Colorectal cancer

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 Travis Zack, MD, PhD
University of California San Francisco
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Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!

96 regimens on this page
157 variants on this page


Guidelines

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

ASCO

ESMO

French Intergroup

Japanese Society for Cancer of the Colon and Rectum (JSCCR)

NCCN

SIOG

Adjuvant therapy

Capecitabine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kerr et al. 2016 (QUASAR 2) 2005-2010 Phase 3 (C) Capecitabine & Bevacizumab Did not meet primary endpoint of DFS36
Hamaguchi et al. 2017 (JCOG0910) 2010-2013 Phase 3 (C) S-1 Inconclusive whether non-inferior DFS

Preceding treatment

Chemotherapy

21-day cycle for 8 cycles

References

  1. QUASAR 2: Kerr RS, Love S, Segelov E, Johnstone E, Falcon B, Hewett P, Weaver A, Church D, Scudder C, Pearson S, Julier P, Pezzella F, Tomlinson I, Domingo E, Kerr DJ. Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial. Lancet Oncol. 2016 Nov;17(11):1543-1557. Epub 2016 Sep 19. link to original article contains dosing details in abstract PubMed ISRCTN45133151
  2. 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 contains dosing details in abstract PubMed UMIN000003272

CapeOx

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

Example orders

Regimen variant #1, 3 months

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Iveson et al. 2018 (SCOT) 2008-2013 Phase 3 (E-de-esc) 1a. CapeOx x 6 mo
1b. mFOLFOX6 x 6 mo 		Seems to have non-inferior DFS (primary endpoint)
DFS36: 76.7% vs 77.1%
(HR 1.01, 95% CI 0.91-1.11)

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles


Regimen variant #2, 6 months

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pectasides et al. 2015 2005-2008 Phase 3 (E-switch-ic) mFOLFOX6 Did not meet primary endpoint of DFS
Snoeren et al. 2017 (HEPATICA) NR Phase 3 (C) CapeOx & Bevacizumab Did not meet primary endpoint of DFS
Iveson et al. 2018 (SCOT) 2008-2013 Phase 3 (C) 1a. CapeOx x 3 mo
1b. mFOLFOX6 x 3 mo 		Seems to have non-inferior DFS

1Reported efficacy for XELOXA is based on the 2015 update.
Note: HEPATICA enrolled patients with resected colorectal liver metastases.

Preceding treatment

Chemotherapy

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

21-day cycle for 8 cycles

References

  1. 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 dosing details in manuscript link to PMC article PubMed ANZCTR 12610000509066
  2. 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 dosing details in manuscript PubMed
  3. 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 dosing details in manuscript link to PMC article PubMed NCT00749450

mFOLFOX6

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

Example orders

Regimen variant #1, 3 months

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Iveson et al. 2018 (SCOT) 2008-2013 Phase 3 (E-de-esc) 1a. CapeOx x 6 mo
1b. mFOLFOX6 x 6 mo 		Seems to have non-inferior DFS (primary endpoint)
DFS36: 76.7% vs 77.1%
(HR 1.01, 95% CI 0.91-1.11)

Preceding treatment

Chemotherapy

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

14-day cycle for 6 cycles


Regimen variant #2, 6 months (LCV 200 mg/m2)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pectasides et al. 2015 2005-2008 Phase 3 (C) CAPOX Did not meet primary endpoint of DFS

Preceding treatment

Chemotherapy

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

14-day cycle for 12 cycles


Regimen variant #3, 6 months (LCV 350 mg/m2)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Iveson et al. 2018 (SCOT) 2008-2013 Phase 3 (C) 1a. CapeOx x 3 mo
1b. mFOLFOX6 x 3 mo 		Seems to have non-inferior DFS

Preceding treatment

Chemotherapy

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

14-day cycle for 12 cycles

References

  1. 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 dosing details in manuscript link to PMC article PubMed ANZCTR 12610000509066
  2. 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 dosing details in manuscript link to PMC article PubMed NCT00749450
  3. JCOG0603: Kanemitsu Y, Shimizu Y, Mizusawa J, Inaba Y, Hamaguchi T, Shida D, Ohue M, Komori K, Shiomi A, Shiozawa M, Watanabe J, Suto T, Kinugasa Y, Takii Y, Bando H, Kobatake T, Inomata M, Shimada Y, Katayama H, Fukuda H; JCOG Colorectal Cancer Study Group. Hepatectomy Followed by mFOLFOX6 Versus Hepatectomy Alone for Liver-Only Metastatic Colorectal Cancer (JCOG0603): A Phase II or III Randomized Controlled Trial. J Clin Oncol. 2021 Dec 1;39(34):3789-3799. Epub 2021 Sep 14. link to original article PubMed UMIN000000653

mFOLFOX6 (L-Leucovorin)

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

Example orders

Regimen variant #1, 3 months, 175 mg/m2 L-LCV

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Iveson et al. 2018 (SCOT) 2008-2013 Phase 3 (E-de-esc) 1a. CapeOx x 6 mo
1b. mFOLFOX6 x 6 mo 		Seems to have non-inferior DFS (primary endpoint)
DFS36: 76.7% vs 77.1%
(HR 1.01, 95% CI 0.91-1.11)

Preceding treatment

Chemotherapy

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

14-day cycle for 6 cycles


Regimen variant #2, 6 months, 175 mg/m2 L-LCV

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Iveson et al. 2018 (SCOT) 2008-2013 Phase 3 (C) 1a. CapeOx x 3 mo
1b. mFOLFOX6 x 3 mo 		Seems to have non-inferior DFS

Preceding treatment

Chemotherapy

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

14-day cycle for 12 cycles

References

  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 dosing details in manuscript link to PMC article PubMed NCT00749450

FULV

FULV: 5-FU & LeucoVorin (Folinic acid)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ychou et al. 2009 2001-2006 Phase 3 (C) FOLFIRI Did not meet primary endpoint of DFS

Preceding treatment

Chemotherapy

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

14-day cycle for 12 cycles

References

  1. 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 dosing details in abstract PubMed

FULV (L-Leucovorin)

FULV (L-Leucovorin): 5-FU & LevoLeucoVorin

Regimen variant #1, 370/25, weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gray et al. 2000 (QUASAR) 1994-1997 Phase 3 (C) 1. FULV; HDLV Did not meet primary endpoint of OS
2. FULV & Levamisole; LDLV
3. FULV & Levamisole; HDLV 		Might have superior OS

Preceding treatment

Chemotherapy

7-day cycle for 30 cycles


Regimen variant #2, 1850/125, q4wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gray et al. 2000 (QUASAR) 1994-1997 Phase 3 (C) 1. FULV; HDLV Did not meet primary endpoint of OS
2. FULV & Levamisole; LDLV
3. FULV & Levamisole; HDLV 		Might have superior OS

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


Regimen variant #3, q8wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shimada et al. 2014 (JCOG0205) 2003-2006 Phase 3 (C) Tegafur, Uracil, Folinic acid Non-inferior DFS (primary endpoint)

Preceding treatment

  • Surgery with D2/D3 lymph node dissection

Chemotherapy

  • Fluorouracil (5-FU) 500 mg/m2 IV bolus once per day on days 1, 8, 15, 22, 29, 36, given halfway through levoleucovorin infusion
  • Levoleucovorin (Fusilev) 250 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36

8-week cycle for 3 cycles

References

  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 dosing details in manuscript PubMed NCT00005586
  2. QUASAR part 2: Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ; Quasar Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007 Dec 15;370(9604):2020-9. link to original article PubMed NCT00005586
  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 dosing details in manuscript PubMed NCT00190515

