Colon cancer

Page editor		Section editor
	Ryan Nguyen, DO University of Illinois at Chicago Chicago, IL LinkedIn		Neeta K. Venepalli, MD, MBA University of Illinois at Chicago Chicago, IL

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

• See the rectal cancer page for regimens specific to rectal cancer.
• See the BRAF-mutated page for biomarker-specific regimens.
• See the HER2+ page for biomarker-specific regimens.
• See the KRAS wild-type page for biomarker-specific regimens.

10 regimens on this page 20 variants on this page

Guidelines

ASCO

• 2019: Lieu et al. Duration of oxaliplatin-containing adjuvant therapy for stage III colon cancer: ASCO Clinical Practice Guideline

ESMO

• 2019: Stjepanovic et al. Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
• 2016: Van Cutsem et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. PubMed

Older

• 2013: Labianca et al. Early Colon Cancer: ESMO Clinical Practice Guidelines PubMed
• 2013: Balmaña et al. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. PubMed

Japanese Society for Cancer of the Colon and Rectum

• 2016: Watanabe et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer PubMed

NCCN

• NCCN Guidelines - Colon Cancer

SIOG

• 2014: Papamichael et al. Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013

Adjuvant therapy

Capecitabine monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Twelves et al. 2005 (X-ACT)	Phase III (E-RT-switch-ic)	5-FU & Leucovorin	Seems to have superior OS (*)
Kerr et al. 2016 (QUASAR 2)	Phase III (C)	Capecitabine & Bevacizumab	Did not meet primary endpoint of DFS36
Hamaguchi et al. 2017 (JCOG0910)	Phase III (C)	S-1	Inconclusive whether non-inferior DFS
Tomita et al. 2019 (JFMC37-0801)	Phase III (C)	Capecitabine x 12 mo	Might have inferior DFS

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

Preceding treatment

• Surgery

Chemotherapy

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

21-day cycle for 8 cycles

References

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

CapeOx

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

Example orders

• Example orders for CapeOx (XELOX) in colon cancer

Variant #1, 3 months

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

Preceding treatment

• 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

Variant #2, 6 months

Study	Evidence	Comparator	Comparative Efficacy
Schmoll et al. 2007 (XELOXA)	Phase III (E-switch-ic)	5-FU & Leucovorin	Seems to have superior OS (*)
Pectasides et al. 2015	Phase III (C)	mFOLFOX6	Did not meet primary endpoint of DFS
Snoeren et al. 2017 (HEPATICA)	Phase III (C)	CapeOx & Bevacizumab	Did not meet primary endpoint of DFS
Iveson et al. 2018 (SCOT)	Phase III (C)	CapeOx x 3 mo	Seems to have non-inferior DFS

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

Preceding treatment

• Surgery

Chemotherapy

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

21-day cycle for 8 cycles

References

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

Fluorouracil & Folinic acid

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

Example orders

• Example orders for 5-FU & low-dose Leucovorin (Mayo Clinic regimen/LDLV) in colon cancer
• Example orders for 5-FU & high-dose Leucovorin (Roswell Park regimen/HDLV) in colon cancer

Variant #1, 500/200, 6 out of 8 weeks

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

Preceding treatment

• Surgery

Chemotherapy

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

8-week cycle for 4 cycles

Variant #2, 500/500, 6 out of 8 weeks

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

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

Preceding treatment

• Surgery

Chemotherapy

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

8-week cycle for 3 to 6 cycles

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

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

Preceding treatment

• Surgery

Chemotherapy

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

8-week cycle for 4 cycles

Variant #4, 1850/1000

Study	Evidence	Comparator	Comparative Efficacy
Marsoni et al. 1995 (IMPACTCRC)	Phase III (E-esc)	Observation	Seems to have superior OS

Note: this was the lower bound of 5-FU dose for the three included RCTs. This study should not be confused with the studies of the same name in breast cancer and prostate cancer.

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU) 370 mg/m² IV once per day on days 1 to 5
• Folinic acid (Leucovorin) 200 mg/m² IV once per day on days 1 to 5

28-day cycle for 6 cycles

Variant #5, 1850/2500 ("NCI schedule")

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

Preceding treatment

• Surgery

Chemotherapy

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

28-day cycle for 6 cycles

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

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

Reported efficacy for MOSAIC is based on the 2009 update.

Preceding treatment

• Surgery

Chemotherapy

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

14-day cycle for 12 cycles

Variant #7, 2125/100 ("Mayo Clinic regimen")

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

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

Preceding treatment

• Surgery

Chemotherapy

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

28-day cycle for 6 cycles

Variant #8, 2125/100, with cycle elongation ("Mayo Clinic regimen")

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

Preceding treatment

• Surgery

Chemotherapy

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

Variant #9, 2800/400 (LV5FUs)

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

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)
• Folinic acid (Leucovorin) 400 mg/m² IV over 2 hours once on day 1, given first

14-day cycle for 12 cycles

References

1. NSABP C-03: Wolmark N, Rockette H, Fisher B, Wickerham DL, Redmond C, Fisher ER, Jones J, Mamounas EP, Ore L, Petrelli NJ, Spurr CL, Dimitrov N, Romond EH, Sutherland CM, Kardinal CG, DeFusco PA, Jochimsen P. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol. 1993 Oct;11(10):1879-87. link to original article contains verified protocol PubMed
   1. Pooled update: Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. link to original article link to PMC article PubMed
2. IMPACT: Marsoni S, Labianca R, Pancera G, Torri V, Zaniboni A, Erlichman C, Pater J, Shepherd L, Zee B, Seitz JF, Milan C, Pignon JP; International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet. 1995 Apr 15;345(8955):939-44. link to original article PubMed
3. O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, Wieand HS. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997 Jan;15(1):246-50. link to original article contains verified protocol PubMed
   1. Pooled update: Erlichman C, O'Connell M, Kahn M, Marsoni S, Torri V, Tardio B, Zaniboni A, Pancera G, Martignoni G, Labianca R, Barni A, Seitz JF, Milan C, Bedenne L, Giovannini M, Letreut YP, Skillings J, Shepard L, Zee B, Petrioli R, Francini G; International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol. 1999 May;17(5):1356-63. link to original article PubMed
4. NSABP C-05: Wolmark N, Bryant J, Smith R, Grem J, Allegra C, Hyams D, Atkins J, Dimitrov N, Oishi R, Prager D, Fehrenbacher L, Romond E, Colangelo L, Fisher B. Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst. 1998 Dec 2;90(23):1810-6. link to original article PubMed
   1. Pooled update: Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. link to original article link to PMC article PubMed
5. NSABP C-04: Wolmark N, Rockette H, Mamounas E, Jones J, Wieand S, Wickerham DL, Bear HD, Atkins JN, Dimitrov NV, Glass AG, Fisher ER, Fisher B. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol. 1999 Nov;17(11):3553-9. link to original article contains verified protocol PubMed
   1. Pooled update: Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. link to original article link to PMC article PubMed
6. Fountzilas G, Zisiadis A, Dafni U, Konstantaras C, Hatzitheoharis G, Papavramidis S, Bousoulegas A, Basdanis G, Giannoulis E, Dokmetzioglou J, Katsohis C, Nenopoulou E, Karvounis N, Briassoulis E, Aravantinos G, Kosmidis P, Skarlos D, Pavlidis N. Fluorouracil and leucovorin with or without interferon alfa-2a as adjuvant treatment, in patients with high-risk colon cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Oncology. 2000 Apr;58(3):227-36. link to original article contains protocol PubMed
7. Study 157-002: Punt CJ, Nagy A, Douillard JY, Figer A, Skovsgaard T, Monson J, Barone C, Fountzilas G, Riess H, Moylan E, Jones D, Dethling J, Colman J, Coward L, MacGregor S. Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study. Lancet. 2002 Aug 31;360(9334):671-7. link to original article contains verified protocol PubMed
8. GERCOR C96.1: Andre T, Colin P, Louvet C, Gamelin E, Bouche O, Achille E, Colbert N, Boaziz C, Piedbois P, Tubiana-Mathieu N, Boutan-Laroze A, Flesch M, Buyse M, de Gramont A. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol. 2003 Aug 1;21(15):2896-903. link to original article PubMed
   1. Update: André T, Quinaux E, Louvet C, Colin P, Gamelin E, Bouche O, Achille E, Piedbois P, Tubiana-Mathieu N, Boutan-Laroze A, Flesch M, Lledo G, Raoul Y, Debrix I, Buyse M, de Gramont A. Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1. J Clin Oncol. 2007 Aug 20;25(24):3732-8. link to original article PubMed
9. MOSAIC: André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004 Jun 3;350(23):2343-51. link to original article contains verified protocol PubMed
   1. Update: André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009 Jul 1;27(19):3109-16. Epub 2009 May 18. link to original article PubMed
   2. Update: André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, Scriva A, Hickish T, Tabernero J, Van Laethem JL, Banzi M, Maartense E, Shmueli E, Carlsson GU, Scheithauer W, Papamichael D, Möehler M, Landolfi S, Demetter P, Colote S, Tournigand C, Louvet C, Duval A, Fléjou JF, de Gramont A. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol. 2015 Dec 10;33(35):4176-87. Epub 2015 Nov 2. link to original article PubMed
10. X-ACT: Twelves C, Wong A, Nowacki MP, Abt M, Burris HA 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005 Jun 30;352(26):2696-704. link to original article contains verified protocol PubMed
    1. Update: Twelves C, Scheithauer W, McKendrick J, Seitz JF, Van Hazel G, Wong A, Díaz-Rubio E, Gilberg F, Cassidy J. Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy. Ann Oncol. 2012 May;23(5):1190-7. Epub 2011 Sep 6. link to original article PubMed
11. Intergroup 0089: Haller DG, Catalano PJ, Macdonald JS, O'Rourke MA, Frontiera MS, Jackson DV, Mayer RJ. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 2005 Dec 1;23(34):8671-8. link to original article contains verified protocol PubMed
12. Lembersky BC, Wieand HS, Petrelli NJ, O'Connell MJ, Colangelo LH, Smith RE, Seay TE, Giguere JK, Marshall ME, Jacobs AD, Colman LK, Soran A, Yothers G, Wolmark N. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 2006 May 1;24(13):2059-64. link to original article contains verified protocol PubMed
13. XELOXA: Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A, Maroun J, Price T, Lim R, Van Cutsem E, Park YS, McKendrick J, Topham C, Soler-Gonzalez G, de Braud F, Hill M, Sirzén F, Haller DG. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007 Jan 1;25(1):102-9. link to original article contains verified protocol PubMed
    1. Update: Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011 Apr 10;29(11):1465-71. Epub 2011 Mar 7. link to original article contains verified protocol PubMed
    2. Update: Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: Final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015 Nov 10;33(32):3733-40. Epub 2015 Aug 31. link to original article PubMed
14. NSABP C-07: Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, Zapas JL, Goodwin JW, Fehrenbacher L, Ramanathan RK, Conley BA, Flynn PJ, Soori G, Colman LK, Levine EA, Lanier KS, Wolmark N. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007 Jun 1;25(16):2198-204. Epub 2007 Apr 30. link to original article contains protocol PubMed
    1. Update: Yothers G, O'Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, Wolmark N. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011 Oct 1;29(28):3768-74. Epub 2011 Aug 22. link to original article link to PMC article PubMed
15. CALGB 89803: Saltz LB, Niedzwiecki D, Hollis D, Goldberg RM, Hantel A, Thomas JP, Fields AL, Mayer RJ. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol. 2007 Aug 10;25(23):3456-61. link to original article contains verified protocol PubMed
16. PETACC-1: Popov I, Carrato A, Sobrero A, Vincent M, Kerr D, Labianca R, Raffaele Bianco A, El-Serafi M, Bedenne L, Paillot B, Mini E, Sanches E, Welch J, Collette L, Praet M, Wils J. Raltitrexed (Tomudex) versus standard leucovorin-modulated bolus 5-fluorouracil: Results from the randomised phase III Pan-European Trial in Adjuvant Colon Cancer 01 (PETACC-1). Eur J Cancer. 2008 Oct;44(15):2204-11. Epub 2008 Aug 15. link to original article PubMed
17. FFCD 9802: Ychou M, Raoul JL, Douillard JY, Gourgou-Bourgade S, Bugat R, Mineur L, Viret F, Becouarn Y, Bouché O, Gamelin E, Ducreux M, Conroy T, Seitz JF, Bedenne L, Kramar A. A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). Ann Oncol. 2009 Apr;20(4):674-80. Epub 2009 Jan 29. link to original article contains protocol PubMed
18. Study 157-001: Fields AL, Keller A, Schwartzberg L, Bernard S, Kardinal C, Cohen A, Schulz J, Eisenberg P, Forster J, Wissel P. Adjuvant therapy with the monoclonal antibody edrecolomab plus fluorouracil-based therapy does not improve overall survival of patients with stage III colon cancer. J Clin Oncol. 2009 Apr 20;27(12):1941-7. Epub 2009 Mar 9. link to original article contains verified protocol PubMed
19. PETACC-3: Van Cutsem E, Labianca R, Bodoky G, Barone C, Aranda E, Nordlinger B, Topham C, Tabernero J, André T, Sobrero AF, Mini E, Greil R, Di Costanzo F, Collette L, Cisar L, Zhang X, Khayat D, Bokemeyer C, Roth AD, Cunningham D. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol. 2009 Jul 1;27(19):3117-25. Epub 2009 May 18. link to original article contains protocol PubMed
20. Ychou M, Hohenberger W, Thezenas S, Navarro M, Maurel J, Bokemeyer C, Shacham-Shmueli E, Rivera F, Kwok-Keung Choi C, Santoro A. A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer. Ann Oncol. 2009 Dec;20(12):1964-70. Epub 2009 Jun 30. link to original article contains protocol PubMed
21. Papadimitriou CA, Papakostas P, Karina M, Malettou L, Dimopoulos MA, Pentheroudakis G, Samantas E, Bamias A, Miliaras D, Basdanis G, Xiros N, Klouvas G, Bafaloukos D, Kafiri G, Papaspirou I, Pectasides D, Karanikiotis C, Economopoulos T, Efstratiou I, Korantzis I, Pisanidis N, Makatsoris T, Matsiakou F, Aravantinos G, Kalofonos HP, Fountzilas G. A randomized phase III trial of adjuvant chemotherapy with irinotecan, leucovorin and fluorouracil versus leucovorin and fluorouracil for stage II and III colon cancer: a Hellenic Cooperative Oncology Group study. BMC Med. 2011 Jan 31;9:10. link to original article link to PMC article contains protocol PubMed
22. PETACC-2: Köhne CH, Bedenne L, Carrato A, Bouché O, Popov I, Gaspà L, Valladares M, Rougier P, Gog C, Reichardt P, Wils J, Pignatti F, Biertz F. A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: the Pan-European Trial in Adjuvant Colon Cancer 2 study. Eur J Cancer. 2013 May;49(8):1868-75. Epub 2013 Apr 6. link to original article PubMed

