chemotherapy====
*Capecitabine (Xeloda) 800 mg/m2 PO twice per day on days 1 to 14
*Irinotecan (Camptosar) 200 mg/m2 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. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01238094
#AXEPT: Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01996306
==CAPIRI-Bev==
CAPIRI-Bev: CAPecitabine, IRInotecan, Bevacizumab
mXELIRI & Bevacizumab: modified XELox (Capecitabine), IRInotecan, Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2018 (AXEPT)	2013-2015 	Phase 3 (E-switch-ic)	1a. FOLFIRI1b. FOLFIRI & Bevacizumab	Non-inferior OS (primary endpoint)Median OS: 16.8 vs 15.4 mo(HR 0.85, 95% CI 0.71-1.02)
====Chemotherapy====
*Capecitabine (Xeloda) 800 mg/m2 PO twice per day on days 1 to 14
*Irinotecan (Camptosar) 200 mg/m2 IV over 90 minutes once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 7.5 mg/kg IV over 30 to 90 minutes once on day 1
21-day cycles
===References===
#AXEPT: Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01996306
==Fluorouracil monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Rougier et al. 1998 (V302)	1995-1997 	Phase 3 (C)	Irinotecan	Seems to have shorter OS (primary endpoint)Median OS: 8.5 vs 10.8 mo(HR not reported, p=0.035)
Note: this was one of three control regimens; see paper for details.
====Chemotherapy====
*Fluorouracil (5-FU) 250 to 300 mg/m2/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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==FOLFIRI==
FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan
===Example orders===
*Example orders for FOLFIRI in colon cancer
===Regimen variant #1, lower-dose leucovorin===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Lim et al. 2015 (SMC 2009-11-017)	2010-2013 	Phase 3 (C)	1a. FOLFIRI & Simvastatin1b. XELIRI & Simvastatin	Did not meet primary endpoint of PFS
====Chemotherapy====
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once on day 1, given second
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours, given third (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1, given first
14-day cycles
===Regimen variant #2, higher-dose leucovorin===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Tournigand et al. 2003 	1997-1999 	Phase 3 (E-switch-ic)	mFOLFOX6 	Did not meet primary endpoint of PFS15
Bennouna et al. 2012 (ML18147) 	2006-2010 	Phase 3 (C) 	Second-line chemotherapy & Bevacizumab (see note)	Shorter OS (primary endpoint)Median OS: 9.8 vs 11.2 mo(HR 1.23, 95% CI 1.06-1.45)
Van Cutsem et al. 2012 (VELOUR)	2007-2010 	Phase 3 (C) 	FOLFIRI & Ziv-aflibercept 	Shorter OSMedian OS: 12.1 vs 13.5 mo(HR 1.22, 95.34% CI 1.06-1.41)
Masi et al. 2015 (BEBYP) 	2008-2012 	Phase 3 (C) 	FOLFIRI & Bevacizumab 	Shorter PFS (primary endpoint)Median PFS: 5 vs 6.8 mo(HR 1.43, 95% CI 1.05-1.92)
Tabernero et al. 2015 (RAISE) 	2010-2013 	Phase 3 (C) 	FOLFIRI & Ramucirumab 	Seems to have shorter OSMedian OS: 11.7 vs 13.3 mo(HR 1.19, 95% CI 1.02-1.37)
Xu et al. 2018 (AXEPT) 	2013-2015 	Phase 3 (C) 	1a. mXELIRI1b. mXELIRI & Bevacizumab 	Non-inferior OSMedian OS: 15.4 vs 16.8 mo(HR 1.18, 95% CI 0.98-1.41)
Shah et al. 2023 (CanStem303C) 	2016-08-31 to 2019-03-18	Phase 3 (C) 	FOLFIRI & Napabucasin 	Did not meet primary endpoint of OSMedian OS: 13.8 vs 14.3 mo(HR 1.02, 95% CI 0.90-1.17)
Note: the abstract of ML18147 did not specify the exact second-line chemotherapy regimen; patients had to be previously bevacizumab-exposed. Masi et al. 2015 did not provide dosing details; this was the most commonly used variant of FOLFIRI.
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given first, with irinotecan
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours, given second (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first, with leucovorin
14-day cycles
====Subsequent treatment====
*Tournigand et al. 2003, upon progression: mFOLFOX6
====Dose and schedule modifications====
*In Tournigand et al. 2003, if no toxicity greater than grade 1 in cycles 1 & 2, fluorouracil increased to: 400 mg/m2 IV bolus once on day 1, then 3000 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 3400 mg/m2)
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#FFCD 2000-05: Ducreux M, Malka D, Mendiboure J, Etienne PL, Texereau P, Auby D, Rougier P, Gasmi M, Castaing M, Abbas M, Michel P, Gargot D, Azzedine A, Lombard-Bohas C, Geoffroy P, Denis B, Pignon JP, Bedenne L, Bouché O; Fédération Francophone de Cancérologie Digestive. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol. 2011 Oct;12(11):1032-44. Epub 2011 Sep 6. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT00126256
#VELOUR: Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012 Oct 1;30(28):3499-506. Epub 2012 Sep 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00561470
##Subgroup analysis: Tabernero J, Van Cutsem E, Lakomý R, Prausová J, Ruff P, van Hazel GA, Moiseyenko VM, Ferry DR, McKendrick JJ, Soussan-Lazard K, Chevalier S, Allegra CJ. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014 Jan;50(2):320-31. Epub 2013 Oct 16. link to original article EuroPMC
##Subgroup analysis: Ruff P, Van Cutsem E, Lakomy R, Prausova J, van Hazel GA, Moiseyenko VM, Soussan-Lazard K, Dochy E, Magherini E, Macarulla T, Papamichael D. Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: An age-based analysis from the randomized placebo-controlled phase III VELOUR trial. J Geriatr Oncol. 2018 Jan;9(1):32-39. Epub 2017 Aug 12. link to original article EuroPMC