Tegafur, Uracil, Folinic acid

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

Regimen variant #1, 300/75

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shimada et al. 2014 (JCOG0205) 2003-2006 Phase 3 (E-switch-ic) FULV (L-Leucovorin) Non-inferior DFS (primary endpoint)
(HR 1.02, 91.3% CI 0.84-1.23)
Hasegawa et al. 2016 2004-2010 Phase 3 (E-esc) Observation Superior RFS (primary endpoint)
Median RFS: 1.45 vs 0.7 yrs
(HR 0.56, 95% CI 0.38-0.83)
Miyake et al. 2018 (MCSGO-CCTG-0501) 2006-2010 Phase 3 (C) UFT/PSK Inconclusive whether non-inferior DFS36

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

Preceding treatment

Chemotherapy

35-day cycle for 5 cycles

References

  1. 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 dosing details in manuscript PubMed NCT00190515
  2. 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 dosing details in manuscript PubMed UMIN C000000013
    1. Update: Kokudo T, Saiura A, Takayama T, Miyagawa S, Yamamoto J, Ijichi M, Teruya M, Yoshimi F, Kawasaki S, Koyama H, Oba M, Takahashi M, Mizunuma N, Matsuyama Y, Ishihara S, Makuuchi M, Kokudo N, Hasegawa K. Adjuvant chemotherapy can prolong recurrence-free survival but did not influence the type of recurrence or subsequent treatment in patients with colorectal liver metastases. Surgery. 2021 Oct;170(4):1151-1154. Epub 2021 May 22. link to original article PubMed
  3. MCSGO-CCTG-0501: Miyake Y, Nishimura J, Kato T, Ikeda M, Tsujie M, Hata T, Takemasa I, Mizushima T, Yamamoto H, Sekimoto M, Nezu R, Doki Y, Mori M; Multi-center Clinical Study Group of Osaka, Colorectal Cancer Treatment Group (MCSGO). Phase III trial comparing UFT + PSK to UFT + LV in stage IIB, III colorectal cancer (MCSGO-CCTG). Surg Today. 2018 Jan;48(1):66-72. Epub 2017 Jun 20. link to original article PubMed NCT00385970

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

FOLFIRI

FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fiorentini et al. 2012 2006-2008 Phase 3 (C) DEBIRI Seems to have inferior OS

Chemotherapy

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

14-day cycle for 8 cycles

References

  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

FOLFOX4: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Nordlinger et al. 2008 (EORTC 40983) 2000-2004 Phase 3 (E-esc) Observation Might have superior PFS (primary endpoint)
PFS36: 35.4% vs 28.1%
(HR 0.79, 95.66% CI 0.62-1.02)
Hebbar et al. 2014 (MIROX) 2004-2010 Phase 3 (C) FOLFOX7, then 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

Chemotherapy

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

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

References

  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; Australasian Gastro-Intestinal Trials Group; Fédération Francophone de Cancérologie Digestive. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008 Mar 22;371(9617):1007-16. link to original article link to PMC article does not contain dosing details PubMed NCT00006479
    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; Australasian Gastro-Intestinal Trials Group; Fédération Francophone de Cancérologie Digestive. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectalcancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1208-15. Epub 2013 Oct 11. link to original article 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. 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 NCT00268398

mFOLFOX6

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tang et al. 2020 (BECOME) 2013-2017 Phase 3 (C) mFOLFOX6-B Seems to have inferior OS

Chemotherapy

14-day cycles

References

  1. BECOME: Tang W, Ren L, Liu T, Ye Q, Wei Y, He G, Lin Q, Wang X, Wang M, Liang F, Cui Y, Xu J. Bevacizumab Plus mFOLFOX6 Versus mFOLFOX6 Alone as First-Line Treatment for RAS Mutant Unresectable Colorectal Liver-Limited Metastases: The BECOME Randomized Controlled Trial. J Clin Oncol. 2020 Sep 20;38(27):3175-3184. Epub 2020 Aug 4. link to original article contains dosing details in manuscript PubMed NCT01972490

mFOLFOX6 (L-Leucovorin)

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cashin et al. 2016 (SPS-1) 2004-2011 Randomized (C) IP 5-FU & LV Seems to have inferior OS

Chemotherapy

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 original article contains dosing details in manuscript PubMed NCT01524094

mFOLFOX6-B

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tang et al. 2020 (BECOME) 2013-2017 Phase 3 (E-esc) mFOLFOX6 Seems to have superior OS (secondary endpoint)
Median OS: 25.7 vs 20.5 mo
(HR 0.71)

Chemotherapy

Targeted therapy

14-day cycles

References

  1. BECOME: Tang W, Ren L, Liu T, Ye Q, Wei Y, He G, Lin Q, Wang X, Wang M, Liang F, Cui Y, Xu J. Bevacizumab Plus mFOLFOX6 Versus mFOLFOX6 Alone as First-Line Treatment for RAS Mutant Unresectable Colorectal Liver-Limited Metastases: The BECOME Randomized Controlled Trial. J Clin Oncol. 2020 Sep 20;38(27):3175-3184. Epub 2020 Aug 4. link to original article contains dosing details in manuscript PubMed NCT01972490

FULV

FULV: 5-FU & LeucoVorin

Regimen variant #1, 2000/1000

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Portier et al. 2006 (FFCD 9002) 1991-2001 Phase 3 (E-esc) Observation Seems to have superior DFS
DFS60: 33.5% vs 26.7%
(OR 0.66, 95% CI 0.46-0.96)

Might have superior PFS1 (secondary endpoint)

1Reported efficacy is based on the 2008 pooled update.

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


Regimen variant #2, 2125/100 with dose escalation

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kemeny et al. 2006 (CALGB 9481) 1996-2000 Phase 3 (C) HAI Inferior OS

Note: FU dose was increased only in the absence of GI or hematologic toxicity.

Chemotherapy

  • Fluorouracil (5-FU) given second, as follows:
    • Cycle 1: 425 mg/m2 IV once per day on days 1 to 5
    • Cycle 2 onwards: 490 mg/m2 IV once per day on days 1 to 5
  • Leucovorin (Folinic acid) 20 mg/m2 IV once per day on days 1 to 5, given first

28-day cycles

References

  1. CALGB 9481: Kemeny NE, Niedzwiecki D, Hollis DR, Lenz HJ, Warren RS, Naughton MJ, Weeks JC, Sigurdson ER, Herndon JE 2nd, Zhang C, Mayer RJ. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol. 2006 Mar 20;24(9):1395-403. Epub 2006 Feb 27. link to original article contains dosing details in manuscript PubMed NCT00002716
  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 contains dosing details in manuscript 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

Intrahepatic floxuridine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Allen-Mersh et al. 1994 1988-1993 Phase 3 (E-esc) Observation Seems to have superior OS
Kemeny et al. 1999 NR Phase 3 (E-esc) Observation Seems to have superior OS

Preceding treatment

Local therapy

Supportive therapy

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

Intrahepatic floxuridine & IV 5-FU

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kemeny et al. 2002 (ECOG E9288) 1990-08 to 1997-01 Phase 3 (E-esc) Observation Seems to have superior RFS48

Preceding treatment

Local therapy

  • Floxuridine (FUDR) as follows:
    • Cycles 1 to 4: 0.1 mg/kg/day IA continuous infusion over 14 days, started on day 1 (total dose per cycle: 1.4 mg)