Fluorouracil & Levoleucovorin

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Variant #1, 370/25, weekly

Study	Evidence	Comparator	Comparative Efficacy
Gray et al. 2000 (QUASAR)	Phase III (C)	1. 5-FU & HDLV	Did not meet primary endpoint of OS
		2. 5-FU, LDLV, Levamisole 3. 5-FU, HDLV, Levamisole	Might have superior 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

Variant #2, 1850/125, q4wk

Study	Evidence	Comparator	Comparative Efficacy
Gray et al. 2000 (QUASAR)	Phase III (C)	1. 5-FU & HDLV	Did not meet primary endpoint of OS
		2. 5-FU, LDLV, Levamisole 3. 5-FU, HDLV, Levamisole	Might have superior 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

References

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

FLOX

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FLOX: Fluorouracil, Leucovorin, OXaliplatin

Example orders

• Example orders for FLOX in colon cancer

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Kuebler et al. 2007 (NSABP C-07)	Phase III (E-esc)	5-FU & Leucovorin	Superior DFS

Preceding treatment

• Surgery

Chemotherapy

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

8-week cycle for 3 cycles

References

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

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study	Evidence	Comparator	Comparative Efficacy
André et al. 2004 (MOSAIC)	Phase III (E-RT-esc)	5-FU & Folinic acid	Seems to have superior OS (*)
de Gramont et al. 2012 (AVANT)	Phase III (C)	1. FOLFOX4 & Bevacizumab	Did not meet primary endpoint of DFS
		2. XELOX & Bevacizumab	Did not meet primary endpoint of DFS
Taieb et al. 2014 (PETACC-8)	Phase III (C)	FOLFOX4 & Cetuximab	Did not meet primary endpoint of DFS
Grothey et al. 2018 (IDEA)	Phase III (C)	FOLFOX4 x 6	Inconclusive whether non-inferior DFS36

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

Preceding treatment

• Surgery

Chemotherapy

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

14-day cycle for 12 cycles

References

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

mFOLFOX6

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mFOLFOX6: modified FOLinic acid, Fluorouracil, OXaliplatin

Example orders

• Example orders for mFOLFOX 6 in colon cancer

Variant #1, 3 months

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

Preceding treatment

• Surgery

Chemotherapy

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

14-day cycle for 6 cycles

Variant #2, 6 months (LCV 200 mg/m²)

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

Preceding treatment

• Surgery, within 10 weeks

Chemotherapy

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

14-day cycle for 12 cycles

Variant #3, 6 months (LCV 350 mg/m²)

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

Preceding treatment

• Surgery, within 10 weeks

Chemotherapy

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

14-day cycle for 12 cycles

Variant #4, 6 months (LCV 400 mg/m²)

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

Preceding treatment

• Surgery, within 10 weeks

Chemotherapy

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

14-day cycle for 12 cycles

References

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

mFOLFOX6 (L-Leucovorin)

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mFOLFOX6: modified L-FOLinic acid, Fluorouracil, OXaliplatin

Example orders

• Example orders for mFOLFOX 6 in colon cancer

Variant #1, 3 months

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

Preceding treatment

• Surgery

Chemotherapy

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

14-day cycle for 6 cycles

Variant #2, 6 months

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

Preceding treatment

• Surgery, within 10 weeks

Chemotherapy

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

14-day cycle for 12 cycles

References

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

Observation

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Regimen, stage II disease

Study	Evidence	Comparator	Comparative Efficacy
Moertel et al. 1995 (INT-0035)	Phase III (C)	5-FU & Levamisole	Did not meet primary endpoint of OS
Gray et al. 2000 (QUASAR)	Phase III (C)	5-FU & Leucovorin	Inferior OS
Hartung et al. 2005	Phase III (C)	Edrecolomab	Did not meet primary endpoint of OS
Schippinger et al. 2007	Phase III (C)	5-FU & Leucovorin	Did not meet primary endpoint of OS
Laffer et al. 2008 (SAKK 40/87)	Phase III (C)	1. Portal venous 5-FU & Mitomycin 2. 5-FU & Mitomycin	Did not meet primary endpoint of OS
Niedzwiecki et al. 2011 (CALGB 9581)	Phase III (C)	Edrecolomab	Did not meet primary endpoint of OS

No systemic treatment after surgery for stage II colon cancer.

Preceding treatment

• Surgery

Regimen, stage III disease

Study	Evidence	Comparator	Comparative Efficacy
Lessner et al. 1984	Phase III (C)	1. 5-FU & Semustine 2. 5-FU, Semustine, BCG 3. BCG	Did not meet primary endpoint of OS
Wolmark et al. 1988 (NSABP C-01)	Phase III (C)	1. MOF 2. BCG	Did not meet primary endpoint of OS (*)
Panettiere et al. 1988 (SWOG S7510)	Phase III (C)	1. 5-FU & Semustine 2. 5-FU, Semustine, BCG	Did not meet primary endpoint
Wolmark et al. 1990 (NSABP C-02)	Phase III (C)	Portal venous chemotherapy	Might have inferior OS
Fielding et al. 1992 (AXIS-CRC)	Phase III (C)	Portal venous chemotherapy	Did not meet primary endpoint of OS
Riethmüller et al. 1994	Phase III (C)	Edrecolomab	Seems to have inferior OS
Laffer et al. 1995 (SAKK 40/81)	Phase III (C)	Portal venous chemotherapy	Seems to have inferior OS
Marsoni et al. 1995 (IMPACTCRC)	Phase III (C)	5-FU & Leucovorin	Seems to have inferior OS
O'Connell et al. 1997	Phase III (C)	5-FU & Leucovorin	Seems to have inferior OS
Rougier et al. 1998	Phase III (C)	Portal venous chemotherapy	Did not meet primary endpoint of OS
Vaillant et al. 2000	Phase III (C)	IP 5-FU	Did not meet primary endpoints of DFS60/OS60
Laffer et al. 2008 (SAKK 40/87)	Phase III (C)	1. Portal venous 5-FU & Mitomycin 2. 5-FU & Mitomycin	Did not meet primary endpoint of OS
Hasegawa et al. 2016	Phase III (C)	Tegafur, Uracil, Leucovorin	Inferior RFS

No systemic treatment after surgery. The AXIS trial is named "AXIS-CRC" here so as not to confuse it with the AXIS trial in renal cell carcinoma. IMPACT should not be confused with the studies of the same name in breast cancer and prostate cancer. Reported efficacy for NSABP C-01 is based on the 2004 update.

Preceding treatment

• Surgery

References

1. Lessner HE, Mayer RJ, Ellenberg SS, Holyoke ED; Gastrointestinal Tumor Study Group. Adjuvant therapy of colon cancer--results of a prospectively randomized trial. N Engl J Med. 1984 Mar 22;310(12):737-43. link to original article PubMed
2. NSABP C-01: Wolmark N, Fisher B, Rockette H, Redmond C, Wickerham DL, Fisher ER, Jones J, Glass A, Lerner H, Lawrence W, Prager D, Wexler M, Evans J, Cruz A, Dimitrov N, Jochimsen P; Other NSABP Investigators. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst. 1988 Mar 2;80(1):30-6. link to original article PubMed
   1. Update: Smith RE, Colangelo L, Wieand HS, Begovic M, Wolmark N. Randomized trial of adjuvant therapy in colon carcinoma: 10-year results of NSABP protocol C-01. J Natl Cancer Inst. 2004 Aug 4;96(15):1128-32. link to original article PubMed
   2. Pooled update: Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. link to original article link to PMC article PubMed
3. SWOG S7510: Panettiere FJ, Goodman PJ, Costanzi JJ, Cruz AB Jr, Vaitkevicius VK, McCracken JD, Brownlee RW, Laufman L, Stephens RL, Bonnet J, Bottomley R, Rivkin S, Fletcher W, Oishi N, Chen TT. Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study. J Clin Oncol. 1988 Jun;6(6):947-54. link to original article PubMed
4. Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, Veeder MH, Mailliard JA. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990 Feb 8;322(6):352-8. link to original article PubMed
   1. Update: Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Tangen CM, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, Veeder MH, Mailliard JA. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med. 1995 Mar 1;122(5):321-6. link to original article PubMed
5. NSABP C-02: Wolmark N, Rockette H, Wickerham DL, Fisher B, Redmond C, Fisher ER, Potvin M, Davies RJ, Jones J, Robidoux A, Wexler M, Gordon P, Cruz AB, Horsley S, Nims TA, Thirlwell M, Phillips WA, Prager D, Stern HS, Lerner HJ, Frazier TG. Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: preliminary results of National Surgical Adjuvant Breast and Bowel Project protocol C-02. J Clin Oncol. 1990 Sep;8(9):1466-75. link to original article PubMed
   1. Pooled update: Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. link to original article link to PMC article PubMed
6. AXIS-CRC: Fielding LP, Hittinger R, Grace RH, Fry JS. Randomised controlled trial of adjuvant chemotherapy by portal-vein perfusion after curative resection for colorectal adenocarcinoma. Lancet. 1992 Aug 29;340(8818):502-6. link to original article PubMed
7. Riethmüller G, Schneider-Gädicke E, Schlimok G, Schmiegel W, Raab R, Höffken K, Gruber R, Pichlmaier H, Hirche H, Pichlmayr R, Buggisch P, Witte J; German Cancer Aid 17-1A Study Group. Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes' C colorectal carcinoma. Lancet. 1994 May 14;343(8907):1177-83. link to original article PubMed
8. SAKK 40/81: Laffer U, Metzger U, Aeberhard P, Maibach R, Castiglione M, Goldhirsch A; Swiss Group for Clinical Cancer Research (SAKK). Long-term results of single course of adjuvant intraportal chemotherapy for colorectal cancer. Lancet. 1995 Feb 11;345(8946):349-53. link to original article PubMed
9. IMPACT: Marsoni S, Labianca R, Pancera G, Torri V, Zaniboni A, Erlichman C, Pater J, Shepherd L, Zee B, Seitz JF, Milan C, Pignon JP; International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet. 1995 Apr 15;345(8955):939-44. link to original article PubMed
10. INT-0035: Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Tangen CM, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, Veeder MH, Mailliard JA; North Central Cancer Treatment Group; Southwest Oncology Group; Eastern Cooperative Oncology Group. Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes' B2 colon cancer. J Clin Oncol. 1995 Dec;13(12):2936-43. link to original article PubMed
11. O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, Wieand HS. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997 Jan;15(1):246-50. link to original article contains verified protocol PubMed
    1. Pooled update: Erlichman C, O'Connell M, Kahn M, Marsoni S, Torri V, Tardio B, Zaniboni A, Pancera G, Martignoni G, Labianca R, Barni A, Seitz JF, Milan C, Bedenne L, Giovannini M, Letreut YP, Skillings J, Shepard L, Zee B, Petrioli R, Francini G; International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol. 1999 May;17(5):1356-63. link to original article PubMed
12. Rougier P, Sahmoud T, Nitti D, Curran D, Doci R, De Waele B, Nakajima T, Rauschecker H, Labianca R, Pector JC, Marsoni S, Apolone G, Lasser P, Couvreur ML, Wils J; European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group and the Gruppo Interdisciplinare Valutazione Interventi in Oncologia and the Japanese Foundation for Cancer Research. Adjuvant portal-vein infusion of fluorouracil and heparin in colorectal cancer: a randomised trial. Lancet. 1998 Jun 6;351(9117):1677-81. link to original article PubMed
13. Vaillant JC, Nordlinger B, Deuffic S, Arnaud JP, Pelissier E, Favre JP, Jaeck D, Fourtanier G, Grandjean JP, Marre P, Letoublon C. Adjuvant intraperitoneal 5-fluorouracil in high-risk colon cancer: a multicenter phase III trial. Ann Surg. 2000 Apr;231(4):449-56. link to original article link to PMC article PubMed
14. QUASAR: Gray RG, Kerr DJ, McConkey CC, Williams NS, Hills RK; QUASAR Collaborative Group. Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. Lancet. 2000 May 6;355(9215):1588-96. link to original article contains verified protocol PubMed
    1. Update: Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ; Quasar Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007 Dec 15;370(9604):2020-9. link to original article PubMed
15. Hartung G, Hofheinz RD, Dencausse Y, Sturm J, Kopp-Schneider A, Dietrich G, Fackler-Schwalbe I, Bornbusch D, Gonnermann M, Wojatschek C, Lindemann W, Eschenburg H, Jost K, Edler L, Hochhaus A, Queisser W. Adjuvant therapy with edrecolomab versus observation in stage II colon cancer: a multicenter randomized phase III study. Onkologie. 2005 Jun;28(6-7):347-50. Epub 2005 Jun 2. link to original article PubMed
16. Schippinger W, Samonigg H, Schaberl-Moser R, Greil R, Thödtmann R, Tschmelitsch J, Jagoditsch M, Steger GG, Jakesz R, Herbst F, Hofbauer F, Rabl H, Wohlmuth P, Gnant M, Thaler J; Austrian Breast and Colorectal Cancer Study Group. A prospective randomised phase III trial of adjuvant chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer. Br J Cancer. 2007 Oct 22;97(8):1021-7. Epub 2007 Sep 25. link to original article link to PMC article PubMed
17. SAKK 40/87: Laffer U, Metzger U, Aeberhard P, Lorenz M, Harder F, Maibach R, Zuber M, Herrmann R. Adjuvant perioperative portal vein or peripheral intravenous chemotherapy for potentially curative colorectal cancer: long-term results of a randomized controlled trial. Int J Colorectal Dis. 2008 Dec;23(12):1233-41. Epub 2008 Aug 8. link to original article PubMed
18. CALGB 9581: Niedzwiecki D, Bertagnolli MM, Warren RS, Compton CC, Kemeny NE, Benson AB 3rd, Eckhardt SG, Alberts S, Porjosh GN, Kerr DJ, Fields A, Rougier P, Pipas JM, Schwartz JH, Atkins J, O'Rourke M, Perry MC, Goldberg RM, Mayer RJ, Colacchio TA. Documenting the natural history of patients with resected stage II adenocarcinoma of the colon after random assignment to adjuvant treatment with edrecolomab or observation: results from CALGB 9581. J Clin Oncol. 2011 Aug 10;29(23):3146-52. Epub 2011 Jul 11. link to original article link to PMC article PubMed
19. Hasegawa K, Saiura A, Takayama T, Miyagawa S, Yamamoto J, Ijichi M, Teruya M, Yoshimi F, Kawasaki S, Koyama H, Oba M, Takahashi M, Mizunuma N, Matsuyama Y, Watanabe T, Makuuchi M, Kokudo N. Adjuvant oral uracil-tegafur with leucovorin for colorectal cancer liver metastases: A randomized controlled trial. PLoS One. 2016 Sep 2;11(9):e0162400. eCollection 2016. link to original article link to PMC article contains verified protocol PubMed