#ML18147: Bennouna J, Sastre J, Arnold D, Österlund P, Greil R, Van Cutsem E, von Moos R, Viéitez JM, Bouché O, Borg C, Steffens CC, Alonso-Orduña V, Schlichting C, Reyes-Rivera I, Bendahmane B, André T, Kubicka S; ML18147 Study Investigators. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013 Jan;14(1):29-37. Epub 2012 Nov 16. link to original article does not contain dosing details in manuscript EuroPMC NCT00700102
#BEBYP: Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-30. Epub 2015 Jan 18. link to original article does not contain dosing details EuroPMC NCT00720512
#RAISE: Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F; RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 May;16(5):499-508. Epub 2015 Apr 12. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01183780
##Subgroup analysis: Obermannová R, Van Cutsem E, Yoshino T, Bodoky G, Prausová J, Garcia-Carbonero R, Ciuleanu T, Garcia Alfonso P, Portnoy D, Cohn A, Yamazaki K, Clingan P, Lonardi S, Kim TW, Yang L, Nasroulah F, Tabernero J. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016 Nov;27(11):2082-2090. Epub 2016 Aug 29. link to original article link to PMC article EuroPMC
#SMC 2009-11-017: Lim SH, Kim TW, Hong YS, Han SW, Lee KH, Kang HJ, Hwang IG, Lee JY, Kim HS, Kim ST, Lee J, Park JO, Park SH, Park YS, Lim HY, Jung SH, Kang WK. A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer. Br J Cancer. 2015 Nov 17;113(10):1421-6. Epub 2015 Oct 27. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01238094
#AXEPT: Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01996306
#CanStem303C: Shah MA, Yoshino T, Tebbutt NC, Grothey A, Tabernero J, Xu RH, Cervantes A, Oh SC, Yamaguchi K, Fakih M, Falcone A, Wu C, Chiu VK, Tomasek J, Bendell J, Fontaine M, Hitron M, Xu B, Taieb J, Van Cutsem E. Napabucasin Plus FOLFIRI in Patients With Previously Treated Metastatic Colorectal Cancer: Results From the Open-Label, Randomized Phase III CanStem303C Study. Clin Colorectal Cancer. 2023 Mar;22(1):100-110. Epub 2022 Nov 11. link to original article EuroPMC NCT02753127
#KRYSTAL-10: NCT04793958
==FOLFIRI (L-Leucovorin)==
FOLFIRI: FOLinic acid (L-Leucovorin), Fluorouracil, IRInotecan
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tournigand et al. 2003	1997-1999 	Phase 3 (E-switch-ic)	mFOLFOX6 	Did not meet primary endpoint of PFS15
Xu et al. 2018 (AXEPT)	2013-2015 	Phase 3 (C) 	1a. mXELIRI1b. mXELIRI & Bevacizumab	Non-inferior OSMedian OS: 15.4 vs 16.8 mo(HR 1.18, 95% CI 0.98-1.41)
====Chemotherapy====
*Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given first, with irinotecan
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1, given first, with levoleucovorin
14-day cycles
====Subsequent treatment====
*Tournigand et al. 2003, upon progression: mFOLFOX6
====Dose and schedule modifications====
*In Tournigand et al. 2003, if no toxicity greater than grade 1 in cycles 1 & 2, fluorouracil increased to: 400 mg/m2 IV bolus once on day 1, then 3000 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 3400 mg/m2)
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#AXEPT: Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01996306
==FOLFIRI & Bevacizumab==
FOLFIRI & Bevacizumab: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan, Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bennouna et al. 2012 (ML18147)	2006-2010 	Phase 3 (E-RT-esc)	Second-line chemotherapy (see note) 	Longer OS (primary endpoint)Median OS: 11.2 vs 9.8 mo(HR 0.81, 95% CI 0.69-0.94)
Masi et al. 2015 (BEBYP) 	2008-2012 	Phase 3 (E-esc) 	FOLFIRI 	Longer PFS (primary endpoint)Median PFS: 6.8 vs 5 mo(HR 0.70, 95% CI 0.52-0.95)
Xu et al. 2018 (AXEPT) 	2013-2015 	Phase 3 (C) 	1a. mXELIRI1b. mXELIRI & Bevacizumab	Non-inferior OSMedian OS: 15.4 vs 16.8 mo(HR 1.18, 95% CI 0.98-1.41)
Note: the abstract of ML18147 did not specify the exact second-line chemotherapy regimen; patients had to be previously bevacizumab-exposed. BEBYP did not provide dosing details; this was the most commonly used variant of FOLFIRI.
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given first, with irinotecan
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours, given third (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1, given first, with leucovorin
====Targeted therapy====
*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. link to original article contains partial dosing details in manuscript EuroPMC NCT00700102
#BEBYP: Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-30. Epub 2015 Jan 18. link to original article does not contain dosing details EuroPMC NCT00720512
#AXEPT: Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01996306
==FOLFIRI & Bevacizumab (L-Leucovorin)==
FOLFIRI & Bevacizumab: FOLinic acid (L-Leucovorin), Fluorouracil, IRInotecan, Bevacizumab
===Regimen variant #1, 200/2800/150/5===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Iwamoto et al. 2015 (EAGLECRC)	2009-2012 	Phase 3 (C)	FOLFIRI & Bevacizumab; lower-dose bevacizumab (10 mg/kg)	Did not meet primary endpoint of PFS
Note: this study should not be confused by the one of the same name for head & neck cancer.