Chemotherapy

  • Fluorouracil (5-FU) as follows:
    • Cycles 1 to 4: 200 mg/m2/day IV continuous infusion over 14 days, started on day 15 (total dose per cycle: 2800 mg/m2)
    • Cycles 5 to 12: 300 mg/m2/day IV continuous infusion over 14 days, started on day 15 (total dose per cycle: 4200 mg/m2)

'28-day cycle for 12 cycles

References

  1. ECOG E9288: Kemeny MM, Adak S, Gray B, Macdonald JS, Smith T, Lipsitz S, Sigurdson ER, O'Dwyer PJ, Benson AB 3rd. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy--an intergroup study. J Clin Oncol. 2002 Mar 15;20(6):1499-505. link to original article contains dosing details in manuscript PubMed

Intraperitoneal 5-FU

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cashin et al. 2016 (SPS-1) 2004-2011 Randomized (E-switch-ooc) mFOLFOX6 Seems to have superior OS (primary endpoint)
Median OS: 25 vs 18 mo
(HR 0.51, 95% CI 0.27-0.96)

Preceding treatment

Chemotherapy

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

1-month cycle for 6 cycles

References

  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 original article contains dosing details in manuscript PubMed NCT01524094

Intraperitoneal hyperthermic mitomycin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Verwaal et al. 2003 1998-2001 Phase 3 (E-switch-ooc) FULV; modified Laufman regimen Seems to have superior OS (primary endpoint)
Median OS: 22.3 vs 12.6 mo

Preceding treatment

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

Intraperitoneal hyperthermic oxaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Quenet et al. 2021 (PRODIGE 7) 2008-2014 Phase 3 (E-esc) Cytoreductive surgery without HIPEC Did not meet primary endpoint of OS

Patients enrolled had a peritoneal cancer index of 25 or less

Preceding treatment

Chemotherapy

One treatment

References

  1. PRODIGE 7: Quénet F, Elias D, Roca L, Goéré D, Ghouti L, Pocard M, Facy O, Arvieux C, Lorimier G, Pezet D, Marchal F, Loi V, Meeus P, Juzyna B, de Forges H, Paineau J, Glehen O; UNICANCER-GI Group and BIG Renape Group. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):256-266. Epub 2021 Jan 18. link to original article contains dosing details in abstract PubMed NCT00769405

Advanced or metastatic disease, first-line

Capecitabine monotherapy

C: Capecitabine

Regimen variant #1, 2000 mg/m2/day

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Kwakman et al. 2017 (SALTO) 2014-01 to 2015-07 Phase 3 (C) S-1 Did not meet secondary efficacy endpoints1 Higher incidence of hand-foot syndrome

1Reported efficacy is based on the 2019 update.
Note: this trial had a primary toxicity endpoint; this dose was intended for patients at least 70 years old.

Chemotherapy

21-day cycles


Regimen variant #2, 2500 mg/m2/day

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Hoff et al. 2001 (SO14695) 1996-1998 Phase 3 (E-RT-switch-ic) FULV Superior ORR (primary endpoint)
Van Cutsem et al. 2001 (SO14796) 1996-1998 Phase 3 (E-RT-switch-ic) FULV Equivalent ORR (primary endpoint)
Koopman et al. 2007 (CAIRO) 2003-01 to 2004-12 Phase 3 (C) See link See link
Tebbutt et al. 2010 (AGITG MAX) 2005-2007 Phase 3 (C) 1. Capecitabine & Bevacizumab Inferior PFS
2. CBM Inferior PFS
Cunningham et al. 2013 (AVEX) 2007-2010 Phase 3 (C) Capecitabine & Bevacizumab Inferior PFS
Kwakman et al. 2017 (SALTO) 2014-01 to 2015-07 Phase 3 (C) S-1 Did not meet secondary efficacy endpoints1 Higher incidence of hand-foot syndrome

1Reported efficacy for SALTO is based on the 2019 update.
Note: SALTO had a primary toxicity endpoint; this dose was intended for patients less than 70 years old.

Chemotherapy

21-day cycles

Subsequent treatment

References

  1. SO14695: Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001 Apr 15;19(8):2282-92. link to original article contains dosing details in manuscript 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. SO14796: Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P; Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001 Nov 1;19(21):4097-106. link to original article contains dosing details in manuscript 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; Dutch Colorectal Cancer Group. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article contains dosing details in manuscript PubMed NCT00312000
  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 dosing details in manuscript 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 NCT00484939
  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; Dutch Colorectal Cancer Group. Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group. Ann Oncol. 2017 Jun 1;28(6):1288-1293. link to original article contains dosing details in abstract PubMed NCT01918852
    1. Update: Kwakman JJM, van Werkhoven E, Simkens LHJ, van Rooijen JM, van de Wouw YAJ, ten Tije AJ, Creemers GM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, Punt CJA; Dutch Colorectal Cancer Group. Updated Survival Analysis of the Randomized Phase III Trial of S-1 Versus Capecitabine in the First-Line Treatment of Metastatic Colorectal Cancer by the Dutch Colorectal Cancer Group. Clin Colorectal Cancer. 2019 Jun;18(2):e229-e230. Epub 2019 Jan 29. link to original article PubMed

Capecitabine & Bevacizumab

CB: Capecitabine & Bevacizumab

Regimen variant #1, 1000/7.5

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cunningham et al. 2013 (AVEX) 2007-2010 Phase 3 (E-esc) Capecitabine Superior PFS (primary endpoint)
Median PFS: 9.1 vs 5.1 mo
(HR 0.53, 95% CI 0.41-0.69)

Chemotherapy

Targeted therapy

21-day cycles


Regimen variant #2, 1250/7.5

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tebbutt et al. 2010 (AGITG MAX) 2005-2007 Phase 3 (E-esc) 1. Capecitabine Superior PFS (primary endpoint)
Median PFS: 8.5 vs 5.7 mo
(HR 0.63, 95% CI 0.50-0.79)
2. CBM Not reported
André et al. 2022 (SOLSTICE) 2019-03-21 to 2020-09-14 Phase 3 (C) Trifluridine-tipiracil & Bevacizumab Might have inferior PFS

Chemotherapy

Targeted therapy

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 dosing details in abstract PubMed NCT00484939
  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 dosing details in manuscript PubMed NCT01249638
  4. SOLSTICE: André T, Falcone A, Shparyk Y, Moiseenko F, Polo-Marques E, Csöszi T, Campos-Bragagnoli A, Liposits G, Chmielowska E, Aubel P, Martín L, Fougeray R, Amellal N, Saunders MP. Trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer ineligible for intensive therapy (SOLSTICE): a randomised, open-label phase 3 study. Lancet Gastroenterol Hepatol. 2023 Feb;8(2):133-144. Epub 2022 Dec 2. link to original article PubMed NCT03869892

CapeOx

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

Example orders

Regimen variant #1, 850/130

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hochster et al. 2008 (TREE-1) 2002-12 to 2003-11 Phase 3 (E-switch-ic) 1. bFOL Did not meet secondary efficacy endpoints
2. mFOLFOX6 Did not meet secondary efficacy endpoints

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

Chemotherapy

21-day cycles


Regimen variant #2, 1000/70

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Porschen et al. 2007 2002-2004 Phase 3 (E-switch-ic) FUFOX Inconclusive whether non-inferior PFS (primary endpoint)