Placebo

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Midgley et al. 2010 (VICTOR)	Phase III (C)	Rofecoxib	Did not meet primary endpoint of OS

No active antineoplastic treatment.

Preceding treatment

• Surgery

References

1. VICTOR: Midgley RS, McConkey CC, Johnstone EC, Dunn JA, Smith JL, Grumett SA, Julier P, Iveson C, Yanagisawa Y, Warren B, Langman MJ, Kerr DJ. Phase III randomized trial assessing rofecoxib in the adjuvant setting of colorectal cancer: final results of the VICTOR trial. J Clin Oncol. 2010 Oct 20;28(30):4575-80. Epub 2010 Sep 13. link to original article PubMed

SOX

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SOX: S-1, OXaliplatin

Regimen

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

Preceding treatment

• Surgery

Chemotherapy

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

21-day cycle for 8 cycles

References

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

Tegafur, Uracil, Folinic acid

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

Variant #1, 300/75

Study	Evidence	Comparator	Comparative Efficacy
Yoshida et al. 2014 (ACTS-CC)	Phase III (C)	S-1	Non-inferior DFS
Shimada et al. 2014 (JCOG0205)	Phase III (E-switch-ic)	5-FU & Leucovorin	Non-inferior DFS
Sadahiro et al. 2015 (JFMC33-0502)	Phase III (C)	UFT + LV weekly x 18 mo	Did not meet primary endpoint of DFS
Hasegawa et al. 2016	Phase III (E-esc)	Observation	Superior RFS
Miyake et al. 2018	Phase III (C)	UFT/PSK	Inconclusive whether non-inferior DFS36

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

Preceding treatment

• 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
• Folinic acid (Leucovorin) 25 mg PO every 8 hours on days 1 to 28

35-day cycle for 5 cycles

Variant #2, 300/90

Study	Evidence	Comparator	Comparative Efficacy
Lembersky et al. 2006 (NSABP C-06)	Phase III (E-switch-ic)	5-FU & Leucovorin	Did not meet primary endpoints of DFS/OS

Preceding treatment

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

Chemotherapy

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

35-day cycle for 5 cycles

References

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

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

Fluorouracil & Folinic acid

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Regimen

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

Reported 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
• Folinic acid (Leucovorin) 200 mg/m² IV once per day on days 1 to 5, given first

28-day cycle for 6 cycles

References

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

FOLFIRI

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Regimen

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

Chemotherapy

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

14-day cycle for 8 cycles

References

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

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

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

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

Preceding treatment

• Surgical resection of oligometastatic disease

Chemotherapy

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

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

References

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

mFOLFOX6 (L-Leucovorin)

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mFOLFOX6: modified L-FOLinic acid, Fluorouracil, OXaliplatin

Regimen

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

Chemotherapy

• 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

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

Hepatic arterial chemotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Allen-Mersh et al. 1994	Phase III (E-esc)	Best supportive care	Seems to have superior OS
Kemeny et al. 1999	Phase III (E-esc)	Observation	Seems to have superior OS

Of historic interest; unlikely to be completed.

Preceding treatment

• Surgical resection of oligometastatic disease

Chemotherapy

• Floxuridine (FUDR)

Supportive medications

• Dexamethasone (Decadron)

References

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

Intraperitoneal 5-FU

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Regimen

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

Preceding treatment

• Cytoreductive surgery

Chemotherapy

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

1-month cycle for 6 cycles

References

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

Intraperitoneal hyperthermic mitomycin

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Verwaal et al. 2003	Phase III (E-switch-ooc)	5-FU & LV (modified Laufman regimen)	Seems to have superior OS

Preceding treatment

• Cytoreductive surgery

Chemotherapy

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

One treatment

References

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

Observation

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Kemeny et al. 1999	Phase III (C)	Hepatic arterial chemotherapy	Seems to have inferior OS
Portier et al. 2006 (FFCD 9002)	Phase III (C)	5-FU & LV	Might have inferior PFS (*)
Nordlinger et al. 2008 (EORTC 40983)	Phase III (C)	FOLFOX4	Inferior PFS

No treatment other than surgical resection of oligometastatic disease. Reported efficacy for FFCD 9002 is based on the 2008 pooled update.

References

1. Kemeny N, Huang Y, Cohen AM, Shi W, Conti JA, Brennan MF, Bertino JR, Turnbull AD, Sullivan D, Stockman J, Blumgart LH, Fong Y. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med. 1999 Dec 30;341(27):2039-48. link to original article PubMed
2. 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 PubMed
   1. Pooled update: Mitry E, Fields AL, Bleiberg H, Labianca R, Portier G, Tu D, Nitti D, Torri V, Elias D, O'Callaghan C, Langer B, Martignoni G, Bouché O, Lazorthes F, Van Cutsem E, Bedenne L, Moore MJ, Rougier P. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol. 2008 Oct 20;26(30):4906-11. Epub 2008 Sep 15. link to original article PubMed
3. EORTC 40983: Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008 Mar 22;371(9617):1007-16. link to original article link to PMC article does not contain protocol PubMed
   1. Update: Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Mauer M, Tanis E, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und–tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectalcancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1208-15. Epub 2013 Oct 11. link to original article PubMed

Advanced or metastatic disease, first-line

Capecitabine monotherapy

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C: Capecitabine

Variant #1, 2000 mg/m²/day

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

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

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

21-day cycles

Variant #2, 2500 mg/m²/day

Study	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Hoff et al. 2001	Phase III (E-RT-switch-ic)	5-FU + Folinic acid	Superior ORR
Van Cutsem et al. 2001	Phase III (E-RT-switch-ic)	5-FU + Folinic acid	Equivalent ORR
Koopman et al. 2007 (CAIRO)	Phase III (C)	See link	See link
Tebbutt et al. 2010 (AGITG MAX)	Phase III (C)	1. Capecitabine & Bevacizumab	Inferior PFS
		2. CBM	Inferior PFS
Cunningham et al. 2013 (AVEX)	Phase III (C)	Capecitabine & Bevacizumab	Inferior PFS
Kwakman et al. 2017 (SALTO)	Phase III (C)	S-1	Did not meet secondary efficacy endpoints (*)	Higher incidence of hand-foot syndrome

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

Chemotherapy

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

21-day cycles

Subsequent treatment

• CAIRO, upon progression: Irinotecan

References

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

Capecitabine & Bevacizumab

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CB: Capecitabine & Bevacizumab

Variant #1, 1000/7.5

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

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycles

Variant #2, 1250/7.5

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

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycles

References

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

CapeOx

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

Example orders

• Example orders for CapeOx (XELOX) in colon cancer

Variant #1, 850/130

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

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

Chemotherapy

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

21-day cycles

Variant #2, 1000/70

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

Chemotherapy

• 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

Variant #3, 1000/130

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

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

Chemotherapy

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

21-day cycles (see note)

Subsequent treatment

• SMC 2008-03-012: Optional capecitabine maintenance after 9 cycles

References

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

CapeOx & Bevacizumab

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

Variant #1, 850/130/7.5

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

Chemotherapy

• Capecitabine (Xeloda) 850 mg/m² PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
  • In TREE-2, patients with a CrCl of 30 to 50 mL/min/1.73m² received 650 mg/m² PO twice per day
• Oxaliplatin (Eloxatin) 130 mg/m² IV over 2 hours once on day 1
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycles

Variant #2, 1000/130/7.5 x 6

Study	Evidence	Comparator	Comparative Efficacy
Tol et al. 2009 (CAIRO2)	Phase III (C)	CapeOx, Bevacizumab, Cetuximab	Superior PFS
Díaz-Rubio et al. 2012 (MACRO)	Non-randomized portion of RCT
Johnsson et al. 2013 (Nordic ACT)	Non-randomized portion of RCT
Simkens et al. 2015 (CAIRO3)	Non-randomized portion of 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
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycle for 6 cycles

Subsequent treatment

• CAIRO2: Capecitabine & Bevacizumab maintenance
• MACRO: Bevacizumab versus XELOX & Bevacizumab maintenance
• Nordic ACT: Bevacizumab versus Erlotinib & Bevacizumab maintenance
• CAIRO3: Capecitabine & Bevacizumab maintenance versus Observation

Variant #3, 1000/130/7.5, indefinite

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

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

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
  • Note: In Saltz et al. 2008--the same study as Cassidy et al. 2008--capecitabine was described as being given 1000 mg/m² PO twice per day on days 1 to 14
• Oxaliplatin (Eloxatin) 130 mg/m² IV over 2 hours once on day 1, given second
• Bevacizumab (Avastin) 7.5 mg/kg IV over 30 to 90 minutes once on day 1, given first

21-day cycles

References

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

CAPIRI

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

Regimen

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

Note: EORTC 40015 was closed prematurely.