====Chemotherapy====
*Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given second, with irinotecan
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours, given third (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 150 mg/m2 IV over 90 minutes once on day 1, given second, with levoleucovorin
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV over 30 minutes once on day 1, given first
14-day cycles
===Regimen variant #2, 200/2800/180/5===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2018 (AXEPT)	2013-2015 	Phase 3 (C)	1a. mXELIRI1b. mXELIRI & Bevacizumab	Non-inferior OSMedian OS: 15.4 vs 16.8 mo(HR 1.18, 95% CI 0.98-1.41)
====Chemotherapy====
*Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given first, with irinotecan
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours, given third (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1, given first, with levoleucovorin
====Targeted therapy====
*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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000002557
#AXEPT: Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01996306
==FOLFIRI & Ramucirumab==
FOLFIRI & Ramucirumab: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan & Ramucirumab
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Tabernero et al. 2015 (RAISE)	2010-2013 	Phase 3 (E-RT-esc)	FOLFIRI 	Seems to have longer OS (primary endpoint)Median OS: 13.3 vs 11.7 mo(HR 0.84, 95% CI 0.73-0.98)
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, either given third or concurrently with irinotecan
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 1200 mg/m2/day IV continuous infusion over 48 hours, given third (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1, given second
====Targeted therapy====
*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. Epub 2015 Apr 12. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01183780
##Subgroup analysis: Obermannová R, Van Cutsem E, Yoshino T, Bodoky G, Prausová J, Garcia-Carbonero R, Ciuleanu T, Garcia Alfonso P, Portnoy D, Cohn A, Yamazaki K, Clingan P, Lonardi S, Kim TW, Yang L, Nasroulah F, Tabernero J. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016 Nov;27(11):2082-2090. Epub 2016 Aug 29. link to original article link to PMC article EuroPMC
==FOLFIRI & Ziv-aflibercept==
FOLFIRI & Ziv-aflibercept: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan, Ziv-aflibercept
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Van Cutsem et al. 2012 (VELOUR)	2007-2010 	Phase 3 (E-RT-esc)	FOLFIRI 	Longer OS (primary endpoint)Median OS: 13.5 vs 12.1 mo(HR 0.82, 95.34% CI 0.71-0.94)
Li et al. 2018 (AFLAME) 	2012-2014 	Phase 3 (E-esc) 	FOLFIRI 	Longer PFS (primary endpoint)Median PFS: 6.9 vs 5.6 mo(HR 0.63, 95% CI 0.49-0.81)
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given second
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours, given third (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1, given second
====Targeted therapy====
*Ziv-aflibercept (Zaltrap) 4 mg/kg IV over 60 minutes once on day 1, given first
====Supportive therapy====
*"Premedication with Atropine (Atropen) and anti-emetics was permitted. Granulocyte-colony stimulating factor (G-CSF) was used according to the American Society of Clinical Oncology guidelines (2006)."
14-day cycles
===References===
#VELOUR: Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012 Oct 1;30(28):3499-506. Epub 2012 Sep 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00561470
##Subgroup analysis: Tabernero J, Van Cutsem E, Lakomý R, Prausová J, Ruff P, van Hazel GA, Moiseyenko VM, Ferry DR, McKendrick JJ, Soussan-Lazard K, Chevalier S, Allegra CJ. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014 Jan;50(2):320-31. Epub 2013 Oct 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Subgroup analysis: Ruff P, Van Cutsem E, Lakomy R, Prausova J, van Hazel GA, Moiseyenko VM, Soussan-Lazard K, Dochy E, Magherini E, Macarulla T, Papamichael D. Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: An age-based analysis from the randomized placebo-controlled phase III VELOUR trial. J Geriatr Oncol. 2018 Jan;9(1):32-39. Epub 2017 Aug 12. link to original article EuroPMC
#AFLAME: Li J, Xu R, Qin S, Liu T, Pan H, Xu J, Bi F, Lim R, Zhang S, Ba Y, Bai Y, Fan N, Tsuji A, Yeh KH, Ma B, Wei V, Shi D, Magherini E, Shen L. Aflibercept plus FOLFIRI in Asian patients with pretreated metastatic colorectal cancer: a randomized Phase III study. Future Oncol. 2018 Aug;14(20):2031-2044. Epub 2018 Aug 17. Erratum in: Future Oncol. 2019 Feb;15(4):451. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01661270
==FOLFOX4==
FOLFOX4: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rothenberg et al. 2003 (BRCC-00036)	2000-11 to 2001-09 	Phase 3 (E-RT-esc) 	1. LV5FU2 	Longer TTP (secondary endpoint)Median TTP: 4.6 vs 2.7 mo(HR not reported)Higher ORR (primary endpoint)ORR: 9.9% vs 0%
Rothenberg et al. 2003 (BRCC-00036)	2000-11 to 2001-09 	Phase 3 (E-RT-esc) 	2. Oxaliplatin	Not directly compared
Rothenberg et al. 2008 (NO16967) 	2003-2005 	Phase 3 (E-switch-ic)	XELOX 	Non-inferior PFS (primary endpoint)
====Chemotherapy====
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, given first, with oxaliplatin on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given second (total dose per cycle: 2000 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first
14-day cycles
===References===
#BRCC-00036: Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, Hart LL, Gupta S, Garay CA, Burger BG, Le Bail N, Haller DG. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol. 2003 Jun 1;21(11):2059-69. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#NO16967: Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, Gollins S, Siu LL, Laguerre S, Cunningham D. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008 Oct;19(10):1720-6. Epub 2008 Jun 10. link to original article does not contain dosing details in manuscript; refers to de Gramont et al. 2000 protocol EuroPMC NCT00069108
==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
Masi et al. 2015 (BEBYP)	2008-2012 	Phase 3 (C)	mFOLFOX6-B	Shorter PFS (primary endpoint)Median PFS: 5 vs 6.8 mo(HR 1.43, 95% CI 1.05-1.92)
Note: Masi et al. 2015 did not provide dosing details; this is the most commonly used variant of mFOLFOX6.
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 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. link to original article does not contain dosing details EuroPMC NCT00720512
#KRYSTAL-10: NCT04793958
==mFOLFOX6-B==
mFOLFOX6-B: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Masi et al. 2015 (BEBYP)	2008-2012 	Phase 3 (E-esc)	mFOLFOX6 	Longer PFS (primary endpoint)Median PFS: 6.8 vs 5 mo(HR 0.70, 95% CI 0.52-0.95)
Note: Masi et al. 2015 did not provide dosing details; this is the most commonly used variant of mFOLFOX6.
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once on day 1
14-day cycles
===References===
#BEBYP: Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-30. Epub 2015 Jan 18. link to original article does not contain dosing details EuroPMC NCT00720512
==FULV==
FULV: 5-FU & LeucoVorin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rothenberg et al. 2003 (BRCC-00036)	2000-11 to 2001-09 	Phase 3 (C)	1. FOLFOX4 	Lower ORR
Rothenberg et al. 2003 (BRCC-00036)	2000-11 to 2001-09 	Phase 3 (C)	2. Oxaliplatin	Did not meet primary endpoint of ORR
====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 cycles
===References===
#BRCC-00036: Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, Hart LL, Gupta S, Garay CA, Burger BG, Le Bail N, Haller DG. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol. 2003 Jun 1;21(11):2059-69. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Irinotecan monotherapy==
===Example orders===
*Example orders for Irinotecan (Camptosar) in colon cancer
===Regimen variant #1, 100 mg/m2, 4 weeks out of 6===
Study 	Dates of enrollment	Evidence
Rothenberg et al. 1999	1994 	Phase 2 (RT)
Note: this was a mid-protocol dose amendment for excess toxicity.