Chemotherapy

21-day cycles


Regimen variant #3, 1000/130

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Díaz-Rubio et al. 2007 (03-TTD-01) 2002-2004 Phase 3 (E-switch-ic) FUOX Did not meet primary endpoint of TTP
Ducreux et al. 2011 2003-05-16 to 2004-08-31 Phase 3 (E-switch-ic) mFOLFOX6 Non-inferior OS (secondary endpoint)
Median OS: 19.9 vs 20.5 mo
Cassidy et al. 2008 (NO16966) 2003-2005 Phase 3 (C) 1. FOLFOX4
2. FOLFOX4 & Bevacizumab 		Non-inferior PFS
3. XELOX & Bevacizumab Not reported
Saltz et al. 2008 (NO16966) 2003-2005 Phase 3 (C) 1. FOLFOX4 & Bevacizumab
2. XELOX & Bevacizumab 		Inferior PFS
3. FOLFOX4 Not reported
Maughan et al. 2011 (UK MRC COIN) 2005-2008 Phase 3 (C) 1a. CapeOx & Cetuximab
1b. mFOLFOX6 & Cetuximab 		Did not meet primary endpoint of OS1
Hoff et al. 2012 (HORIZON II) 2006-NR Phase 3 (C) 1a. CAPOX & Cediranib
1b. FOLFOX4 & Cediranib
1c. mFOLFOX6 & Cediranib 		Seems to have inferior PFS
Hong et al. 2012 (SMC 2008-03-012) 2008-05-14 to 2009-09-23 Phase 3 (C) SOX Non-inferior PFS

1Reported efficacy for UK MRC COIN is for KRAS wild-type patients.
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. Although NO16966 was one study, it was published simultaneously as two manuscripts looking at different aspects of the 2 x 2 factorial design (Cassidy et al. 2008 and Saltz et al. 2008).

Chemotherapy

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

21-day 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 dosing details in manuscript PubMed
  2. 03-TTD-01: Díaz-Rubio E, Tabernero J, Gómez-España A, Massutí B, Sastre J, Chaves M, Abad A, Carrato A, Queralt B, Reina JJ, Maurel J, González-Flores E, Aparicio J, Rivera F, Losa F, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol. 2007 Sep 20;25(27):4224-30. Epub 2007 Jun 4. link to original article contains dosing details in manuscript PubMed NCT00202774
  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 dosing details in manuscript PubMed NCT00069095
    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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00182715
    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 dosing details in manuscript PubMed NCT00399035
  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 dosing details in abstract PubMed NCT00677443
    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

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

Regimen variant #1, 850/130/7.5

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Hochster et al. 2008 (TREE-2) 2003-11 to 2004-04 Phase 3 (E-switch-ic) 1. bFOL & Bevacizumab Did not meet secondary efficacy endpoints Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
2. mFOLFOX6-B Did not meet secondary efficacy endpoints Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment

Chemotherapy

  • Capecitabine (Xeloda) by the following renal function-based criteria:
    • CrCl more than 50 mL/min/1.73 m2: 850 mg/m2 PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
    • CrCl 30 to 50 mL/min/1.73 m2: 650 mg/m2 PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
  • Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1

Targeted therapy

21-day cycles


Regimen variant #2, 1000/130/7.5 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tol et al. 2009 (CAIRO2) 2005-06 to 2006-12 Phase 3 (C) CapeOx, Bevacizumab, Cetuximab Seems to have superior PFS
Median PFS: 10.7 vs 9.4 mo
(HR 0.82, 95% CI 0.70-0.96)
Díaz-Rubio et al. 2012 (MACRO) 2006-2008 Non-randomized part of phase 3 RCT
Johnsson et al. 2013 (Nordic ACT) 2007-2009 Non-randomized part of phase 3 RCT
Simkens et al. 2015 (CAIRO3) 2007-2012 Non-randomized part of phase 3 RCT

Chemotherapy

Targeted therapy

21-day cycle for 6 cycles

Subsequent treatment


Regimen variant #3, 1000/130/7.5, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cassidy et al. 2008 (NO16966) 2003-2005 Phase 3 (E-RT-esc) 1. FOLFOX4
2. FOLFOX4 & Bevacizumab 		Non-inferior PFS (primary endpoint)
3. XELOX Not reported
Saltz et al. 2008 (NO16966) 2003-2005 Phase 3 (E-RT-esc) 1. FOLFOX4
2. XELOX 		Superior PFS (primary endpoint)
Median PFS: 9.4 vs 8 mo
(HR 0.83, 97.5% CI 0.72-0.95)
3. FOLFOX4 & Bevacizumab Not reported
Yamada et al. 2018 (TRICOLORE) 2012-2014 Phase 3 (C) IRIS & Bevacizumab Non-inferior PFS
Nakayama 2018 (CCOG-1201) 2012-2016 Randomized Phase 2 (C) CAPIRI & Bevacizumab Did not meet primary endpoint of ORR

Note: NO16966 specified that initial treatment could be given up to 16 cycles, but then could continue beyond that for patients who did not have progression of disease. Although this was one study, it was published simultaneously as two manuscripts looking at different aspects of the 2 x 2 factorial design (Cassidy et al. 2008 and Saltz et al. 2008).

Chemotherapy

  • Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
    • Alternate dosing: 1000 mg/m2 PO twice per day from the evening of day 1 to the morning of day 15 (28 doses per cycle)
  • Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1, given second

Targeted therapy

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 dosing details in manuscript PubMed NCT00069095
    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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00399750
  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; Dutch Colorectal Cancer Group. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009 Feb 5;360(6):563-72. Erratum in: N Engl J Med. 2010 Dec 23;363(26):2573. link to original article contains dosing details in manuscript PubMed NCT00208546
    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
    2. Update: Ten Hoorn S, Mol L, Sommeijer DW, Nijman L, van den Bosch T, de Back TR, Ylstra B, van Dijk E, van Noesel CJM, Reinten RJ, Nagtegaal ID, Koopman M, Punt CJA, Vermeulen L. Long-term Survival Update and Extended RAS Mutational Analysis of the CAIRO2 Trial: Addition of Cetuximab to CAPOX/Bevacizumab in Metastatic Colorectal Cancer. Clin Colorectal Cancer. 2023 Mar;22(1):67-75. Epub 2022 Dec 5. link to original article 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 dosing details in manuscript PubMed NCT00335595
  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 dosing details in manuscript PubMed NCT00598156
  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; Dutch Colorectal Cancer Group. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015 May 9;385(9980):1843-52. Epub 2015 Apr 7. link to original article contains dosing details in manuscript PubMed NCT00442637
    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 dosing details in manuscript link to PMC article PubMed UMIN000007834
  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 dosing details in abstract link to PMC article PubMed UMIN000006478

CAPIRI

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Moehler et al. 2009a 2001-2006 Phase 2
Koopman et al. 2007 (CAIRO) 2003-01 to 2004-12 Phase 3 (E-switch-ic) See link See link
Fuchs et al. 2007 (BICC-C) 2003-02 to 2004-12 Phase 3 (E-switch-ic) 1. FOLFIRI Seems to have inferior PFS (primary endpoint)
2. mIFL Did not meet primary endpoint of PFS
Köhne et al. 2007 (EORTC 40015) 2003-2005 Phase 3 (E-switch-ic) FOLFIRI +/- Celecoxib Inconclusive whether non-inferior PFS (primary endpoint)

Note: EORTC 40015 was closed prematurely.

Chemotherapy

21-day cycles

Subsequent treatment

  • CAIRO, with progression: Second-line 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; Dutch Colorectal Cancer Group. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article contains dosing details in manuscript PubMed NCT00312000
  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 dosing details in manuscript 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 dosing details in abstract PubMed NCT00064181
  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 original article contains dosing details in manuscript link to PMC article PubMed

CAPIRI-Bev

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

Regimen variant #1, 750/150/7.5

Study Dates of enrollment Evidence
Johnsson et al. 2013 (Nordic ACT) 2007-2009 Non-randomized part of phase 3 RCT

Note: This dose was recommended for patients older than 65 years.