Chemotherapy

• 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

Subsequent treatment

• CAIRO, with progression: CapeOx

References

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

CAPIRI-Bev

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

Variant #1, 750/150/7.5

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

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
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycle for 6 cycles

Subsequent treatment

• Bevacizumab versus Erlotinib & Bevacizumab maintenance

Variant #2, 800/200/7.5

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

Chemotherapy

• Capecitabine (Xeloda) 800 mg/m² PO twice per day on days 1 to 14
• Irinotecan (Camptosar) 200 mg/m² IV once on day 1
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycles

Variant #3, 1000/180/7.5

Study	Evidence
Johnsson et al. 2013 (Nordic ACT)	Non-randomized portion of 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
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycle for 6 cycles

Subsequent treatment

• Bevacizumab versus Erlotinib & Bevacizumab maintenance

Variant #4, 1000/200/7.5

Study	Evidence
Moehler et al. 2009a	Phase II

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
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycles

Variant #5, 1000/240/7.5

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

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
• Irinotecan (Camptosar) 240 mg/m² IV once on day 1
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycle for 6 cycles

References

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

Fluorouracil monotherapy

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Variant #1, 400 mg/m² intermittent bolus

Study	Evidence	Comparator	Comparative Efficacy
Borner et al. 1998	Phase III (C)	5-FU & LV	Seems to have inferior OS

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus once per day on days 1 to 5

1-month cycles

Variant #2, 450 mg/m² intermittent bolus

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

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

Chemotherapy

• Fluorouracil (5-FU) 450 mg/m² IV bolus once per day on days 1 to 5

28-day cycles

Variant #3, 500 mg/m² intermittent bolus

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

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV bolus once per day on days 1 to 5

4- to 5-week cycles

Variant #4, 600 mg/m²/week

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

Chemotherapy

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1

7-day cycles

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

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

Variant #6, weekly bolus with CI lead-in

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

Chemotherapy

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

7-day cycles

Variant #7, weekly CI

Study	Evidence	Comparator	Comparative Efficacy
Aranda et al. 1998	Phase III (E-switch-ic)	Mayo Clinic regimen	Seems to have superior ORR

Chemotherapy

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

7-day cycles

Variant #8, PVI ("Lokich regimen")

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

Chemotherapy

• Fluorouracil (5-FU) 300 mg/m²/day IV continuous infusion

Continued indefinitely

Variant #9, load to toxicity

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

Chemotherapy

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

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

References

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

Fluorouracil & Folinic acid

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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

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

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

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1
• Folinic acid (Leucovorin) 80 mg/m² IV once on day 1

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

Variant #2, 450/200

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

Chemotherapy

• Fluorouracil (5-FU) 450 mg/m² IV bolus once on day 1, given halfway through
• Folinic acid (Leucovorin) 200 mg/m² IV over 2 hours once on day 1

7-day cycles

Variant #3, 500/20

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

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV bolus once on day 1, given second, 1 hour after start of leucovorin
• Folinic acid (Leucovorin) 20 mg/m² IV over 2 hours once on day 1, given first

7-day cycles

Variant #4, 500/200, 6 out of 8 weeks

Study	Evidence	Comparator	Comparative Efficacy
Blanke et al. 2002	Phase III (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
• Folinic acid (Leucovorin) 200 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36

8-week cycles

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

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

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

Chemotherapy

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

8-week cycles

Variant #6, 1500/400

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

Chemotherapy

• Fluorouracil (5-FU) 1500 mg/m² IV over 8 hours once on day 1
• Folinic acid (Leucovorin) 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

Variant #7, 1850/1000

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

Chemotherapy

• Fluorouracil (5-FU) 370 mg/m² IV once per day on days 1 to 5
• Folinic acid (Leucovorin) 200 mg/m² IV once per day on days 1 to 5

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

Variant #8, 2000/100

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

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV once per day on days 1 to 5
• Folinic acid (Leucovorin) 20 mg/m² IV once per day on days 1 to 5

1-month cycles

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

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

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

Chemotherapy

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

14-day cycles (see note)

Variant #10, 2000/1000

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

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV over 15 minutes once per day on days 1 to 5
• Folinic acid (Leucovorin) 200 mg/m² IV once per day on days 1 to 5

28-day cycles

Variant #11, 2125/100 ("Mayo Clinic regimen")

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

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

Chemotherapy

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

Variant #12, 2560/175 (reduced-dose sLV5FU2)

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

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

Chemotherapy

• 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)
• Folinic acid (Leucovorin) 175 mg/m² IV over 2 hours once on day 1

14-day cycles

Variant #13, 2600/500

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

Chemotherapy

• Fluorouracil (5-FU) 2600 mg/m² IV continuous infusion over 24 hours, started on day 1
• Folinic acid (Leucovorin) 500 mg/m² IV once on day 1

7-day cycles

Variant #14, 2800/350 ("modified de Gramont regimen")

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

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

Chemotherapy

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

Supportive medications

• 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

Variant #15, 2800/400 (sLV5FU2)

Study	Evidence	Comparator	Comparative Efficacy
Ducreux et al. 2011 (FFCD 2000-05)	Phase III (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)
• Folinic acid (Leucovorin) 400 mg/m² IV over 2 hours once on day 1

14-day cycles

Subsequent treatment

• Upon progression: mFOLFOX6

Variant #16, other

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

See papers for details.

Chemotherapy

• Fluorouracil (5-FU)
• Folinic acid (Leucovorin)

References

1. Petrelli N, Herrera L, Rustum Y, Burke P, Creaven P, Stulc J, Emrich LJ, Mittelman A. A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol. 1987 Oct;5(10):1559-65. link to original article contains verified protocol PubMed
2. O'Connell MJ. A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer: a Mayo Clinic/North Central Cancer Treatment Group study. Cancer. 1989 Mar 15;63(6 Suppl):1026-30. link to original article PubMed
3. Poon MA, O'Connell MJ, Moertel CG, Wieand HS, Cullinan SA, Everson LK, Krook JE, Mailliard JA, Laurie JA, Tschetter LK, Wiesenfeld M. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol. 1989 Oct;7(10):1407-18. link to original article PubMed
   1. Update: Poon MA, O'Connell MJ, Wieand HS, Krook JE, Gerstner JB, Tschetter LK, Levitt R, Kardinal CG, Mailliard JA. Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol. 1991 Nov;9(11):1967-72. link to original article PubMed
4. Petrelli N, Douglass HO Jr, Herrera L, Russell D, Stablein DM, Bruckner HW, Mayer RJ, Schinella R, Green MD, Muggia FM, Megibow A, Greenwald ES, Bukowski RM, Harris J, Levin B, Gaynor E, Loutfi A, Kaiser MH, Barkin JS, Benedetto P, Woolley PV, Nauta R, Weaver DW, Leichman LP; Gastrointestinal Tumor Study Group. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. J Clin Oncol. 1989 Oct;7(10):1419-26. Erratum in: J Clin Oncol 1990 Jan;8(1):185. link to original article contains protocol PubMed
5. Labianca R, Pancera G, Aitini E, Barni S, Beretta A, Beretta GD, Cesana B, Comella G, Cozzaglio L, Cristoni M, Spagnolli P, Frontini L, Gottardi O, Martignoni G, Scapaticci R, Smerieri F, Vinci M, Zadro A, Zaniboni A, Luporini G. Folinic acid + 5-fluorouracil (5-FU) versus equidose 5-FU in advanced colorectal cancer: phase III study of 'GISCAD' (Italian Group for the Study of Digestive Tract Cancer). Ann Oncol. 1991 Oct;2(9):673-9. link to original article contains protocol PubMed
6. Buroker TR, O'Connell MJ, Wieand HS, Krook JE, Gerstner JB, Mailliard JA, Schaefer PL, Levitt R, Kardinal CG, Gesme DH Jr. Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol. 1994 Jan;12(1):14-20. link to original article contains protocol PubMed
7. Corfu-A: Man A, Levi J, Weinerman B, Kjaer M, Yap AKL; Corfu-A Study Group. Phase III randomized study of two fluorouracil combinations with either interferon alfa-2a or leucovorin for advanced colorectal cancer. J Clin Oncol. 1995 Apr;13(4):921-8. link to original article contains protocol PubMed
8. Jones DV Jr, Winn RJ, Brown BW, Levy LB, Pugh RP, Wade JL 3rd, Gross HM, Pendergrass KB, Levin B, Abbruzzese JL. Randomized phase III study of 5-fluorouracil plus high dose folinic acid versus 5-fluorouracil plus folinic acid plus methyl-lomustine for patients with advanced colorectal cancer. Cancer. 1995 Nov 15;76(10):1709-14. link to original article PubMed
9. Heys SD, Eremin O, Ruggeri EM, Pein F, Rainer H, Oskam R, de Peuter RA, Palmer PA, Franks CR. A phase III study of recombinant interleukin-2, 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in patients with unresectable or metastatic colorectal carcinoma. Eur J Cancer. 1995;31A(1):19-25. link to original article PubMed
10. Jäger E, Heike M, Bernhard H, Klein O, Bernhard G, Lautz D, Michaelis J, Meyer zum Büschenfelde KH, Knuth Al; Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. J Clin Oncol. 1996 Aug;14(8):2274-9. link to original article contains verified protocol PubMed
11. Kosmidis PA, Tsavaris N, Skarlos D, Theocharis D, Samantas E, Pavlidis N, Briassoulis E, Fountzilas G; Hellenic Cooperative Oncology Group. Fluorouracil and leucovorin with or without interferon alfa-2b in advanced colorectal cancer: analysis of a prospective randomized phase III trial. J Clin Oncol. 1996 Oct;14(10):2682-7. link to original article contains protocol PubMed
12. FFCD 9101: de Gramont A, Bosset JF, Milan C, Rougier P, Bouché O, Etienne PL, Morvan F, Louvet C, Guillot T, François E, Bedenne L. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol. 1997 Feb;15(2):808-15. link to original article contains verified protocol PubMed
13. Goldberg RM, Hatfield AK, Kahn M, Sargent DJ, Knost JA, O'Connell MJ, Krook JE, Maillard JA, Wiesenfeld M, Schaefer PL, Tirona MT, Moertel CG. Prospectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. J Clin Oncol. 1997 Nov;15(11):3320-9. link to original article contains protocol PubMed
14. Borner MM, Castiglione M, Bacchi M, Weber W, Herrmann R, Fey MF, Pagani O, Leyvraz S, Morant R, Pestalozzi B, Hanselmann S, Goldhirsch A; Swiss Group for Clinical Cancer Research (SAKK). The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: results of a phase III trial. Ann Oncol. 1998 May;9(5):535-41. link to original article contains protocol PubMed
15. Aranda E, Díaz-Rubio E, Cervantes A, Antón-Torres A, Carrato A, Massutí T, Tabernero JM, Sastre J, Trés A, Aparicio J, López-Vega JM, Barneto I, García-Conde J. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol. 1998 Jul;9(7):727-31. link to original article contains protocol PubMed
16. Hausmaninger H, Moser R, Samonigg H, Mlineritsch B, Schmidt H, Pecherstorfer M, Fridrik M, Kopf C, Nitsche D, Kaider A, Ludwig H. Biochemical modulation of 5-fluorouracil by leucovorin with or without interferon-alpha-2c in patients with advanced colorectal cancer: final results of a randomised phase III study. Eur J Cancer. 1999 Mar;35(3):380-5. link to original article PubMed
17. Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet P, Llory JF, Letourneau Y, Coudert B, Bertheaut-Cvitkovic F, Larregain-Fournier D, Le Rol A, Walter S, Adam R, Misset JL, Lévi F. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2000 Jan;18(1):136-47. link to original article PubMed
18. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-7. link to original article contains verified protocol PubMed
19. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. link to original article contains verified protocol PubMed
20. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. link to original article contains verified protocol PubMed
21. Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001 Apr 15;19(8):2282-92. link to original article contains verified protocol PubMed
    1. Pooled update: Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. link to original article link to PMC article PubMed
22. Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P; Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001 Nov 1;19(21):4097-106. link to original article contains verified protocol PubMed
    1. Pooled update: Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004 Mar 22;90(6):1190-7. link to original article link to PMC article PubMed
23. Blanke CD, Shultz J, Cox J, Modiano M, Isaacs R, Kasimis B, Schilsky R, Fleagle J, Moore M, Kemeny N, Carlin D, Hammershaimb L, Haller D. A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer. Ann Oncol. 2002 Jan;13(1):87-91. link to original article contains protocol PubMed
24. FUMA3008: Schilsky RL, Levin J, West WH, Wong A, Colwell B, Thirlwell MP, Ansari RH, Bell WN, White RL, Yates BB, McGuirt PV, Pazdur R. Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. J Clin Oncol. 2002 Mar 15;20(6):1519-26. link to original article contains protocol PubMed
25. Maughan TS, James RD, Kerr DJ, Ledermann JA, McArdle C, Seymour MT, Cohen D, Hopwood P, Johnston C, Stephens RJ; British MRC Colorectal Cancer Working Party. Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2002 May 4;359(9317):1555-63. link to original article PubMed
26. Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12;87(4):393-9. link to original article contains verified protocol link to PMC article PubMed
27. Douillard JY, Hoff PM, Skillings JR, Eisenberg P, Davidson N, Harper P, Vincent MD, Lembersky BC, Thompson S, Maniero A, Benner SE. Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2002 Sep 1;20(17):3605-16. link to original article contains protocol PubMed
28. Carmichael J, Popiela T, Radstone D, Falk S, Borner M, Oza A, Skovsgaard T, Munier S, Martin C. Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2002 Sep 1;20(17):3617-27. link to original article contains protocol PubMed
29. AVF0780: Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, Griffing S, Bergsland E. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003 Jan 1;21(1):60-5. link to original article contains verified protocol PubMed
30. Kerr DJ, McArdle CS, Ledermann J, Taylor I, Sherlock DJ, Schlag PM, Buckels J, Mayer D, Cain D, Stephens RJ; Medical Research Council's colorectal cancer study group; European Organisation for Research and Treatment of Cancer colorectal cancer study group. Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. Lancet. 2003 Feb 1;361(9355):368-73. link to original article contains protocol PubMed
31. Maughan TS, James RD, Kerr DJ, Ledermann JA, Seymour MT, Topham C, McArdle C, Cain D, Stephens RJ; Medical Research Council Colorectal Cancer Group. Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial. Lancet. 2003 Feb 8;361(9356):457-64. link to original article PubMed
32. EORTC 40952: Köhne CH, Wils J, Lorenz M, Schöffski P, Voigtmann R, Bokemeyer C, Lutz M, Kleeberg C, Ridwelski K, Souchon R, El-Serafi M, Weiss U, Burkhard O, Rückle H, Lichnitser M, Langenbuch T, Scheithauer W, Baron B, Couvreur ML, Schmoll HJ; European Organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952. Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952. J Clin Oncol. 2003 Oct 15;21(20):3721-8. Epub 2003 Sep 8. link to original article contains protocol PubMed
33. Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003 Oct 15;21(20):3737-43. link to original article PubMed
34. Chong G, Bhatnagar A, Cunningham D, Cosgriff TM, Harper PG, Steward W, Bridgewater J, Moore M, Cassidy J, Coleman R, Coxon F, Redfern CH, Jones JJ, Hawkins R, Northfelt D, Sreedharan S, Valone F, Carmichael J. Phase III trial of 5-fluorouracil and leucovorin plus either 3H1 anti-idiotype monoclonal antibody or placebo in patients with advanced colorectal cancer. Ann Oncol. 2006 Mar;17(3):437-42. Epub 2005 Nov 25. link to original article contains verified protocol PubMed
35. Hospers GA, Schaapveld M, Nortier JW, Wils J, van Bochove A, de Jong RS, Creemers GJ, Erjavec Z, de Gooyer DJ, Slee PH, Gerrits CJ, Smit JM, Mulder NH. Randomised Phase III study of biweekly 24-h infusion of high-dose 5FU with folinic acid and oxaliplatin versus monthly plus 5-FU/folinic acid in first-line treatment of advanced colorectal cancer. Ann Oncol. 2006 Mar;17(3):443-9. link to original article contains protocol PubMed
36. FFCD 9601: Ducreux M, Bouche O, Pignon JP, Mousseau M, Raoul JL, Cassan P, Leduc B, Berger C, Dunant A, Fournet J, Bedenne L; FFCD 9601 Collaborative Group. Randomised trial comparing three different schedules of infusional 5FU and raltitrexed alone as first-line therapy in metastatic colorectal cancer: final results of the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 trial. Oncology. 2006;70(3):222-30. Epub 2006 Jun 30. link to original article PubMed
37. MRC FOCUS: Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, Smith DB, Shepherd S, Maraveyas A, Ferry DR, Meade AM, Thompson L, Griffiths GO, Parmar MK, Stephens RJ; FOCUS Trial Investigators; National Cancer Research Institute Colorectal Clinical Studies Group. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007 Jul 14;370(9582):143-52. Erratum in: Lancet. 2007 Aug 18;370(9587):566. link to original article PubMed
38. Gamelin E, Delva R, Jacob J, Merrouche Y, Raoul JL, Pezet D, Dorval E, Piot G, Morel A, Boisdron-Celle M. Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer. J Clin Oncol. 2008 May 1;26(13):2099-105. Erratum in: J Clin Oncol. 2013 Oct 1;31(28):3612. link to original article contains verified protocol PubMed
39. Cunningham D, Sirohi B, Pluzanska A, Utracka-Hutka B, Zaluski J, Glynne-Jones R, Koralewski P, Bridgewater J, Mainwaring P, Wasan H, Wang JY, Szczylik C, Clingan P, Chan RT, Tabah-Fisch I, Cassidy J. Two different first-line 5-fluorouracil regimens with or without oxaliplatin in patients with metastatic colorectal cancer. Ann Oncol. 2009 Feb;20(2):244-50. Epub 2008 Oct 14. link to original article contains protocol PubMed
40. MRC FOCUS2: Seymour MT, Thompson LC, Wasan HS, Middleton G, Brewster AE, Shepherd SF, O'Mahony MS, Maughan TS, Parmar M, Langley RE; FOCUS2 Investigators; National Cancer Research Institute Colorectal Cancer Clinical Studies Group. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. Lancet. 2011 May 21;377(9779):1749-59. Epub 2011 May 11. link to original article link to PMC article contains verified protocol PubMed
41. FFCD 2000-05: Ducreux M, Malka D, Mendiboure J, Etienne PL, Texereau P, Auby D, Rougier P, Gasmi M, Castaing M, Abbas M, Michel P, Gargot D, Azzedine A, Lombard-Bohas C, Geoffroy P, Denis B, Pignon JP, Bedenne L, Bouché O; Fédération Francophone de Cancérologie Digestive (FFCD) 2000–05 Collaborative Group. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol. 2011 Oct;12(11):1032-44. Epub 2011 Sep 6. link to original article contains protocol PubMed
42. FFCD 2001-02: Aparicio T, Lavau-Denes S, Phelip JM, Maillard E, Jouve JL, Gargot D, Gasmi M, Locher C, Adhoute X, Michel P, Khemissa F, Lecomte T, Provençal J, Breysacher G, Legoux JL, Lepère C, Charneau J, Cretin J, Chone L, Azzedine A, Bouché O, Sobhani I, Bedenne L, Mitry E; FFCD investigators. Randomized phase III trial in elderly patients comparing LV5FU2 with or without irinotecan for first-line treatment of metastatic colorectal cancer (FFCD 2001-02). Ann Oncol. 2016 Jan;27(1):121-7. Epub 2015 Oct 20. link to original article contains verified protocol in supplement PubMed