====Chemotherapy====
*Irinotecan (Camptosar) 100 mg/m2 IV once per day on days 1, 8, 15, 22
42-day cycles
===Regimen variant #2, 125 mg/m2, 4 weeks out of 6===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rothenberg et al. 1996	Not reported 	Phase 2 (RT) 	 	
Pitot et al. 1997 	1993-1994 	Phase 2 (RT) 	 	
Fuchs et al. 2003 	1998-2001 	Phase 3 (E-switch-ic)	Irinotecan; every 3 weeks	Did not meet primary endpoint of OSOS12: 46% vs 41%
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/m2 IV over 90 minutes once per day on days 1, 8, 15, 22
42-day cycles
===Regimen variant #3, 250 mg/m2 q3wk===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Haller et al. 2008 (EFC4585)	2001-2004 	Phase 3 (C)	IROX 	Shorter OSMedian OS: 11.1 vs 13.4 mo(HR 1.28, 95% CI 1.06-1.54)
Note: 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/m2 IV over 90 minutes once on day 1
21-day cycles
===Regimen variant #4, 300 mg/m2 q3wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rougier et al. 1998 (V302)	1995-1997 	Phase 3 (E-RT-switch-ic)	CI 5-FU 	Seems to have longer OS (primary endpoint)Median OS: 10.8 vs 8.5 mo(HR not reported, p=0.035)
Fuchs et al. 2003 	1998-2001 	Phase 3 (E-switch-ic) 	Irinotecan; 4 weeks out of 6	Did not meet primary endpoint of OSOS12: 41% vs 46%
Kim et al. 2009 (N9841) 	1999-2003 	Phase 3 (C) 	FOLFOX4 	Non-inferior OSMedian OS: 14.3 vs 13.8 mo(HR 1.09, 95% CI 0.91-1.25)
Sobrero et al. 2008 (EPIC)	2003-2006 	Phase 3 (C) 	Irinotecan & Cetuximab 	Did not meet primary endpoint of OS
Note: In some trials, this starting dose was intended for patients who were at least 70 years old, had ECOG performance status 2 or more, or had prior pelvic radiation. Patients in N9841 had not previously received irinotecan or oxaliplatin.
====Chemotherapy====
*Irinotecan (Camptosar) 300 mg/m2 IV over 90 minutes once on day 1
21-day cycles
===Regimen variant #5, 350 mg/m2 q3wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rougier et al. 1997 	1992-1993 	Phase 2 (RT) 	 	
Rougier et al. 1998 (V302) 	1995-1997 	Phase 3 (E-RT-switch-ic)	CI 5-FU 	Seems to have longer OS (primary endpoint)Median OS: 10.8 vs 8.5 mo(HR not reported, p=0.035)
Lal et al. 2004 	1997-2002 	Phase 3 (C) 	Irinotecan x 8 	Did not meet primary endpoint of FFS
Fuchs et al. 2003 	1998-2001 	Phase 3 (E-switch-ic) 	Irinotecan; 4 weeks out of 6	Did not meet primary endpoint of OSOS12: 41% vs 46%
Kim et al. 2009 (N9841) 	1999-2003 	Phase 3 (C) 	FOLFOX4 	Non-inferior OSMedian OS: 14.3 vs 13.8 mo(HR 1.09, 95% CI 0.91-1.25)
Haller et al. 2008 (EFC4585)	2001-2004 	Phase 3 (C) 	IROX 	Shorter OSMedian OS: 11.1 vs 13.4 mo(HR 1.28, 95% CI 1.06-1.54)
Koopman et al. 2007 (CAIRO) 	2003-01 to 2004-12 	Phase 3 (C) 	See link 	See link
Sobrero et al. 2008 (EPIC) 	2003-2006 	Phase 3 (C) 	Irinotecan & Cetuximab 	Did not meet primary endpoint of OS
Note: This was the standard dosing described by Rougier et al. 1998. Patients in N9841 had not previously received irinotecan or oxaliplatin.
====Preceding treatment====
*CAIRO: First-line Capecitabine, with progression
====Chemotherapy====
*Irinotecan (Camptosar) 350 mg/m2 IV over 90 minutes once on day 1
====Supportive therapy====
*(varied depending on reference):
*"Standard regimens of 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: Third-line CapeOx
===References===
#Rothenberg ML, Eckardt JR, Kuhn JG, Burris HA 3rd, Nelson J, Hilsenbeck SG, Rodriguez GI, Thurman AM, Smith LS, Eckhardt SG, Weiss GR, Elfring GL, Rinaldi DA, Schaaf LJ, Von Hoff DD. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol. 1996 Apr;14(4):1128-35. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#Rougier P, Bugat R, Douillard JY, Culine S, Suc E, Brunet P, Becouarn Y, Ychou M, Marty M, Extra JM, Bonneterre J, Adenis A, Seitz JF, Ganem G, Namer M, Conroy T, Negrier S, Merrouche Y, Burki F, Mousseau M, Herait P, Mahjoubi M. Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol. 1997 Jan;15(1):251-60. link to original article EuroPMC
#Pitot HC, Wender DB, O'Connell MJ, Schroeder G, Goldberg RM, Rubin J, Mailliard JA, Knost JA, Ghosh C, Kirschling RJ, Levitt R, Windschitl HE. Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol. 1997 Aug;15(8):2910-9. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#Rothenberg ML, Cox JV, DeVore RF, Hainsworth JD, Pazdur R, Rivkin SE, Macdonald JS, Geyer CE Jr, Sandbach J, Wolf DL, Mohrland JS, Elfring GL, Miller LL, Von Hoff DD. A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer. 1999 Feb 15;85(4):786-95. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#V302: Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Awad L, Herait P, Jacques C. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1407-12. Erratum in: Lancet 1998 Nov 14;352(9140):1634. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Fuchs CS, Moore MR, Harker G, Villa L, Rinaldi D, Hecht JR. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003 Mar 1;21(5):807-14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Lal R, Dickson J, Cunningham D, Chau I, Norman AR, Ross PJ, Topham C, Middleton G, Hill M, Oates J. A randomized trial comparing defined-duration with continuous irinotecan until disease progression in fluoropyrimidine and thymidylate synthase inhibitor-resistant advanced colorectal cancer. J Clin Oncol. 2004 Aug 1;22(15):3023-31. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#CAIRO: Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ; Dutch Colorectal Cancer Group. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00312000
#EPIC: Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kröning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008 May 10;26(14):2311-9. Epub 2008 Apr 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00063141
#EFC4585: Haller DG, Rothenberg ML, Wong AO, Koralewski PM, Miller WH Jr, Bodoky G, Habboubi N, Garay C, Olivatto LO. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008 Oct 1;26(28):4544-50. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00012389
#N9841: Kim GP, Sargent DJ, Mahoney MR, Rowland KM Jr, Philip PA, Mitchell E, Mathews AP, Fitch TR, Goldberg RM, Alberts SR, Pitot HC; NCCTG. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol. 2009 Jun 10;27(17):2848-54. Epub 2009 Apr 20. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00005036
==IRI-S==
IRI-S: IRInotecan & S-1
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Muro et al. 2010 (FIRIS)	2006-2008 	Phase 3 (E-switch-ic)	FOLFIRI 	Non-inferior OS1 (secondary endpoint)
1Reported efficacy is based on the 2014 update.