Chemotherapy

Targeted therapy

21-day cycle for 6 cycles

Subsequent treatment


Regimen variant #2, 800/200/7.5

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Modest et al. 2018 (XELAVIRI) 2010-2016 Phase 3 (E-esc) Cape-Bev Inconclusive whether non-inferior TFS (primary endpoint)

Chemotherapy

Targeted therapy

21-day cycles


Regimen variant #3, 1000/180/7.5

Study Dates of enrollment Evidence
Johnsson et al. 2013 (Nordic ACT) 2007-2009 Non-randomized part of phase 3 RCT

Chemotherapy

Targeted therapy

21-day cycle for 6 cycles

Subsequent treatment


Regimen variant #4, 1000/200/7.5

Study Evidence
Moehler et al. 2009a Phase 2

Chemotherapy

Targeted therapy

21-day cycles


Regimen variant #5, 1000/240/7.5

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pectasides et al. 2012 2006-2008 Phase 3 (E-switch-ic) FOLFIRI-Bev Did not meet primary endpoint of PFS

Chemotherapy

Targeted therapy

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 original article contains dosing details in manuscript 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; Hellenic Cooperative Oncology Group. XELIRI-bevacizumab versus FOLFIRI-bevacizumab as first-line treatment in patients with metastatic colorectal cancer: a Hellenic Cooperative Oncology Group phase III trial with collateral biomarker analysis. BMC Cancer. 2012 Jun 29;12:271. link to original article contains dosing details in manuscript link to PMC article PubMed ACTRN12610000270011
  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 dosing details in manuscript PubMed NCT00598156
  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 dosing details in manuscript PubMed NCT01249638

Fluorouracil monotherapy

Regimen variant #1, 370 mg/m2 intermittent bolus

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bobbio-Pallavicini et al. 1993 NR in abstract Phase 3 (C) FULV Seems to have inferior OS

Chemotherapy

28-day cycles


Regimen variant #2, 400 mg/m2 intermittent bolus

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Labianca et al. 1991 1987-1989 Phase 3 (C) FULV Seems to have inferior ORR
Borner et al. 1998 1991-1995 Phase 3 (C) FULV Seems to have inferior OS

Chemotherapy

28-day cycles


Regimen variant #3, 450 mg/m2 intermittent bolus

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Molinaro et al. 1989 1984-06 to 1985-09 Phase 3 (C) Epirubicin Superior ORR

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

Chemotherapy

28-day cycles


Regimen variant #4, 500 mg/m2 intermittent bolus

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Molinaro et al. 1989 1984-06 to 1985-09 Phase 3 (C) Epirubicin Superior ORR
Lokich et al. 1989 1984-1986 Phase 3 (C) 5-FU; PVI Inferior ORR
Poon et al. 1989 1984-1987 Phase 3 (C) FULV Seems to have inferior OS
O'Connell 1989 NR Phase 3 (C) 1. FULV; LDLV Seems to have inferior OS
2. FULV; HDLV Did not meet primary efficacy endpoint

Chemotherapy

4- to 5-week cycles


Regimen variant #5, 600 mg/m2/week

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Douglass et al. 1978 (ECOG E4273) NR Phase 2/3 (E-switch-ic) 1. 5-FU; PO
2. Cyclophosphamide & 5-FU
3. 5-FU & 6-TG
4. Semustine 		Did not meet endpoint of OS
Smyth et al. 1995 (F-trial) 1989-1992 Phase 3 (C) TCNU Did not meet efficacy endpoint

Note: it is not clear from ECOG E4273 whether 5-FU was a control or experimental arm; the IV formulation appears to be experimental in this trial.

Chemotherapy

7-day cycles


Regimen variant #6, 600 mg/m2/week, 6 out of 8 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Richards et al. 1986 1977-1980 Phase 3 (C) MMF Did not meet efficacy endpoints
Kalofonos et al. 2002 1993-1998 Phase 3 (C) 1. 5-FU & IFN alfa
2. FULV 		Did not meet primary endpoint of OS

Chemotherapy

8-week cycles


Regimen variant #7, weekly bolus with CI lead-in

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Greco et al. 1996 1989-1992 Phase 3 (C) 5-FU & IFN alfa-2a Did not meet primary endpoint of ORR
Hill et al. 1995 1990-1992 Phase 3 (C) 5-FU & IFN alfa-2b Did not meet efficacy endpoints

Chemotherapy

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

7-day cycles


Regimen variant #8, weekly CI

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Aranda et al. 1998 1994-1996 Phase 3 (E-switch-ic) FULV; Mayo Clinic regimen Seems to have 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


Regimen variant #9, PVI ("Lokich regimen")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lokich et al. 1989 1984-1986 Phase 3 (E-switch-ic) 5-FU; bolus Superior ORR
Hansen et al. 1996 (ECOG E2286) 1987-1990 Phase 3 (E-switch-ic) 5-FU; bolus Superior TTP
Maughan et al. 2002 (MRC CR06) 1996-1998 Phase 3 (C) 1. FULV; de Gramont regimen Did not meet primary endpoint of OS
2. Raltitrexed Did not meet primary endpoint of OS

Chemotherapy

Continued indefinitely


Regimen variant #10, load to toxicity

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Witte et al. 2001 1982-NR Phase 3 (C) 5-FU & Levamisole Did not meet primary endpoint of OS