Fluorouracil & Levoleucovorin

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Variant #1, 1870/50

Study	Evidence	Comparator	Comparative Efficacy
Labianca et al. 1997	Phase III (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
• Levoleucovorin (Fusilev) 10 mg/m² IV once per day on days 1 to 5

28-day cycles

Variant #2, 1875/500

Study	Evidence	Comparator	Comparative Efficacy
Colucci et al. 1999	Phase III (C)	5-FU, LV, IFN alfa-2b	Did not meet primary efficacy endpoints

Chemotherapy

• Fluorouracil (5-FU) 375 mg/m² IV once per day on days 1 to 5, given second
• Levoleucovorin (Fusilev) 100 mg/m² IV once per day on days 1 to 5, given first

21-day cycles

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

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

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

Chemotherapy

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

Supportive medications

• 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

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

FOLFIRI

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

Example orders

• Example orders for FOLFIRI in colon cancer

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

Study	Evidence	Comparator	Comparative Efficacy
Douillard et al. 2000	Phase III (E-RT-esc)	5-FU & LV	Seems to have superior OS
Souglakos et al. 2006	Phase III (C)	FOLFOXIRI	Did not meet primary endpoint of OS
Köhne et al. 2007 (EORTC 40015)	Phase III (C)	CAPIRI	Inconclusive whether non-inferior PFS
Glimelius et al. 2008	Phase III (C)	FLIRI	Did not meet primary endpoint of PFS
Aranda et al. 2008	Phase III (C)	FUIRI	Did not meet primary endpoint of ORR (*)
Passardi et al. 2015 (ITACa)	Phase III (C)	FOLFIRI & Bevacizumab	Did not meet primary endpoint of PFS

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

Chemotherapy

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

14-day cycles

Variant #2, 400/2800/180

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

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

Chemotherapy

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

14-day cycles

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

Study	Evidence	Comparator	Comparative Efficacy
Köhne et al. 2005 (EORTC 40986)	Phase III (E-esc)	5-FU & LV	Superior PFS
Fischer von Weikersthal et al. 2011	Phase III (C)	mIROX	Did not meet primary endpoint of PFS

Chemotherapy

• Folinic acid (Leucovorin) 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
• Irinotecan (Camptosar) 80 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22, 29, 36

7-week cycles

Variant #4, 500/2300/80, weekly

Study	Evidence	Comparator	Comparative Efficacy
Douillard et al. 2000	Phase III (E-RT-esc)	5-FU & LV	Seems to have superior OS
Passardi et al. 2015 (ITACa)	Phase III (C)	FOLFIRI & Bevacizumab	Did not meet primary endpoint of PFS

Chemotherapy

• Folinic acid (Leucovorin) 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

1. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-7. link to original article contains verified protocol PubMed
2. EORTC 40986: Köhne CH, van Cutsem E, Wils J, Bokemeyer C, El-Serafi M, Lutz MP, Lorenz M, Reichardt P, Rückle-Lanz H, Frickhofen N, Fuchs R, Mergenthaler HG, Langenbuch T, Vanhoefer U, Rougier P, Voigtmann R, Müller L, Genicot B, Anak O, Nordlinger B; European Organisation for Research and Treatment of Cancer Gastrointestinal Group. Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol. 2005 Aug 1;23(22):4856-65. Epub 2005 Jun 6. link to original article contains verified protocol PubMed
3. Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, Kakolyris S, Tsousis S, Kouroussis Ch, Vamvakas L, Kalykaki A, Samonis G, Mavroudis D, Georgoulias V. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-805. link to original article link to PMC article contains verified protocol PubMed
4. Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6. link to original article contains verified protocol PubMed
5. BICC-C: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article contains verified protocol PubMed
   1. Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article PubMed
6. EORTC 40015: Köhne CH, De Greve J, Hartmann JT, Lang I, Vergauwe P, Becker K, Braumann D, Joosens E, Müller L, Janssens J, Bokemeyer C, Reimer P, Link H, Späth-Schwalbe E, Wilke HJ, Bleiberg H, Van Den Brande J, Debois M, Bethe U, Van Cutsem E. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer: EORTC study 40015. Ann Oncol. 2008 May;19(5):920-6. Epub 2007 Dec 6. link to original article contains protocol PubMed
7. Glimelius B, Sørbye H, Balteskard L, Byström P, Pfeiffer P, Tveit K, Heikkilä R, Keldsen N, Albertsson M, Starkhammar H, Garmo H, Berglund A. A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer. Ann Oncol. 2008 May;19(5):909-14. Epub 2008 Jan 21. link to original article contains protocol PubMed
8. Aranda E, Valladares M, Martinez-Villacampa M, Benavides M, Gomez A, Massutti B, Marcuello E, Constenla M, Cámara JC, Carrato A, Dueñas R, Reboredo M, Navarro M, Díaz-Rubio E. Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study. Ann Oncol. 2009 Feb;20(2):251-7. Epub 2008 Aug 20. link to original article contains verified protocol PubMed
9. CRYSTAL: Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. link to original article contains verified protocol PubMed
   1. Update: Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. link to original article contains verified protocol PubMed
   2. Pooled Update: Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article PubMed
   3. Biomarker analysis: Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. link to original article PubMed
10. Fischer von Weikersthal L, Schalhorn A, Stauch M, Quietzsch D, Maubach PA, Lambertz H, Oruzio D, Schlag R, Weigang-Köhler K, Vehling-Kaiser U, Schulze M, Truckenbrodt J, Goebeler M, Mittermüller J, Bosse D, Szukics B, Grundeis M, Zwingers T, Giessen C, Heinemann V. Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer. Eur J Cancer. 2011 Jan;47(2):206-14. link to SD article contains protocol PubMed
11. ITACa: Passardi A, Nanni O, Tassinari D, Turci D, Cavanna L, Fontana A, Ruscelli S, Mucciarini C, Lorusso V, Ragazzini A, Frassineti GL, Amadori D. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015 Jun;26(6):1201-7. Epub 2015 Mar 3. link to original article refers to Douillard et al. 2000 PubMed
12. Sanoff HK, Goldberg RM, Ivanova A, O'Reilly S, Kasbari SS, Kim RD, McDermott R, Moore DT, Zamboni W, Grogan W, Cohn AL, Bekaii-Saab TS, Leonard G, Ryan T, Olowokure OO, Fernando NH, McCaffrey J, El-Rayes BF, Horgan AM, Sherrill GB, Yacoub GH, O'Neil BH. Multicenter, randomized, double-blind phase 2 trial of FOLFIRI with regorafenib or placebo as second-line therapy for metastatic colorectal cancer. Cancer. 2018 Aug 1;124(15):3118-3126. Epub 2018 Jun 15. link to original article contains verified protocol PubMed

FOLFIRI (L-Leucovorin)

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FOLFIRI: L-FOLinic acid, Fluorouracil, IRInotecan