====Chemotherapy====
*Irinotecan (Camptosar) 125 mg/m2 IV once per day on days 1 & 15
*Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
**Less than 1.25 m2: 40 mg PO twice per day on days 1 to 14
**Between 1.25 m2 and 1.5 m2: 50 mg PO twice per day on days 1 to 14
**1.5 m2 or more: 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00284258
##Update: Yasui H, Muro K, Shimada Y, Tsuji A, Sameshima S, Baba H, Satoh T, Denda T, Ina K, Nishina T, Yamaguchi K, Esaki T, Tokunaga S, Kuwano H, Boku N, Komatsu Y, Watanabe M, Hyodo I, Morita S, Sugihara K. A phase 3 non-inferiority study of 5-FU/l-leucovorin/irinotecan (FOLFIRI) versus irinotecan/S-1 (IRIS) as second-line chemotherapy for metastatic colorectal cancer: updated results of the FIRIS study. J Cancer Res Clin Oncol. 2015 Jan;141(1):153-60. Epub 2014 Aug 9. link to original article EuroPMC
==IROX==
IROX: IRinotecan & OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Haller et al. 2008 (EFC4585)	2001-2004 	Phase 3 (E-esc)	Irinotecan	Longer OS (primary endpoint)Median OS: 13.4 vs 11.1 mo(HR 0.78, 95% CI 0.65-0.94)
====Chemotherapy====
*Irinotecan (Camptosar) 200 mg/m2 IV over 30 to 90 minutes once on day 1, given second
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first
21-day cycles
===References===
#EFC4585: Haller DG, Rothenberg ML, Wong AO, Koralewski PM, Miller WH Jr, Bodoky G, Habboubi N, Garay C, Olivatto LO. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008 Oct 1;26(28):4544-50. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00012389
=Advanced or metastatic disease, third-line therapy=
==CapeOx==
CapeOX: Capecitabine, OXaliplatin
===Example orders===
*Example orders for CapeOx (XELOX) in colon cancer
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Koopman et al. 2007 (CAIRO)	2003-01 to 2004-12 	Phase 3 (C)	See link 	See link
====Preceding treatment====
*Second-line irinotecan, with progression
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
21-day cycles 
===References===
#CAIRO: Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ; Dutch Colorectal Cancer Group. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00312000
==FOLFIRI==
FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan
===Example orders===
*Example orders for FOLFIRI in colon cancer
===Regimen===
Study 	Dates of enrollment	Evidence
André et al. 1999	1996-12 to 1997-11 	Non-randomized
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given first, with irinotecan
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours, given second (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first, with leucovorin
14-day cycles
====Dose and schedule modifications====
*In André et al. 1999, the continuous 5-FU infusion dose could be increased from 1200 mg/m2/day to 1500 mg/m2/day if there were no toxicities higher than grade 1
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Regorafenib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Eng et al. 2019 (IMblaze370)	2016-07-27 to 2017-01-19	Phase 3 (C)	1. Atezolizumab2. Cobimetinib & Atezolizumab	Did not meet primary endpoint of OS
====Targeted therapy====
*Regorafenib (Stivarga) 160 mg PO once per day on days 1 to 21
28-day cycles
===References===
#IMblaze370: Eng C, Kim TW, Bendell J, Argilés G, Tebbutt NC, Di Bartolomeo M, Falcone A, Fakih M, Kozloff M, Segal NH, Sobrero A, Yan Y, Chang I, Uyei A, Roberts L, Ciardiello F; IMblaze370 Investigators. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2019 Jun;20(6):849-861. Epub 2019 Apr 16. Erratum in: Lancet Oncol. 2019 Jun;20(6):e293. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02788279
=Advanced or metastatic disease, subsequent lines of therapy=
Note: these are trials that are for lines other than first-line; trials that specify an inclusion criteria restricted to second-line or third-line therapy are to be found in the sections above.