Chemotherapy

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

6-week course, then 5-week cycles

References

  1. ECOG E4273: Douglass HO Jr, Lavin PT, Woll J, Conroy JF, Carbone P. Chemotherapy of advanced measurable colon and rectal carcinoma with oral 5-fluorouracil, alone or in combination with cyclophosphamide or 6-thioguanine, with intravenous 5-fluorouracil or beta-2'-deoxythioguanosine or with oral 3(4-methyl-cyclohexyl)-1(2-chlorethyl)-1-nitrosourea: a Phase II-III study of the Eastern Cooperative Oncology Group (EST 4273). Cancer. 1978 Dec;42(6):2538-45. link to original article contains dosing details in manuscript PubMed
  2. 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
  3. O'Connell MJ; North Central Cancer Treatment Group. A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer: a Mayo Clinic/North Central Cancer Treatment Group study. Cancer. 1989 Mar 15;63(6 Suppl):1026-30. link to original article PubMed
  4. Lokich JJ, Ahlgren JD, Gullo JJ, Philips JA, Fryer JG; MAOP. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol. 1989 Apr;7(4):425-32. link to original article contains dosing details in manuscript PubMed
  5. Molinaro P, Lafleur F, Blum RH. A phase III randomized trial of epirubicin versus 5-fluorouracil in metastatic rectal/sigmoid adenocarcinoma. Am J Clin Oncol. 1989 Aug;12(4):332-4. link to original article PubMed
  6. Poon MA, O'Connell MJ, Moertel CG, Wieand HS, Cullinan SA, Everson LK, Krook JE, Mailliard JA, Laurie JA, Tschetter LK, Wiesenfeld M; NCCTG. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol. 1989 Oct;7(10):1407-18. link to original article 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
  7. Labianca R, Pancera G, Aitini E, Barni S, Beretta A, Beretta GD, Cesana B, Comella G, Cozzaglio L, Cristoni M, Spagnolli P, Frontini L, Gottardi O, Martignoni G, Scapaticci R, Smerieri F, Vinci M, Zadro A, Zaniboni A, Luporini G; GISCAD. Folinic acid + 5-fluorouracil (5-FU) versus equidose 5-FU in advanced colorectal cancer: phase III study of 'GISCAD' (Italian Group for the Study of Digestive Tract Cancer). Ann Oncol. 1991 Oct;2(9):673-9. link to original article contains dosing details in abstract PubMed
  8. Bobbio-Pallavicini E, Porta C, Moroni M, Spaghi A, Casagranda I, Nastasi G. Folinic acid does improve 5-fluorouracil activity in vivo: results of a phase III study comparing 5-fluorouracil to 5-fluorouracil and folinic acid in advanced colon cancer patients. J Chemother. 1993 Feb;5(1):52-5. link to original article contains dosing details in abstract PubMed
  9. 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 dosing details in abstract PubMed
  10. 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
  11. ECOG E2286: Hansen RM, Ryan L, Anderson T, Krzywda B, Quebbeman E, Benson A 3rd, Haller DG, Tormey DC. Phase III study of bolus versus infusion fluorouracil with or without cisplatin in advanced colorectal cancer. J Natl Cancer Inst. 1996 May 15;88(10):668-74. link to original article PubMed
  12. 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 dosing details in abstract PubMed
  13. Aranda E, Díaz-Rubio E, Cervantes A, Antón-Torres A, Carrato A, Massutí T, Tabernero JM, Sastre J, Trés A, Aparicio J, López-Vega JM, Barneto I, García-Conde J; Spanish Cooperative Group for Gastrointestinal Tumor Therapy. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol. 1998 Jul;9(7):727-31. link to original article contains dosing details in abstract PubMed
  14. Witte RS, Cnaan A, Mansour EG, Barylak E, Harris JE, Schutt AJ; ECOG. Comparison of 5-fluorouracil alone, 5-fluorouracil with levamisole, and 5-fluorouracil with hepatic irradiation in the treatment of patients with residual, nonmeasurable, intra-abdominal metastasis after undergoing resection for colorectal carcinoma. Cancer. 2001 Mar 1;91(5):1020-8. link to original article contains dosing details in manuscript PubMed
  15. Kalofonos HP, Nicolaides C, Samantas E, Mylonakis N, Aravantinos G, Dimopoulos MA, Gennatas C, Kouvatseas G, Giannoulis E, Dervenis C, Basdanis G, Pavlidis N, Androulakis I, Fountzilas G; Hellenic Cooperative Oncology Group. A phase III study of 5-fluorouracil versus 5-fluorouracil plus interferon alpha 2b versus 5-fluorouracil plus leucovorin in patients with advanced colorectal cancer: a Hellenic Cooperative Oncology Group (HeCOG) study. Am J Clin Oncol. 2002 Feb;25(1):23-30. link to original article PubMed
  16. MRC CR06: Maughan TS, James RD, Kerr DJ, Ledermann JA, McArdle C, Seymour MT, Cohen D, Hopwood P, Johnston C, Stephens RJ; British MRC Colorectal Cancer Working Party. Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2002 May 4;359(9317):1555-63. link to original article PubMed NCT00002893

FOLFIRI

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

Example orders

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

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Douillard et al. 2000 1997-05 to 1998-02 Phase 3 (E-RT-esc) FULV Seems to have superior OS
Souglakos et al. 2006 2000-2004 Phase 3 (C) FOLFOXIRI Did not meet primary endpoint of OS
Glimelius et al. 2008 2001-2004 Phase 3 (C) FLIRI Did not meet primary endpoint of PFS
Aranda et al. 2008 2001-2005 Phase 3 (C) FUIRI Did not meet primary endpoint of ORR1
Köhne et al. 2007 (EORTC 40015) 2003-2005 Phase 3 (C) CAPIRI Inconclusive whether non-inferior PFS
Passardi et al. 2015 (ITACa) 2007-2012 Phase 3 (C) 1a. FOLFIRI & Bevacizumab
1b. FOLFOX4 & Bevacizumab 		Did not meet primary endpoint of PFS

1Aranda et al. 2008 is described by the authors as a non-inferiority trial but the statistics used are superiority-based.
Note: EORTC 40015 was closed prematurely.

Chemotherapy

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

14-day cycles


Regimen variant #2, 400/2800/180

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Falcone et al. 2007 (GONO ASL601LIOM03) 2001-2005 Phase 3 (C) FOLFOXIRI Seems to have inferior OS
Fuchs et al. 2007 (BICC-C) 2003-02 to 2004-12 Phase 3 (E-switch-ic) 1. CapeIRI Seems to have superior PFS (primary endpoint)
2. mIFL Superior PFS (primary endpoint)
Van Cutsem et al. 2009 (CRYSTAL) 2004-07 to 2005-11 Phase 3 (C) FOLFIRI & Cetuximab Inferior OS1
Sanoff et al. 2018 (LCCC 1029) 2011-2015 Randomized Phase 2 (C) FOLFIRI & Regorafenib Might have inferior PFS

1Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.

Chemotherapy

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

14-day cycles


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

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Köhne et al. 2005 (EORTC 40986) 1999-2001 Phase 3 (E-esc) FULV Superior PFS (primary endpoint)
Median PFS: 8.5 vs 6.4 mo
(HR 0.65, 95% CI 0.53-0.79)
Fischer von Weikersthal et al. 2011 2000-2004 Phase 3 (C) mIROX Did not meet primary endpoint of PFS

Chemotherapy

7-week cycles


Regimen variant #4, 500/2300/80, weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Douillard et al. 2000 1997-05 to 1998-02 Phase 3 (E-RT-esc) FULV Seems to have superior OS
Passardi et al. 2015 (ITACa) 2007-2012 Phase 3 (C) 1a. FOLFIRI & Bevacizumab
1b. FOLFOX4 & Bevacizumab 		Did not meet primary endpoint of PFS

Chemotherapy

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 dosing details in manuscript 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; EORTC Gastrointestinal Group. Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol. 2005 Aug 1;23(22):4856-65. Epub 2005 Jun 6. link to original article contains dosing details in manuscript PubMed NCT00004885
  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; Hellenic Oncology Research Group. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-805. link to original article link to PMC article contains dosing details in manuscript PubMed
  4. GONO ASL601LIOM03: Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6. link to original article contains dosing details in manuscript PubMed NCT01219920
  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 dosing details in manuscript 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 dosing details in abstract PubMed NCT00064181
  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 dosing details in abstract 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; TTD. Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study. Ann Oncol. 2009 Feb;20(2):251-7. Epub 2008 Aug 20. link to original article contains dosing details in manuscript 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 dosing details in manuscript PubMed NCT00154102
    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 dosing details in manuscript 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 original article contains dosing details in abstract 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 NCT01878422
  12. LCCC 1029: Sanoff HK, Goldberg RM, Ivanova A, O'Reilly S, Kasbari SS, Kim RD, McDermott R, Moore DT, Zamboni W, Grogan W, Cohn AL, Bekaii-Saab TS, Leonard G, Ryan T, Olowokure OO, Fernando NH, McCaffrey J, El-Rayes BF, Horgan AM, Sherrill GB, Yacoub GH, O'Neil BH. Multicenter, randomized, double-blind phase 2 trial of FOLFIRI with regorafenib or placebo as second-line therapy for metastatic colorectal cancer. Cancer. 2018 Aug 1;124(15):3118-3126. Epub 2018 Jun 15. link to original article contains dosing details in manuscript PubMed NCT01298570