Variant #1, 200/2000/150

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

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

Chemotherapy

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

14-day cycles

Variant #2, 200/2000/180

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

Chemotherapy

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

14-day cycles

Variant #3, 200/2800/180

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

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

Chemotherapy

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

14-day cycles

References

1. GOIM 9901: Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N, Cartenì G, Agostara B, Pezzella G, Manzione L, Borsellino N, Misino A, Romito S, Durini E, Cordio S, Di Seri M, Lopez M, Maiello E, Montemurro S, Cramarossa A, Lorusso V, Di Bisceglie M, Chiarenza M, Valerio MR, Guida T, Leonardi V, Pisconti S, Rosati G, Carrozza F, Nettis G, Valdesi M, Filippelli G, Fortunato S, Mancarella S, Brunetti C; Gruppo Oncologico Dell'Italia Meridionale. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol. 2005 Aug 1;23(22):4866-75. Epub 2005 Jun 6. link to original article contains verified protocol PubMed
2. CRYSTAL: Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. link to original article contains verified protocol PubMed
   1. Update: Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. link to original article contains verified protocol PubMed
   2. Pooled Update: Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article PubMed
   3. Biomarker analysis: Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. link to original article PubMed
3. Labianca R, Sobrero A, Isa L, Cortesi E, Barni S, Nicolella D, Aglietta M, Lonardi S, Corsi D, Turci D, Beretta GD, Fornarini G, Dapretto E, Floriani I, Zaniboni A; Italian Group for the Study of Gastrointestinal Cancer-GISCAD. Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised 'GISCAD' trial. Ann Oncol. 2011 May;22(5):1236-42. Epub 2010 Nov 15. link to original article contains verified protocol PubMed
4. SUN 1122: Carrato A, Swieboda-Sadlej A, Staszewska-Skurczynska M, Lim R, Roman L, Shparyk Y, Bondarenko I, Jonker DJ, Sun Y, De la Cruz JA, Williams JA, Korytowsky B, Christensen JG, Lin X, Tursi JM, Lechuga MJ, Van Cutsem E. Fluorouracil, leucovorin, and irinotecan plus either sunitinib or placebo in metastatic colorectal cancer: a randomized, phase III trial. J Clin Oncol. 2013 Apr 1;31(10):1341-7. Epub 2013 Jan 28. link to original article contains verified protocol PubMed

FOLFIRI & Bevacizumab

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

Variant #1, indefinite

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

Chemotherapy

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

14-day cycles

Variant #2, lower dose leucovorin

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

Chemotherapy

• 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)
• Folinic acid (Leucovorin) 200 mg/m² IV over 120 minutes once on day 1
• Irinotecan (Camptosar) 180 mg/m² IV once on day 1
• Bevacizumab (Avastin) 5 mg/kg IV once on day 1

14-day cycle for 9 cycles

Subsequent treatment

• Nordic ACT: Bevacizumab versus Erlotinib & Bevacizumab maintenance

References

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

FOLFIRI & Bevacizumab (L-Leucovorin)

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

Regimen

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

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

Chemotherapy

• 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
• Bevacizumab (Avastin) 5 mg/kg IV over 30 minutes once on day 1

14-day cycle for up to 12 cycles

Subsequent treatment

• Fluorouracil, leucovorin, bevacizumab maintenance

References

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

FOLFIRINOX

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

Regimen

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

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

Chemotherapy

• Fluorouracil (5-FU) 1600 mg/m²/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 3200 mg/m²)
• Folinic acid (Leucovorin) 200 mg/m² IV once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1
• Irinotecan (Camptosar) 165 mg/m² IV once on day 1

14-day cycles

References

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

FOLFIRINOX & Bevacizumab (L-Leucovorin)

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

Regimen

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

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

Chemotherapy

• 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)
• Levoleucovorin (Fusilev) 200 mg/m² IV over 2 hours once on day 1, given third, with oxaliplatin
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1, given third, with levoleucovorin
• Irinotecan (Camptosar) 165 mg/m² IV over 60 minutes once on day 1, given second
• Bevacizumab (Avastin) 5 mg/kg IV over 30 minutes once on day 1, given first

14-day cycle for up to 12 cycles

Subsequent treatment

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

References

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

FOLFOX2

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FOLFOX2: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

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

Chemotherapy

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

14-day cycles

References

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

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study	Evidence	Comparator	Comparative Efficacy
de Gramont et al. 2000	Phase III (E-esc)	5-FU & Folinic acid	Superior PFS
Goldberg et al. 2003 (NCCTG N9741)	Phase III (E-RT-switch-ic)	1. IFL	Superior OS
		2. IROX	Did not meet primary endpoint of TTP
Tournigand et al. 2006 (OPTIMOX1)	Phase III (C)	FOLFOX7/LV5FU2	Did not meet primary endpoint of DDC
Cassidy et al. 2008 (NO16966)	Phase III (C)	1. FOLFOX4 & Bevacizumab	Not reported
		2. XELOX 3. XELOX & Bevacizumab	Non-inferior PFS
Saltz et al. 2008 (NO16966)	Phase III (C)	1. FOLFOX4 & Bevacizumab 2. XELOX & Bevacizumab	Inferior PFS
		3. XELOX	Not reported
Bokemeyer et al. 2008 (OPUS)	Randomized Phase II (C)	FOLFOX4 & Cetuximab	Inferior OS (*)
Douillard et al. 2010 (PRIME)	Phase III (C)	FOLFOX4 & Panitumumab	Seems to have superior PFS (*)
Hecht et al. 2011	Phase III (C)	FOLFOX4 & Vatalanib	Did not meet primary endpoint of PFS
Hoff et al. 2012 (HORIZON II)	Phase III (C)	1. CAPOX & Cediranib 2. FOLFOX4 & Cediranib 3. mFOLFOX6 & Cediranib	Seems to have inferior PFS
Passardi et al. 2015 (ITACa)	Phase III (C)	FOLFOX4 & Bevacizumab	Did not meet primary endpoint of PFS

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

Chemotherapy

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

14-day cycles

References

1. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. link to original article contains verified protocol PubMed
2. NCCTG N9741: Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. Epub 2003 Dec 9. link to original article contains verified protocol PubMed
3. OPTIMOX1: Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, Mineur L, Carola E, Etienne PL, Rivera F, Chirivella I, Perez-Staub N, Louvet C, André T, Tabah-Fisch I, de Gramont A. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006 Jan 20;24(3):394-400. link to original article contains verified protocol PubMed
4. Retrospective: Goldberg RM, Tabah-Fisch I, Bleiberg H, de Gramont A, Tournigand C, Andre T, Rothenberg ML, Green E, Sargent DJ. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol. 2006 Sep 1;24(25):4085-91. link to original article PubMed content property of HemOnc.org
5. NO16966: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. link to original article PubMed
   1. Update: Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. link to original article refers to de Gramont et al. 2000 for protocol PubMed
   2. Update: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64. Epub 2011 Jun 14. link to original article link to PMC article PubMed
6. OPUS: Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29. link to original article contains verified protocol PubMed
   1. Update: Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011 Jul;22(7):1535-46. Epub 2011 Jan 12. link to original article PubMed
   2. Pooled Update: Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article PubMed
7. PRIME: Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010 Nov 1;28(31):4697-705. Epub 2010 Oct 4. link to original article PubMed
   1. Biomarker analysis: Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013 Sep 12;369(11):1023-34. link to original article PubMed
   2. Update: Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jul;25(7):1346-55. Epub 2014 Apr 8. link to original article PubMed
8. Hecht JR, Trarbach T, Hainsworth JD, Major P, Jäger E, Wolff RA, Lloyd-Salvant K, Bodoky G, Pendergrass K, Berg W, Chen BL, Jalava T, Meinhardt G, Laurent D, Lebwohl D, Kerr D. Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):1997-2003. Epub 2011 Apr 4. link to original article contains verified protocol PubMed
9. HORIZON II: Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012 Oct 10;30(29):3596-603. Epub 2012 Sep 10. link to original article contains verified protocol PubMed
10. ITACa: Passardi A, Nanni O, Tassinari D, Turci D, Cavanna L, Fontana A, Ruscelli S, Mucciarini C, Lorusso V, Ragazzini A, Frassineti GL, Amadori D. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015 Jun;26(6):1201-7. Epub 2015 Mar 3. link to original article refers to de Gramont et al. 2000 PubMed

FOLFOX4 (L-Leucovorin)

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FOLFOX4: L-FOLinic acid, Fluorouracil, OXaliplatin

Regimen

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

Chemotherapy

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

14-day cycles

References

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

mFOLFOX6

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

Example orders

• Example orders for mFOLFOX 6 in colon cancer

Variant #1, LCV 200 mg/m²

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

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

Chemotherapy

• 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)
• Folinic acid (Leucovorin) 200 mg/m² IV once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1

14-day cycles

Variant #2, LCV 350 mg/m²

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

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

Chemotherapy

• 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)
• Folinic acid (Leucovorin) 350 mg/m² IV over 2 hours once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1

14-day cycles

Variant #3, LCV 400 mg/m²

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

Chemotherapy

• 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)
• Folinic acid (Leucovorin) 400 mg/m² IV once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1

14-day cycles

References

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

mFOLFOX6 (L-Leucovorin)

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mFOLFOX6: modified FOLinic acid, Fluorouracil, OXaliplatin

Regimen

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

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

Chemotherapy

• 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)
• Levoleucovorin (Fusilev) 175 mg IV over 2 hours once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1

14-day cycles

References

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

FOLFOX 7/sLV5FU2

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

Regimen

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

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

Chemotherapy, FOLFOX 7 portion

• Fluorouracil (5-FU) 2400 mg/m² IV continuous infusion over 46 hours, started on day 1, given third
• Folinic acid (Leucovorin) 400 mg/m² IV over 2 hours once on day 1, given first
• 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)
• Folinic acid (Leucovorin) 400 mg/m² IV over 2 hours once on day 1, given first

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

References

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

FOLFOX 7/sLV5FU2 (L-Leucovorin)

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

Regimen

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

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

Chemotherapy, FOLFOX 7 portion

• Fluorouracil (5-FU) 2400 mg/m² IV continuous infusion over 46 hours, started on day 1, given third
• Levoleucovorin (Fusilev) 200 mg/m² IV over 2 hours once on day 1, given first
• 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

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

mFOLFOX7

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mFOLFOX7: modified FOLinic acid, Fluorouracil, OXaliplatin

Regimen

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

Chemotherapy, FOLFOX 7 portion

• Fluorouracil (5-FU) 3000 mg/m² IV continuous infusion over 46 hours, started on day 1, given second
• Folinic acid (Leucovorin) 400 mg/m² IV over 2 hours once on day 1, given first, with oxaliplatin
• 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 versus no further treatment

References

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

mFOLFOX7 (L-Leucovorin)

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mFOLFOX7: modified L-FOLinic acid, Fluorouracil, OXaliplatin

Regimen

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

Chemotherapy, FOLFOX 7 portion

• Fluorouracil (5-FU) 3000 mg/m² IV continuous infusion over 46 hours, started on day 1, given second
• Levoleucovorin (Fusilev) 200 mg/m² IV over 2 hours once on day 1, given first, with oxaliplatin
• 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 versus no further treatment

References

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

FOLFOX4 & Bevacizumab

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

Regimen

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

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus once per day on days 1 & 2, then 600 mg/m² IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m²)
• Folinic acid (Leucovorin) 200 mg/m² IV over 2 hours once per day on days 1 & 2
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1
• Bevacizumab (Avastin) 5 mg/kg IV once on day 1, given first
  • Infusion times are 2 hours for cycle 1, 1 hour for cycle 2, then 30 minutes for cycles 3 and later

14-day cycles

References

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

mFOLFOX6 & Bevacizumab

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

Example orders

• Example orders for mFOLFOX 6 & Bevacizumab (Avastin) in colon cancer

Variant #1

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

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

Chemotherapy

• 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)
• Folinic acid (Leucovorin) 400 mg/m² IV over 2 hours once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1
• Bevacizumab (Avastin) 5 mg/kg IV once on day 1

14-day cycles

Variant #2, lower dose leucovorin

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

Chemotherapy

• 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)
• Folinic acid (Leucovorin) 200 mg/m² IV over 120 minutes once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1
• Bevacizumab (Avastin) 5 mg/kg IV once on day 1

14-day cycle for 9 cycles

Subsequent treatment

• Nordic ACT: Bevacizumab versus Erlotinib & Bevacizumab maintenance

References

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

mFOLFOX6 & Bevacizumab (L-Leucovorin)

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

Regimen

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

Chemotherapy

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

14-day cycles

References

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

FUIRI

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FUIRI: 5-FU & IRInotecan

Regimen

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

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

Chemotherapy

• Folinic acid (Leucovorin) 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

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

FUOX

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FUOX: 5-FU & OXaliplatin

Regimen

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

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

Chemotherapy

• 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

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

IFL

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

Variant #1, q3wk

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

Chemotherapy

• Irinotecan (Camptosar) 135 mg/m² IV once on day 1
• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Folinic acid (Leucovorin) 200 mg/m² IV once on day 1

21-day cycles

Variant #2, 4 out of 6 weeks

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

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

Chemotherapy

• 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
• Folinic acid (Leucovorin) 20 mg/m² IV bolus once per day on days 1, 8, 15, 22

42-day cycles

References

1. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL; Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000 Sep 28;343(13):905-14. link to original article contains verified protocol PubMed
2. NCCTG N9741: Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1;22(1):23-30. Epub 2003 Dec 9. link to original article contains verified protocol PubMed
3. AVF2107g: Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. link to original article contains verified protocol PubMed
   1. Update: Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, Hambleton J, Novotny WF, Kabbinavar F. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol. 2005 May 20;23(15):3502-8. link to original article PubMed
4. BICC-C: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. link to original article contains verified protocol PubMed
   1. Update: Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008 Feb 1;26(4):689-90. link to original article PubMed
5. Stathopoulos GP, Batziou C, Trafalis D, Koutantos J, Batzios S, Stathopoulos J, Legakis J, Armakolas A. Treatment of colorectal cancer with and without bevacizumab: a phase III study. Oncology. 2010;78(5-6):376-81. Epub 2010 Aug 27. link to original article contains verified protocol PubMed
6. ARTIST: Guan ZZ, Xu JM, Luo RC, Feng FY, Wang LW, Shen L, Yu SY, Ba Y, Liang J, Wang D, Qin SK, Wang JJ, He J, Qi C, Xu RH. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer. 2011 Oct;30(10):682-9. link to PMC article contains verified protocol PubMed