==Capecitabine monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Awaiting publication (X-PECT)	2010 to not reported	Phase 3 (C)	Capecitabine & Perifosine	Not reported
Note: this trial has not yet been published; dosing details are from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycles
===References===
#X-PECT: NCT01097018
==Durvalumab & Tremelimumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Chen et al. 2020 (NCIC-CTG CO.26)	2016-2017 	Randomized Phase 2 (E-esc)	Best supportive care	Might have longer OS (primary endpoint)Median OS: 6.6 vs 4.1 mo(HR 0.72, 90% CI 0.54-0.97)
====Eligibility criteria====
*Advanced CRC progressed on all available standard systemic therapies, ECOG PS 0-1. PD-L1, TMB, MSI status were NOT used as inclusion criteria
====Immunotherapy====
*Durvalumab (Imfinzi) 1500 mg IV once on day 1
*Tremelimumab (Imjudo) as follows:
**Cycles 1 to 4: 75 mg IV once on day 1
28-day cycles
===References===
#NCIC-CTG CO.26: Chen EX, Jonker DJ, Loree JM, Kennecke HF, Berry SR, Couture F, Ahmad CE, Goffin JR, Kavan P, Harb M, Colwell B, Samimi S, Samson B, Abbas T, Aucoin N, Aubin F, Koski S, Wei AC, Magoski NM, Tu D, O'Callaghan CJ. Effect of Combined Immune Checkpoint Inhibition vs Best Supportive Care Alone in Patients With Advanced Colorectal Cancer: The Canadian Cancer Trials Group CO.26 Study. JAMA Oncol. 2020;6(6):831–838. link to article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02870920
==Fluorouracil monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hendlisz et al. 2010 (Sir-Spheres1)	2004-2007 	Phase 3 (C)	5-FU & Radioembolization	Shorter TTLP (primary endpoint)Median TTLP: 2.1 vs 5.5 mo(HR 2.63, 95% CI 1.39-5.00)Shorter TTP (secondary endpoint)Median TTP: 2.1 vs 4.5 mo(HR 1.96, 95% CI 1.06-3.57)
====Chemotherapy====
*Fluorouracil (5-FU) 300 mg/m2/day IV continuous infusion over 14 days, started on day 1 (total dose per cycle: 4200 mg/m2)
21-day cycles
===References===
#Sir-Spheres1: Hendlisz A, Van den Eynde M, Peeters M, Maleux G, Lambert B, Vannoote J, De Keukeleire K, Verslype C, Defreyne L, Van Cutsem E, Delatte P, Delaunoit T, Personeni N, Paesmans M, Van Laethem JL, Flamen P. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol. 2010 Aug 10;28(23):3687-94. Epub 2010 Jun 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00199173
==FOLFOX4==
FOLFOX4: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Giantonio et al. 2007 (ECOG E3200)	2001-2003 	Phase 3 (C) 	1. FOLFOX4 & Bevacizumab	Shorter OS (primary endpoint)Median OS: 10.8 vs 12.9 mo(HR 1.33, 95% CI 1.12-1.59)
Giantonio et al. 2007 (ECOG E3200)	2001-2003 	Phase 3 (C) 	2. Bevacizumab 	Not reported
Kim et al. 2009 (N9841) 	1999-2003 	Phase 3 (E-esc)	Irinotecan 	Non-inferior OS (primary endpoint)Median OS: 13.8 vs 14.3 mo(HR 0.92, 95% CI 0.80-1.10)
Van Cutsem et al. 2011 (CONFIRM 2)	2003-01 to 2004-10 	Phase 3 (C) 	FOLFOX4 & Vatalanib 	Did not meet primary endpoint of OS
Note: patients in N9841 had not previously received irinotecan or oxaliplatin; patients in CONFIRM 2 had not previously received oxaliplatin.
====Chemotherapy====
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, given first, with oxaliplatin on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given second (total dose per cycle: 2000 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first
14-day cycles
===References===
#ECOG E3200: Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd; ECOG. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007 Apr 20;25(12):1539-44. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00025337
#N9841: Kim GP, Sargent DJ, Mahoney MR, Rowland KM Jr, Philip PA, Mitchell E, Mathews AP, Fitch TR, Goldberg RM, Alberts SR, Pitot HC; NCCTG. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol. 2009 Jun 10;27(17):2848-54. Epub 2009 Apr 20. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00005036
#CONFIRM 2: Van Cutsem E, Bajetta E, Valle J, Köhne CH, Hecht JR, Moore M, Germond C, Berg W, Chen BL, Jalava T, Lebwohl D, Meinhardt G, Laurent D, Lin E. Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):2004-10. Epub 2011 Apr 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00056446
==FOLFOX4 (L-Leucovorin)==
FOLFOX4: FOLinic acid (L-Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Van Cutsem et al. 2011 (CONFIRM 2)	2003-01 to 2004-10 	Phase 3 (C)	FOLFOX4 & Vatalanib	Did not meet primary endpoint of OS
Note: these patients had not previously received oxaliplatin.
====Chemotherapy====
*Levoleucovorin (Fusilev) 100 mg/m2 IV over 2 hours once per day on days 1 & 2, given first, with oxaliplatin on day 1
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given second (total dose per cycle: 2000 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first
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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00056446
==FOLFOX4 & Bevacizumab==
FOLFOX4 & Bevacizumab: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Giantonio et al. 2007 (ECOG E3200)	2001-2003 	Phase 3 (E-RT-esc)	1. FOLFOX4 	Longer OS (primary endpoint)Median OS: 12.9 vs 10.8 mo(HR 0.75, 95% CI 0.63-0.89)
Giantonio et al. 2007 (ECOG E3200)	2001-2003 	Phase 3 (E-RT-esc)	2. Bevacizumab	Not reported
====Chemotherapy====
*Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once per day on days 1 & 2
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 10 mg/kg IV over 30 to 90 minutes once on day 1
14-day cycles
===References===
#ECOG E3200: Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd; ECOG. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007 Apr 20;25(12):1539-44. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00025337
==Fruquintinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Li et al. 2018 (FRESCO) 	2014-2016 	Phase 3 (E-RT-esc)	Placebo 	Longer OS (primary endpoint)Median OS: 9.3 vs 6.6 mo(HR 0.65, 95% CI 0.51-0.83)
Dasari et al. 2023 (FRESCO-2)	2020-08-12 to 2021-12-02	Phase 3 (E-RT-esc)	Placebo 	Longer OS (primary endpoint)Median OS: 7.4 vs 4.8 mo(HR 0.66, 95% CI 0.55-0.80)
====Prior treatment criteria====
*FRESCO: At least 2 lines of chemotherapy but no prior VEGFR inhibitor therapy, with progression
*FRESCO-2: All current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil and/or regorafenib
====Targeted therapy====
*Fruquintinib (Elunate) 5 mg PO once per day on days 1 to 21
28-day cycles
===References===
#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. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02314819
#FRESCO-2: Dasari A, Lonardi S, Garcia-Carbonero R, Elez E, Yoshino T, Sobrero A, Yao J, García-Alfonso P, Kocsis J, Cubillo Gracian A, Sartore-Bianchi A, Satoh T, Randrian V, Tomasek J, Chong G, Paulson AS, Masuishi T, Jones J, Csőszi T, Cremolini C, Ghiringhelli F, Shergill A, Hochster HS, Krauss J, Bassam A, Ducreux M, Elme A, Faugeras L, Kasper S, Van Cutsem E, Arnold D, Nanda S, Yang Z, Schelman WR, Kania M, Tabernero J, Eng C; FRESCO-2 Study Investigators. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023 Jul 1;402(10395):41-53. Epub 2023 Jun 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04322539
==FULV & Bevacizumab==
FULV & Bevacizumab: 5-FU, LeucoVorin, Bevacizumab
===Regimen variant #1, Roswell Park backbone===
Study 	Dates of enrollment	Evidence
Chen et al. 2006 (TRC-301)	2003 	Phase 2 (RT)
Note: this is based on the Roswell Park regimen backbone.