FOLFIRI (L-Leucovorin)

FOLFIRI: FOLinic acid (L-Leucovorin), Fluorouracil, IRInotecan

Regimen variant #1, 200/2000/150

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Colucci et al. 2005 (GOIM 9901) 1999-2002 Phase 3 (C) FOLFOX4 Did not meet primary endpoint of ORR

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

Chemotherapy

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

14-day cycles


Regimen variant #2, 200/2000/180

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Colucci et al. 2005 (GOIM 9901) 1999-2002 Phase 3 (C) FOLFOX4 Did not meet primary endpoint of ORR
Labianca et al. 2010 2001-2005 Phase 3 (C) FOLFIRI; intermittent Did not meet primary endpoint of OS

Chemotherapy

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

14-day cycles


Regimen variant #3, 200/2800/180

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Van Cutsem et al. 2009 (CRYSTAL) 2004-07 to 2005-11 Phase 3 (C) FOLFIRI & Cetuximab Inferior OS1
Carrato et al. 2013 (SUN 1122) 2007-NR Phase 3 (C) FOLFIRI & Sunitinib Did not meet primary endpoint of PFS

1Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.

Chemotherapy

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

14-day cycles

References

  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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00154102
    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 dosing details in manuscript 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. 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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00457691

FOLFIRI & Bevacizumab

FOLFIRI & Bevacizumab: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan, Bevacizumab

Regimen variant #1, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fuchs et al. 2007 (BICC-C) 2003-02 to 2004-12 Phase 3 (E-switch-ic) mIFL & Bevacizumab Seems to have superior OS1 (secondary endpoint)
Median OS: 28 vs 19.2 mo
(HR 0.56, 95% CI 0.35-0.89)
Yamazaki et al. 2016 (WJOG4407G) 2008-2012 Phase 3 (E-switch-ic) mFOLFOX6-B Non-inferior PFS (primary endpoint)
Median PFS: 12.1 vs 10.7 mo
(HR 0.905, 95% CI 0.72-1.13)

1Reported efficacy is based on the 2008 update. Note also that the primary endpoint (PFS) of this study was not met in the original publication, and is not reported in the update.

Chemotherapy

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

Targeted therapy

14-day cycles


Regimen variant #2, lower dose leucovorin

Study Dates of enrollment Evidence
Johnsson et al. 2013 (Nordic ACT) 2007-2009 Non-randomized part of phase 3 RCT

Chemotherapy

Targeted therapy

14-day cycle for 9 cycles

Subsequent treatment

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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00598156
  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 UMIN000001396

FOLFIRI & Bevacizumab (L-Leucovorin)

FOLFIRI & Bevacizumab: FOLinic acid (L-Leucovorin), Fluorouracil, IRInotecan, Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Loupakis et al. 2014 (TRIBE) 2008-2011 Phase 3 (C) FOLFOXIRI & Bevacizumab (L-Leucovorin) 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

Targeted therapy

14-day cycle for up to 12 cycles

Subsequent treatment

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 dosing details in manuscript PubMed NCT00719797
    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. Epub 2015 Aug 31. link to original article PubMed

FOLFIRINOX

FOLFIRINOX: FOLinic acid (Leucovorin), Fluorouracil, IRINotecan, OXaliplatin
FOLFOXIRI: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, IRInotecan

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Souglakos et al. 2006 2000-2004 Phase 3 (E-esc) FOLFIRI Did not meet primary endpoint of OS
Falcone et al. 2007 (GONO ASL601LIOM03) 2001-2005 Phase 3 (E-esc) FOLFIRI Seems to have superior OS (secondary endpoint)
Median OS: 22.6 vs 16.7 mo
(HR 0.70, 95% CI 0.50-0.96)

Superior RR (primary endpoint)

Note: In contrast to GONO ASL601LIOM03, some guidelines list the dose of folinic acid as 400 mg/m2 IV on day 1. No primary reference could be found for this.

Chemotherapy

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; Hellenic Oncology Research Group. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-805. link to original article link to PMC article contains dosing details in manuscript PubMed
  2. GONO ASL601LIOM03: Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6. link to original article contains dosing details in manuscript PubMed NCT01219920

FOLFIRINOX & Bevacizumab

FOLFIRINOX & Bevacizumab: FOLinic acid (Leucovorin), Fluorouracil, IRINotecan, OXaliplatin, Bevacizumab
FOLFOXIRI & Bevacizumab: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, IRInotecan, Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Aranda et al. 2020 (VISNU-1) 2012-2016 Phase 3 (E-esc) mFOLFOX6-B Superior PFS (primary endpoint)
Median PFS: 12.4 vs 9.3 mo
(HR 0.64, 95% CI 0.49-0.82)

Chemotherapy

Targeted therapy

14-day cycles

References

  1. VISNU-1: Aranda E, Viéitez JM, Gómez-España A, Gil Calle S, Salud-Salvia A, Graña B, Garcia-Alfonso P, Rivera F, Quintero-Aldana GA, Reina-Zoilo JJ, González-Flores E, Salgado Fernández M, Guillén-Ponce C, Garcia-Carbonero R, Safont MJ, La Casta Munoa A, García-Paredes B, López López R, Sastre J, Díaz-Rubio E; Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD). FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab for patients with metastatic colorectal cancer and ≥3 circulating tumour cells: the randomised phase III VISNÚ-1 trial. ESMO Open. 2020 Nov;5(6):e000944. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01640405

FOLFIRINOX & Bevacizumab (L-Leucovorin)

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Masi et al. 2010 (FOIB) 2007-2008 Phase 2
Loupakis et al. 2014 (TRIBE) 2008-2011 Phase 3 (E-esc) FOLFIRI & Bevacizumab (L-Leucovorin) Superior PFS (primary endpoint)
Median PFS: 12.1 vs 9.7 mo
(HR 0.75, 95% CI 0.62-0.90)

Seems to have superior OS1 (secondary endpoint)
Median OS: 31 vs 25.8 mo
(HR 0.79, 95% CI 0.63-1.00)

1Reported efficacy for OS in TRIBE is based on the 2015 update.
Note: Loupakis et al. 2014 listed folinic acid 200 mg/m2 in the body of the paper, whereas the protocol in the supplementary material stated that levoleucovorin 200 mg/m2 was used. We have contacted NEJM regarding this suspected error. 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

Targeted therapy

14-day cycle for up to 12 cycles

Subsequent treatment

References

  1. FOIB: Masi G, Loupakis F, Salvatore L, Fornaro L, Cremolini C, Cupini S, Ciarlo A, Del Monte F, Cortesi E, Amoroso D, Granetto C, Fontanini G, Sensi E, Lupi C, Andreuccetti M, Falcone A. Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Lancet Oncol. 2010 Sep;11(9):845-52. Epub 2010 Aug 9. link to original article PubMed NCT01163396
  2. 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 dosing details in manuscript PubMed NCT00719797
    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. Epub 2015 Aug 31. link to original article PubMed

FOLFOX2

FOLFOX2: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Giacchetti et al. 2006 (EORTC 05963) 1998-2002 Phase 3 (C) chronoFLO4 Did not meet primary endpoint of OS

Chemotherapy

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

14-day cycles

References

  1. EORTC 05963: Giacchetti S, Bjarnason G, Garufi C, Genet D, Iacobelli S, Tampellini M, Smaaland R, Focan C, Coudert B, Humblet Y, Canon JL, Adenis A, Lo Re G, Carvalho C, Schueller J, Anciaux N, Lentz MA, Baron B, Gorlia T, Lévi F; EORTC Chronotherapy Group. Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group. J Clin Oncol. 2006 Aug 1;24(22):3562-9. link to original article contains dosing details in manuscript PubMed NCT00003287