IFL & Bevacizumab

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

Variant #1, IFL

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

Chemotherapy

• 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
• Folinic acid (Leucovorin) 20 mg/m² IV bolus once per day on days 1 & 8
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycles

Variant #2, mIFL

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

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

Chemotherapy

• 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
• Folinic acid (Leucovorin) 20 mg/m² IV bolus once per day on days 1, 8, 15, 22
• Bevacizumab (Avastin) 5 mg/kg IV once per day on days 1, 15, 29

42-day cycles

References

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

Irinotecan monotherapy

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Example orders

• Example orders for Irinotecan (Camptosar) in colon cancer

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Saltz et al. 2000	Phase III (E-de-esc)	1. 5-FU & LV	Did not meet primary endpoint of PFS
		2. IFL	Might have inferior OS

Chemotherapy

• Irinotecan (Camptosar) 125 mg/m² IV over 90 minutes once per day on days 1, 8, 15, 22

42-day cycles

References

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

IRIS & Bevacizumab

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IRIS & Bevacizumab: IRInotecan, S-1, Bevacizumab

Variant #1, q3wk

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

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)
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1, given first

21-day cycles

Variant #2, q4wk

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

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)
• Bevacizumab (Avastin) 5 mg/kg IV once per day on days 1 & 15, given first

28-day cycles

References

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

IROX

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IROX: IRinotecan & OXaliplatin

Regimen

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

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

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

Nordic FLOX

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FLOX: Fluorouracil, Leucovorin, OXaliplatin

Example orders

• Example orders for FLOX in colon cancer

Regimen

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

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

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV bolus once per day on days 1 & 2, given second
• Folinic acid (Leucovorin) 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 8 cycles (NORDIC-VII) or indefinitely (Sørbye et al. 2004)

References

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

OXAFAFU

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

Regimen

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

Chemotherapy

• Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1
• Folinic acid (Leucovorin) 250 mg/m² IV once on day 2
• Fluorouracil (5-FU) 850 mg/m² IV once on day 2

14-day cycles

References

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

S-1 monotherapy

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Regimen

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

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

Chemotherapy

• Tegafur, gimeracil, oteracil (S-1) 30 mg/m² PO twice per day on days 1 to 14

21-day cycles

References

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

SOX

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SOX: S-1 & OXaliplatin

Regimen

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

Chemotherapy

• 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

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

SOX & Bevacizumab

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SOX & Bevacizumab: S-1, OXaliplatin, Bevacizumab

Regimen

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

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

Chemotherapy

• Tegafur, gimeracil, oteracil (S-1) as follows:
  • BSA less than 1.25 m²: 40 mg PO twice per day on days 1 to 14 (see note)
  • BSA between 1.25 and 1.5 m²: 50 mg PO twice per day on days 1 to 14 (see note)
  • BSA 1.5 m² or more: 60 mg PO twice per day on days 1 to 14 (see note)
• Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1, given second
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1, given first

21-day cycles

References

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

Maintenance after first-line therapy

Bevacizumab monotherapy

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Regimen

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

Preceding treatment

• Nordic ACT: FOLFIRI & Bevacizumab x 9 or mFOLFOX6 & Bevacizumab x 9 or XELIRI & Bevacizumab x 6 or XELOX & Bevacizumab x 6
• AIO KRK 0207 & OPTIMOX3: Bevacizumab-containing chemotherapy

Chemotherapy

• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycles

References

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

Capecitabine monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Hong et al. 2012	Non-randomized portion of RCT
Luo et al. 2016	Phase III (E-esc)	Observation	Superior PFS

Preceding treatment

• Hong et al. 2012: CapeOX x 9
• Luo et al. 2016: FOLFOX or XELOX

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

21-day cycles

References

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

Capecitabine & Bevacizumab

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CAP-B: CAPecitabine & Bevacizumab

Regimen

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

Preceding treatment

• CAPOX-B x 6

Chemotherapy

• Capecitabine (Xeloda) 625 mg/m² PO twice per day
• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

21-day cycles

References

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

Observation

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Simkens et al. 2015 (CAIRO3)	Phase III (C)	CAP-B	Inferior PFS2
Luo et al. 2016	Phase III (C)	Capecitabine	Inferior PFS
Aparicio et al. 2018 (PRODIGE 9)	Phase III (C)	Bevacizumab	Did not meet primary endpoint of TCD

No further treatment after first-line induction.

Preceding treatment

• CAIRO3: CAPOX-B x 6
• Luo et al. 2016: FOLFOX or XELOX

References

1. CAIRO3: Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoeven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, Honkoop AH, Mol L, Punt CJ, Koopman M. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015 May 9;385(9980):1843-52. Epub 2015 Apr 7. link to original article contains verified protocol PubMed
   1. Update: Goey KKH, Elias SG, van Tinteren H, Laclé MM, Willems SM, Offerhaus GJA, de Leng WWJ, Strengman E, Ten Tije AJ, Creemers GM, van der Velden A, de Jongh FE, Erdkamp FLG, Tanis BC, Punt CJA, Koopman M. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann Oncol. 2017 Sep 1;28(9):2128-2134. link to original article PubMed
2. Luo HY, Li YH, Wang W, Wang ZQ, Yuan X, Ma D, Wang FH, Zhang DS, Lin DR, Lin YC, Jia J, Hu XH, Peng JW, Xu RH. Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety. Ann Oncol. 2016 Jun;27(6):1074-81. Epub 2016 Mar 2. link to original article contains verified protocol PubMed
3. PRODIGE 9: Aparicio T, Ghiringhelli F, Boige V, Le Malicot K, Taieb J, Bouché O, Phelip JM, François E, Borel C, Faroux R, Dahan L, Jacquot S, Genet D, Khemissa F, Suc E, Desseigne F, Texereau P, Lepage C, Bennouna J; PRODIGE 9 Investigators. Bevacizumab maintenance versus no maintenance during chemotherapy-free intervals in metastatic colorectal cancer: a randomized phase III trial (PRODIGE 9). J Clin Oncol. 2018 Mar 1;36(7):674-681. Epub 2018 Jan 18. link to original article PubMed

S-1 monotherapy

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Regimen

Study	Evidence
Hong et al. 2012	Non-randomized portion of RCT

Preceding treatment

• 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

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

Advanced or metastatic disease, second-line therapy

CapeOx

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CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda, OXaliplatin

Example orders

• Example orders for CapeOx (XELOX) in colon cancer

Regimen

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

Preceding treatment

• CAIRO: 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

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

CAPIRI

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

Variant #1, "standard"

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

Chemotherapy

• 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

Variant #2, "modified"

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

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

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

CAPIRI-Bev

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

Regimen

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

Chemotherapy

• 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
• Bevacizumab (Avastin) 7.5 mg/kg IV over 30 to 90 minutes once on day 1

21-day cycles

References

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

Fluorouracil monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Rougier et al. 1998 (V302)	Phase III (C)	Irinotecan	Seems to have inferior OS

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

Chemotherapy

• Fluorouracil (5-FU) 250 to 300 mg/m²/day IV continuous infusion

Continued indefinitely

References

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

FOLFIRI

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Example orders

• Example orders for FOLFIRI in colon cancer

Variant #1, lower-dose leucovorin

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

Chemotherapy

• Folinic acid (Leucovorin) 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

Variant #2, higher-dose leucovorin

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

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

Chemotherapy

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

14-day cycles

Subsequent treatment

• Tournigand et al. 2003, upon progression: mFOLFOX6

References

1. Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15;22(2):229-37. Epub 2003 Dec 2. link to original article contains verified protocol PubMed
2. 20050181: Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010 Nov 1;28(31):4706-13. Epub 2010 Oct 4. link to original article contains verified protocol PubMed
   1. Update: Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tian Y, Sidhu R. Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jan;25(1):107-16. Erratum in: Ann Oncol. 2014 Mar;25(3):757. link to original article PubMed
3. FFCD 2000-05: Ducreux M, Malka D, Mendiboure J, Etienne PL, Texereau P, Auby D, Rougier P, Gasmi M, Castaing M, Abbas M, Michel P, Gargot D, Azzedine A, Lombard-Bohas C, Geoffroy P, Denis B, Pignon JP, Bedenne L, Bouché O; Fédération Francophone de Cancérologie Digestive (FFCD) 2000–05 Collaborative Group. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol. 2011 Oct;12(11):1032-44. Epub 2011 Sep 6. link to original article contains protocol PubMed
4. VELOUR: Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012 Oct 1;30(28):3499-506. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Tabernero J, Van Cutsem E, Lakomý R, Prausová J, Ruff P, van Hazel GA, Moiseyenko VM, Ferry DR, McKendrick JJ, Soussan-Lazard K, Chevalier S, Allegra CJ. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014 Jan;50(2):320-31. link to original article PubMed
   2. Subgroup analysis: Ruff P, Van Cutsem E, Lakomy R, Prausova J, van Hazel GA, Moiseyenko VM, Soussan-Lazard K, Dochy E, Magherini E, Macarulla T, Papamichael D. Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: An age-based analysis from the randomized placebo-controlled phase III VELOUR trial. J Geriatr Oncol. 2018 Jan;9(1):32-39. Epub 2017 Aug 12. link to original article PubMed
5. BEBYP: Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-30. Epub 2015 Jan 18. link to original article does not contain protocol PubMed
6. RAISE: Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F; RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 May;16(5):499-508. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Obermannová R, Van Cutsem E, Yoshino T, Bodoky G, Prausová J, Garcia-Carbonero R, Ciuleanu T, Garcia Alfonso P, Portnoy D, Cohn A, Yamazaki K, Clingan P, Lonardi S, Kim TW, Yang L, Nasroulah F, Tabernero J. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016 Nov;27(11):2082-2090. Epub 2016 Aug 29. link to original article link to PMC article PubMed
7. SMC 2009-11-017: Lim SH, Kim TW, Hong YS, Han SW, Lee KH, Kang HJ, Hwang IG, Lee JY, Kim HS, Kim ST, Lee J, Park JO, Park SH, Park YS, Lim HY, Jung SH, Kang WK. A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer. Br J Cancer. 2015 Nov 17;113(10):1421-6. Epub 2015 Oct 27. link to original article contains verified protocol link to PMC article PubMed
8. AXEPT: Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2018 May;19(5):660-671. Epub 2018 Mar 16. link to original article contains verified protocol PubMed

FOLFIRI (L-Leucovorin)

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FOLFIRI: L-FOLinic acid, Fluorouracil, IRInotecan

Regimen

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

Chemotherapy

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

14-day cycles

Subsequent treatment

• Tournigand et al. 2003, upon progression: mFOLFOX6

References

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

FOLFIRI & Bevacizumab

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

Regimen

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

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

Chemotherapy

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

14-day cycles

References

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

FOLFIRI & Bevacizumab (L-Leucovorin)

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

Variant #1, 200/2800/150/5

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

Chemotherapy

• Levoleucovorin (Fusilev) 200 mg/m² IV over 2 hours once on day 1, given second, with irinotecan
• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours, given third (total dose per cycle: 2800 mg/m²)
• Irinotecan (Camptosar) 150 mg/m² IV over 90 minutes once on day 1, given second, with levoleucovorin
• Bevacizumab (Avastin) 5 mg/kg IV over 30 minutes once on day 1, given first

14-day cycles

Variant #2, 200/2800/180/5

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

Chemotherapy

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

14-day cycles

References

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

FOLFIRI & Ramucirumab

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

Regimen

FDA-recommended dose

Study	Evidence	Comparator	Comparative Efficacy
Tabernero et al. 2015 (RAISE)	Phase III (E-RT-esc)	FOLFIRI	Seems to have superior OS

Chemotherapy

• Folinic acid (Leucovorin) 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
• Ramucirumab (Cyramza) 8 mg/kg IV over 60 minutes once on day 1, given first

14-day cycles

References

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

FOLFIRI & Ziv-aflibercept

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

Regimen

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

Chemotherapy

• Folinic acid (Leucovorin) 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
• Ziv-aflibercept (Zaltrap) 4 mg/kg IV over 60 minutes once on day 1, given first

Supportive medications

• "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

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

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

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

Chemotherapy

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

14-day cycles

References

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

mFOLFOX6

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mFOLFOX6: modified FOLinic acid, Fluorouracil, OXaliplatin

Example orders

• Example orders for mFOLFOX 6 in colon cancer

Regimen

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

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

Chemotherapy

• 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)
• Folinic acid (Leucovorin) 400 mg/m² IV once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1

14-day cycles

References

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

mFOLFOX6 & Bevacizumab

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

Regimen

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

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

Chemotherapy

• 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)
• Folinic acid (Leucovorin) 400 mg/m² IV once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1
• Bevacizumab (Avastin) 5 mg/kg IV once on day 1