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
*Leucovorin (Folinic acid) 500 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once per day on days 1, 15, 29, 43
56-day cycles
===Regimen variant #2, de Gramont backbone===
Study 	Dates of enrollment	Evidence
Chen et al. 2006 (TRC-301)	2003 	Phase 2 (RT)
Note: this is based on the de Gramont regimen backbone.
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, (total dose per cycle: 2000 mg/m2)
*Leucovorin (Folinic acid) 400 mg/m2 IV once per day on days 1 & 2
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once on day 1
14-day cycles
===References===
#TRC-301: Chen HX, Mooney M, Boron M, Vena D, Mosby K, Grochow L, Jaffe C, Rubinstein L, Zwiebel J, Kaplan RS. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. J Clin Oncol. 2006 Jul 20;24(21):3354-60. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00066846
==Irinotecan monotherapy==
===Example orders===
*Example orders for Irinotecan (Camptosar) in colon cancer
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Cunningham et al. 1998 (V301)	1995 to not reported	Phase 3 (E-RT-esc)	Supportive care	Longer OS (primary endpoint)Median OS: 9.2 vs 6.5 mo(aHR 0.58, 95% CI not reported, p=0.001)
====Chemotherapy====
*Irinotecan (Camptosar) 350 mg/m2 IV over 90 minutes once on day 1
====Supportive therapy====
*(varied depending on reference):
*"Standard regimens of 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Regorafenib monotherapy==
===Regimen variant #1, Standard Dosing===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Grothey et al. 2012 (CORRECT) 	2010-04-30 to 2011-03-22	Phase 3 (E-RT-esc)	Placebo 	Longer OS (primary endpoint)Median OS: 6.4 vs 5 mo(HR 0.77, 95% CI 0.64-0.94)
Li et al. 2015 (CONCUR) 	2012-04-29 to 2013-02-06	Phase 3 (E-esc) 	Placebo 	Longer OS (primary endpoint)Median OS: 8.8 vs 6.3 mo(HR 0.55, 95% CI 0.40-0.77)
Kawazoe et al. 2024 (LEAP-017)	2021-04-08 to 2021-12-21	Phase 3 (C) 	Lenvatinib & Pembrolizumab	Might have shorter OS (primary endpoint)Median OS: 9.3 vs 9.8 mo(HR 1.20, 95% CI 0.98-1.47)
====Targeted therapy====
*Regorafenib (Stivarga) 160 mg PO once per day on days 1 to 21, taken with a low-fat (less than 30% fat) breakfast
28-day cycles
===Regimen variant #2, Dose-escalation===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Bekaii-Saab et al. 2019 (ReDOS)	2015-2017 	Randomized Phase 2 (E-esc)	Regorafenib; standard dosing	Did not meet secondary endpoint of OS (secondary endpoint)Median OS: 9.8 vs 6 mo(HR 0.72, 95% CI 0.47-1.10)	Higher rate of patients proceeding to cycle 3 (primary endpoint)
Kawazoe et al. 2024 (LEAP-017) 	2021-04-08 to 2021-12-21	Phase 3 (C) 	Lenvatinib & Pembrolizumab 	Might have shorter OS (primary endpoint)Median OS: 9.3 vs 9.8 mo(HR 1.20, 95% CI 0.98-1.47) 	
====Targeted therapy====
*Regorafenib (Stivarga) as follows:
**Cycle 1: 80 mg PO once per day on days 1 to 7, then 120 mg PO once per day on days 8 to 15, then 160 mg PO once per day on days 16 to 21
**Cycle 2 onwards: 160 mg PO once per day on days 1 to 21
====Supportive therapy====
*ReDOS: Patients received 0.05% Clobetasol cream twice per day 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===
#CORRECT: Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. Epub 2012 Nov 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01103323
##Dataset: 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. link to original article EuroPMC NCT01584830
#ReDOS: Bekaii-Saab TS, Ou FS, Ahn DH, Boland PM, Ciombor KK, Heying EN, Dockter TJ, Jacobs NL, Pasche BC, Cleary JM, Meyers JP, Desnoyers RJ, McCune JS, Pedersen K, Barzi A, Chiorean EG, Sloan J, Lacouture ME, Lenz HJ, Grothey A. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019 Aug;20(8):1070-1082. Epub 2019 Jun 28. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT02368886
#LEAP-017: Kawazoe A, Xu RH, García-Alfonso P, Passhak M, Teng HW, Shergill A, Gumus M, Qvortrup C, Stintzing S, Towns K, Kim TW, Shiu KK, Cundom J, Ananda S, Lebedinets A, Fu R, Jain R, Adelberg D, Heinemann V, Yoshino T, Elez E; LEAP-017 Investigators. Lenvatinib Plus Pembrolizumab Versus Standard of Care for Previously Treated Metastatic Colorectal Cancer: Final Analysis of the Randomized, Open-Label, Phase III LEAP-017 Study. J Clin Oncol. 2024 Aug 20;42(24):2918-2927. Epub 2024 Jun 4. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04776148
#STELLAR-03: NCT05425940
==Trifluridine and tipiracil monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Yoshino et al. 2012 	2009-08-25 to 2010-04-12	Randomized Phase 2 (E-esc)	Placebo 	Longer OS (primary endpoint)Median OS: 9 vs 6.6 mo(HR 0.56, 95% CI 0.39-0.81)
Mayer et al. 2015 (RECOURSE) 	2012-06-17 to 2013-10-08	Phase 3 (E-RT-esc) 	Placebo 	Longer OS (primary endpoint)Median OS: 7.1 vs 5.3 mo(HR 0.68, 95% CI 0.58-0.81)
Xu et al. 2017 (TERRA) 	2013-2015 	Phase 3 (E-esc) 	Placebo 	Seems to have longer OS (primary endpoint)Median OS: 7.8 vs 7.1 mo(HR 0.79, 95% CI 0.62-0.99)
Pfeiffer et al. 2020 	2017-2018 	Randomized Phase 2 (C) 	Trifluridine and tipiracil & Bevacizumab	Shorter PFSMedian PFS: 2.6 vs 4.6 mo(HR 2.22, 95% CI 1.39-3.45)