14-day cycles

References

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

Irinotecan monotherapy

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Example orders

• Example orders for Irinotecan (Camptosar) in colon cancer

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

Study	Evidence
Rothenberg et al. 1999	Phase II (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

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

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

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

Chemotherapy

• Irinotecan (Camptosar) 125 mg/m² IV over 90 minutes once per day on days 1, 8, 15, 22

42-day cycles

Variant #3, 250 mg/m² q3wk

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

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

Chemotherapy

• Irinotecan (Camptosar) 250 mg/m² IV over 90 minutes once on day 1

21-day cycles

Variant #4, 300 mg/m² q3wk

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

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

Chemotherapy

• Irinotecan (Camptosar) 300 mg/m² IV over 90 minutes once on day 1

21-day cycles

Variant #5, 350 mg/m² q3wk

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

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

Preceding treatment

• CAIRO: Capecitabine, with progression

Chemotherapy

• Irinotecan (Camptosar) 350 mg/m² IV over 90 minutes once on day 1

Supportive medications

• (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: CapeOx

References

1. Rothenberg ML, Eckardt JR, Kuhn JG, Burris HA 3rd, Nelson J, Hilsenbeck SG, Rodriguez GI, Thurman AM, Smith LS, Eckhardt SG, Weiss GR, Elfring GL, Rinaldi DA, Schaaf LJ, Von Hoff DD. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol. 1996 Apr;14(4):1128-35. link to original article contains protocol PubMed
2. Rougier P, Bugat R, Douillard JY, Culine S, Suc E, Brunet P, Becouarn Y, Ychou M, Marty M, Extra JM, Bonneterre J, Adenis A, Seitz JF, Ganem G, Namer M, Conroy T, Negrier S, Merrouche Y, Burki F, Mousseau M, Herait P, Mahjoubi M. Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol. 1997 Jan;15(1):251-60. link to original article PubMed
3. Pitot HC, Wender DB, O'Connell MJ, Schroeder G, Goldberg RM, Rubin J, Mailliard JA, Knost JA, Ghosh C, Kirschling RJ, Levitt R, Windschitl HE. Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol. 1997 Aug;15(8):2910-9. link to original article contains protocol PubMed
4. Rothenberg ML, Cox JV, DeVore RF, Hainsworth JD, Pazdur R, Rivkin SE, Macdonald JS, Geyer CE Jr, Sandbach J, Wolf DL, Mohrland JS, Elfring GL, Miller LL, Von Hoff DD. A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer. 1999 Feb 15;85(4):786-95. link to original article contains protocol PubMed
5. V302: Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Awad L, Herait P, Jacques C. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1407-12. Erratum in: Lancet 1998 Nov 14;352(9140):1634. link to original article contains protocol PubMed
6. Fuchs CS, Moore MR, Harker G, Villa L, Rinaldi D, Hecht JR. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003 Mar 1;21(5):807-14. link to original article contains verified protocol PubMed
7. Lal R, Dickson J, Cunningham D, Chau I, Norman AR, Ross PJ, Topham C, Middleton G, Hill M, Oates J. A randomized trial comparing defined-duration with continuous irinotecan until disease progression in fluoropyrimidine and thymidylate synthase inhibitor-resistant advanced colorectal cancer. J Clin Oncol. 2004 Aug 1;22(15):3023-31. link to original article contains protocol PubMed
8. CAIRO: Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article contains verified protocol PubMed
9. EPIC: Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kröning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008 May 10;26(14):2311-9. Epub 2008 Apr 7. link to original article contains verified protocol PubMed
10. Haller DG, Rothenberg ML, Wong AO, Koralewski PM, Miller WH Jr, Bodoky G, Habboubi N, Garay C, Olivatto LO. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008 Oct 1;26(28):4544-50. link to original article contains verified protocol PubMed
11. N9841: Kim GP, Sargent DJ, Mahoney MR, Rowland KM Jr, Philip PA, Mitchell E, Mathews AP, Fitch TR, Goldberg RM, Alberts SR, Pitot HC. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol. 2009 Jun 10;27(17):2848-54. Epub 2009 Apr 20. link to original article link to PMC article contains verified protocol PubMed

IRIS

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IRIS: IRInotecan & S-1

Regimen

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

Note: reported efficacy is based on the 2014 update.

Chemotherapy

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

28-day cycles

References

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

IROX

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IROX: IRinotecan & OXaliplatin

Regimen

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

Chemotherapy

• 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

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

Advanced or metastatic disease, third-line therapy

CapeOx

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CapeOX: Capecitabine, OXaliplatin

Example orders

• Example orders for CapeOx (XELOX) in colon cancer

Regimen

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

Preceding treatment

• 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

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

FOLFIRI

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FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Example orders

• Example orders for FOLFIRI in colon cancer

Regimen

Study	Evidence
André et al. 1999	Non-randomized

Chemotherapy

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

14-day cycles

References

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

Regorafenib monotherapy

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Regimen

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

Chemotherapy

• Regorafenib (Stivarga) 160 mg PO once per day on days 1 to 21

28-day cycles

References

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

Advanced or metastatic disease, subsequent lines of therapy

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

Best supportive care

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Cunningham et al. 1998 (V301)	Phase III (C)	Irinotecan	Inferior OS
Van Cutsem et al. 2007 (20020408)	Phase III (C)	Panitumumab	Inferior PFS
Jonker et al. 2007 (NCIC CTG CO.17)	Phase III (C)	Cetuximab	Inferior OS

No treatment except for supportive care.

References

1. V301: Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1413-8. link to original article contains verified protocol PubMed
2. 20020408: Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1;25(13):1658-64. link to original article contains verified protocol PubMed
3. NCIC CTG CO.17: Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007 Nov 15;357(20):2040-8. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008 Oct 23;359(17):1757-65. link to original article PubMed
   2. Subgroup analysis: Asmis TR, Powell E, Karapetis CS, Jonker DJ, Tu D, Jeffery M, Pavlakis N, Gibbs P, Zhu L, Dueck DA, Whittom R, Langer C, O'Callaghan CJ. Comorbidity, age and overall survival in cetuximab-treated patients with advanced colorectal cancer (ACRC)--results from NCIC CTG CO.17: a phase III trial of cetuximab versus best supportive care. Ann Oncol. 2011 Jan;22(1):118-26. Epub 2010 Jul 5. link to original article contains verified protocol PubMed

Fluorouracil monotherapy

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Regimen

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

Chemotherapy

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

21-day cycles

References

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

FOLFOX4

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FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

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

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

Chemotherapy

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

14-day cycles

References

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

FOLFOX4 (L-Leucovorin)

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FOLFOX4: L-FOLinic acid, Fluorouracil, OXaliplatin

Regimen

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

Note: these patients had not previously received oxaliplatin.

Chemotherapy

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

14-day cycles

References

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

FOLFOX4 & Bevacizumab

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

Regimen

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

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus once per day on days 1 & 2, then 600 mg/m² IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m²)
• Folinic acid (Leucovorin) 200 mg/m² IV over 2 hours once per day on days 1 & 2
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1
• Bevacizumab (Avastin) 10 mg/kg IV over 30 to 90 minutes once on day 1

14-day cycles

References

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

FULV & Bevacizumab

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

Regimen

Study	Evidence
Chen et al. 2006 (TRC-301)	Phase II (RT)

Chemotherapy

• Fluorouracil (5-FU)
• Folinic acid (Leucovorin)
• Bevacizumab (Avastin)

References

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

Irinotecan monotherapy

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Example orders

• Example orders for Irinotecan (Camptosar) in colon cancer

Regimen

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

Chemotherapy

• Irinotecan (Camptosar) 350 mg/m² IV over 90 minutes once on day 1

Supportive medications

• (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

1. V301: Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1413-8. link to original article contains verified protocol PubMed

Nivolumab monotherapy

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Regimen

Study	Evidence
Overman et al. 2017 (CheckMate 142)	Phase II (RT)

Biomarker eligibility criteria

dMMR or MSI-H colorectal cancer.

Immunotherapy

• Nivolumab (Opdivo) 3 mg/kg IV once on day 1

14-day cycles

References

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

Pembrolizumab monotherapy

Pembrolizumab (Keytruda) for unresectable or metastatic colon cancer

Placebo

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Rao et al. 2004	Phase III (C)	Tipifarnib	Did not meet primary endpoint of OS
Yoshino et al. 2012	Randomized Phase II (C)	Trifluridine and tipiracil	Inferior OS
Grothey et al. 2013 (CORRECT)	Phase III (C)	Regorafenib	Inferior OS
Li et al. 2015 (CONCUR)	Phase III (C)	Regorafenib	Inferior OS
Mayer et al. 2015 (RECOURSE)	Phase III (C)	Trifluridine and tipiracil	Inferior OS
Hickish et al. 2017 (2014-PT026)	Phase III (C)	MABp1	Inferior primary endpoint
Xu et al. 2017 (TERRA)	Phase III (C)	Trifluridine and tipiracil	Seems to have inferior OS
Jonker et al. 2018 (NCIC CTG CO.23)	Phase III (C)	Napabucasin	Did not meet primary endpoint of OS
Li et al. 2018 (FRESCO)	Phase III (C)	Fruquintinib	Inferior OS
Van Cutsem et al. 2018 (LUME-Colon 1)	Phase III (C)	Nintedanib	Inferior PFS

No active antineoplastic treatment.

References

1. Rao S, Cunningham D, de Gramont A, Scheithauer W, Smakal M, Humblet Y, Kourteva G, Iveson T, Andre T, Dostalova J, Illes A, Belly R, Perez-Ruixo JJ, Park YC, Palmer PA. Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. J Clin Oncol. 2004 Oct 1;22(19):3950-7. link to original article PubMed
2. Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, Tsuji A, Yamaguchi K, Muro K, Sugimoto N, Tsuji Y, Moriwaki T, Esaki T, Hamada C, Tanase T, Ohtsu A. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2012 Oct;13(10):993-1001. Epub 2012 Aug 28. link to original article contains protocol PubMed
3. 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. link to original article contains verified protocol PubMed
   1. Dataset: Project Data Sphere
4. CONCUR: Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L, Yeh KH, Bi F, Cheng Y, Le AT, Lin JK, Liu T, Ma D, Kappeler C, Kalmus J, Kim TW; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):619-29. Epub 2015 May 13. link to original article PubMed
5. RECOURSE: Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14;372(20):1909-19. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Van Cutsem E, Mayer RJ, Laurent S, Winkler R, Grávalos C, Benavides M, Longo-Munoz F, Portales F, Ciardiello F, Siena S, Yamaguchi K, Muro K, Denda T, Tsuji Y, Makris L, Loehrer P, Lenz HJ, Ohtsu A; RECOURSE Study Group. The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer. Eur J Cancer. 2018 Feb;90:63-72. Epub 2017 Dec 21. link to SD article PubMed
6. 2014-PT026: Hickish T, Andre T, Wyrwicz L, Saunders M, Sarosiek T, Kocsis J, Nemecek R, Rogowski W, Lesniewski-Kmak K, Petruzelka L, Apte RN, Mohanty P, Stecher M, Simard J, de Gramont A. MABp1 as a novel antibody treatment for advanced colorectal cancer: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2017 Feb;18(2):192-201. Epub 2017 Jan 14. link to original article PubMed
7. TERRA: Xu J, Kim TW, Shen L, Sriuranpong V, Pan H, Xu R, Guo W, Han SW, Liu T, Park YS, Shi C, Bai Y, Bi F, Ahn JB, Qin S, Li Q, Wu C, Ma D, Lin D, Li J. Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: The TERRA study. J Clin Oncol. 2018 Feb 1;36(4):350-358. Epub 2017 Dec 7. link to original article contains verified protocol PubMed
8. NCIC CTC CO.23: Jonker DJ, Nott L, Yoshino T, Gill S, Shapiro J, Ohtsu A, Zalcberg J, Vickers MM, Wei AC, Gao Y, Tebbutt NC, Markman B, Price T, Esaki T, Koski S, Hitron M, Li W, Li Y, Magoski NM, Li CJ, Simes J, Tu D, O'Callaghan CJ. Napabucasin versus placebo in refractory advanced colorectal cancer: a randomised phase 3 trial. Lancet Gastroenterol Hepatol. 2018 Apr;3(4):263-270. Epub 2018 Feb 1. link to original article PubMed
9. 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 PubMed
10. LUME-Colon 1: Van Cutsem E, Yoshino T, Lenz HJ, Lonardi S, Falcone A, Limón ML, Saunders M, Sobrero A, Park YS, Ferreiro R, Hong YS, Tomasek J, Taniguchi H, Ciardiello F, Stoehr J, Oum'Hamed Z, Vlassak S, Studeny M, Argiles G. Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study. Ann Oncol. 2018 Sep 1;29(9):1955-1963. link to original article link to PMC article PubMed

Regorafenib monotherapy

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Variant #1, Standard Dosing

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

Chemotherapy

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

28-day cycles

Variant #2, Dose-escalation

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

Chemotherapy

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

Supportive medications

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

28-day cycles

References

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

Trifluridine and tipiracil monotherapy

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Regimen

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

Chemotherapy

• Trifluridine and tipiracil (Lonsurf) 35 mg/m² PO twice per day, used within 1 hour after the morning and evening meals on days 1 to 5, 8 to 12

28-day cycles

References

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