Prager et al. 2023 (SUNLIGHT) 	2020-11-25 to 2022-02-18	Phase 3 (C) 	Trifluridine and tipiracil & Bevacizumab	Shorter OSMedian OS: 7.5 vs 10.8 mo(HR 1.64, 95% CI 1.30-2.04)
Kawazoe et al. 2024 (LEAP-017)	2021-04-08 to 2021-12-21	Phase 3 (C) 	Lenvatinib & Pembrolizumab 	Might have shorter OS (primary endpoint)Median OS: 9.3 vs 9.8 mo(HR 1.20, 95% CI 0.98-1.47)
====Chemotherapy====
*Trifluridine and tipiracil (Lonsurf) 35 mg/m2 PO twice per day on days 1 to 5, 8 to 12, taken within 1 hour after the morning and evening meals
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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC JapicCTI-090880
#RECOURSE: Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14;372(20):1909-19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01607957
##Subgroup analysis: Van Cutsem E, Mayer RJ, Laurent S, Winkler R, Grávalos C, Benavides M, Longo-Munoz F, Portales F, Ciardiello F, Siena S, Yamaguchi K, Muro K, Denda T, Tsuji Y, Makris L, Loehrer P, Lenz HJ, Ohtsu A; RECOURSE Study Group. The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer. Eur J Cancer. 2018 Feb;90:63-72. Epub 2017 Dec 21. link to original article link to PMC article EuroPMC
#TERRA: Xu J, Kim TW, Shen L, Sriuranpong V, Pan H, Xu R, Guo W, Han SW, Liu T, Park YS, Shi C, Bai Y, Bi F, Ahn JB, Qin S, Li Q, Wu C, Ma D, Lin D, Li J. Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: The TERRA study. J Clin Oncol. 2018 Feb 1;36(4):350-358. Epub 2017 Dec 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01955837
# Pfeiffer P, Yilmaz M, Möller S, Zitnjak D, Krogh M, Petersen LN, Poulsen LO, Winther SB, Thomsen KG, Qvortrup C. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol. 2020 Mar;21(3):412-420. Epub 2020 Jan 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC EudraCT 2016-005241-23
#SUNLIGHT: Prager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, Cruz FM, Wyrwicz L, Stroyakovskiy D, Pápai Z, Poureau PG, Liposits G, Cremolini C, Bondarenko I, Modest DP, Benhadji KA, Amellal N, Leger C, Vidot L, Tabernero J; SUNLIGHT Investigators. Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N Engl J Med. 2023 May 4;388(18):1657-1667. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04737187
##HRQoL analysis: Taieb J, Fakih M, Tabernero J, Ciardiello F, Van Cutsem E, Soler G, Calleja E, Barboux V, Roby L, Amellal N, Prager GW. Impact of Treatment With Trifluridine/Tipiracil in Combination With Bevacizumab on Health-Related Quality of Life and Performance Status in Refractory Metastatic Colorectal Cancer: An Analysis of the Phase III SUNLIGHT Trial. Clin Colorectal Cancer. 2024 Dec. Epub ahead of print. link to original article link to EuroPMC
#LEAP-017: Kawazoe A, Xu RH, García-Alfonso P, Passhak M, Teng HW, Shergill A, Gumus M, Qvortrup C, Stintzing S, Towns K, Kim TW, Shiu KK, Cundom J, Ananda S, Lebedinets A, Fu R, Jain R, Adelberg D, Heinemann V, Yoshino T, Elez E; LEAP-017 Investigators. Lenvatinib Plus Pembrolizumab Versus Standard of Care for Previously Treated Metastatic Colorectal Cancer: Final Analysis of the Randomized, Open-Label, Phase III LEAP-017 Study. J Clin Oncol. 2024 Aug 20;42(24):2918-2927. Epub 2024 Jun 4. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04776148
#RAMTAS: NCT03520946
==Trifluridine and tipiracil & Bevacizumab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Pfeiffer et al. 2020 	2017-2018 	Randomized Phase 2 (E-esc)	Trifluridine and tipiracil	Longer PFS (primary endpoint)Median PFS: 4.6 vs 2.6 mo(HR 0.45, 95% CI 0.29-0.72)
Prager et al. 2023 (SUNLIGHT)	2020-11-25 to 2022-02-18	Phase 3 (E-esc) 	Trifluridine and tipiracil	Longer OS (primary endpoint)Median OS: 10.8 vs 7.5 mo(HR 0.61, 95% CI 0.49-0.77)
====Chemotherapy====
*Trifluridine and tipiracil (Lonsurf) 35 mg/m2 PO twice per day on days 1 to 5, 8 to 12, taken within 1 hour after the morning and evening meals 
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV over 30 minutes once per day on days 1 & 15, given first
28-day cycles
===References===
# Pfeiffer P, Yilmaz M, Möller S, Zitnjak D, Krogh M, Petersen LN, Poulsen LO, Winther SB, Thomsen KG, Qvortrup C. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol. 2020 Mar;21(3):412-420. Epub 2020 Jan 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC EudraCT 2016-005241-23
#SUNLIGHT: Prager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, Cruz FM, Wyrwicz L, Stroyakovskiy D, Pápai Z, Poureau PG, Liposits G, Cremolini C, Bondarenko I, Modest DP, Benhadji KA, Amellal N, Leger C, Vidot L, Tabernero J; SUNLIGHT Investigators. Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N Engl J Med. 2023 May 4;388(18):1657-1667. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04737187
##HRQoL analysis: Taieb J, Fakih M, Tabernero J, Ciardiello F, Van Cutsem E, Soler G, Calleja E, Barboux V, Roby L, Amellal N, Prager GW. Impact of Treatment With Trifluridine/Tipiracil in Combination With Bevacizumab on Health-Related Quality of Life and Performance Status in Refractory Metastatic Colorectal Cancer: An Analysis of the Phase III SUNLIGHT Trial. Clin Colorectal Cancer. 2024 Dec. Epub ahead of print. link to original article link to EuroPMC
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