FOLFOX4

FOLFOX4: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
de Gramont et al. 2000 1995-1997 Phase 3 (E-esc) FULV Superior PFS
Goldberg et al. 2003 (NCCTG N9741) 1999-2001 Phase 3 (E-RT-switch-ic) 1. IFL Superior OS (secondary endpoint)
2. IROX Did not meet primary endpoint of TTP
Tournigand et al. 2006 (OPTIMOX1) 2000-2002 Phase 3 (C) FOLFOX7/LV5FU2 Did not meet primary endpoint of DDC
Hecht et al. 2011 (CONFIRM 1) 2003-02-20 to 2004-05-27 Phase 3 (C) FOLFOX4 & Vatalanib Did not meet primary endpoint of PFS
Cassidy et al. 2008 (NO16966) 2003-2005 Phase 3 (C) 1. FOLFOX4 & Bevacizumab Not reported
2. XELOX
3. XELOX & Bevacizumab 		Non-inferior PFS
Saltz et al. 2008 (NO16966) 2003-2005 Phase 3 (C) 1. FOLFOX4 & Bevacizumab
2. XELOX & Bevacizumab 		Inferior PFS
3. XELOX Not reported
Bokemeyer et al. 2008 (OPUS) 2005-2006 Randomized Phase 2 (C) FOLFOX4 & Cetuximab Inferior OS1
Douillard et al. 2010 (PRIME) 2006-2008 Phase 3 (C) FOLFOX4 & Panitumumab Seems to have superior PFS2
Hoff et al. 2012 (HORIZON II) 2006-NR Phase 3 (C) 1a. CAPOX & Cediranib
1b. FOLFOX4 & Cediranib
1c. mFOLFOX6 & Cediranib 		Seems to have inferior PFS
Passardi et al. 2015 (ITACa) 2007-2012 Phase 3 (C) 1a. FOLFIRI & Bevacizumab
1b. FOLFOX4 & Bevacizumab 		Did not meet primary endpoint of PFS

1Reported efficacy for OPUS is based on the 2012 pooled update and is only for KRAS wild-type tumors.
2In PRIME, patients with KRAS wild-type tumors receiving this regimen seem to have inferior OS, based on the 2014 update. Conversely, in KRAS mutants, this regimen seems to have superior PFS.
Note: Although NO16966 was one study, it was published simultaneously as two manuscripts looking at different aspects of the 2 x 2 factorial design (Cassidy et al. 2008 and Saltz et al. 2008).

Chemotherapy

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

14-day cycles

References

  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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00003594
    1. Toxicity analysis: Delaunoit T, Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Findlay BP, Thomas SP, Salim M, Schaefer PL, Stella PJ, Green E, Mailliard JA. Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup Trial N9741. Cancer. 2004 Nov 15;101(10):2170-6. link to original article 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 dosing details in manuscript 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 contains dosing details in manuscript PubMed NCT00069095
    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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00125034
    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 NCT00364013
    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. CONFIRM 1: Hecht JR, Trarbach T, Hainsworth JD, Major P, Jäger E, Wolff RA, Lloyd-Salvant K, Bodoky G, Pendergrass K, Berg W, Chen BL, Jalava T, Meinhardt G, Laurent D, Lebwohl D, Kerr D. Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):1997-2003. Epub 2011 Apr 4. link to original article contains dosing details in manuscript PubMed NCT00056459
  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 dosing details in manuscript PubMed NCT00399035
  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 NCT01878422

FOLFOX4 (L-Leucovorin)

FOLFOX4: FOLinic acid (L-Leucovorin), Fluorouracil, OXaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Colucci et al. 2005 (GOIM 9901) 1999-2002 Phase 3 (E-switch-ic) FOLFIRI Did not meet primary endpoint of ORR
Hecht et al. 2011 (CONFIRM 1) 2003-02-20 to 2004-05-27 Phase 3 (C) FOLFOX4 & Vatalanib Did not meet primary endpoint of PFS
Correale et al. 2014 (GOLFIG-2) 2005-2010 Phase 3 (C) GOLFIG 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 dosing details in manuscript PubMed
  2. CONFIRM 1: Hecht JR, Trarbach T, Hainsworth JD, Major P, Jäger E, Wolff RA, Lloyd-Salvant K, Bodoky G, Pendergrass K, Berg W, Chen BL, Jalava T, Meinhardt G, Laurent D, Lebwohl D, Kerr D. Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol. 2011 May 20;29(15):1997-2003. Epub 2011 Apr 4. link to original article contains dosing details in manuscript PubMed NCT00056459
  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 EudraCT 2005-003458-81

FOLFOX6

FOLFOX6: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hospers et al. 2006 1999-2002 Phase 3 (E-esc) FULV; Mayo Clinic regimen Seems to have superior PFS (secondary endpoint)

Superior RR (primary endpoint)

Chemotherapy

14-day cycles

References

  1. 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 dosing details in abstract PubMed

mFOLFOX6

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

Example orders

Regimen variant #1, LCV 200 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
van Hazel et al. 2016 (SIRFLOX) 2006-2013 Phase 3 (C) mFOLFOX6 plus SIRT Did not meet primary endpoint of PFS
Wasan et al. 2017 (FOXFIRE-Global) 2013-05-20 to 2014-12-23 Phase 3 (C) mFOLFOX6 plus SIRT Did not meet primary endpoint of OS

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

Chemotherapy

14-day cycles


Regimen variant #2, LCV 350 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cheeseman et al. 2002 NR Non-randomized
Hochster et al. 2008 (TREE-1) 2002-12 to 2003-11 Phase 3 (E-switch-ic) 1. bFOL Did not meet secondary efficacy endpoints
2. CapeOx Did not meet secondary efficacy endpoints
Maughan et al. 2011 (UK MRC COIN) 2005-2008 Phase 3 (C) 1a. CapeOx & Cetuximab
1b. mFOLFOX6 & Cetuximab 		Did not meet primary endpoint of OS1
Wasan et al. 2017 (FOXFIRE) 2009-2014 Phase 3 (C) OxMdG plus SIRT Did not meet primary endpoint of OS

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

Chemotherapy

14-day cycles


Regimen variant #3, LCV 400 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hoff et al. 2012 (HORIZON II) 2006-NR Phase 3 (C) 1a. CAPOX & Cediranib
1b. FOLFOX4 & Cediranib
1c. mFOLFOX6 & Cediranib 		Seems to have inferior PFS
Shah et al. 2017 (METGastric) 2012-2014 Phase 3 (C) mFOLFOX6 & Onartuzumab Did not meet primary endpoint of OS

Biomarker eligibility criteria

  • METGastric: MET-positive

Chemotherapy

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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00182715
    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 dosing details in manuscript PubMed NCT00399035
  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 NCT00724503
    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 dosing details in manuscript link to PMC article PubMed
  6. METGastric: Shah MA, Bang YJ, Lordick F, Alsina M, Chen M, Hack SP, Bruey JM, Smith D, McCaffery I, Shames DS, Phan S, Cunningham D. Effect of Fluorouracil, Leucovorin, and Oxaliplatin With or Without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma: The METGastric Randomized Clinical Trial. JAMA Oncol. 2017 May 1;3(5):620-627. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01662869
  7. FOXFIRE: Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay M, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A, van Hazel G, Sharma RA; FOXFIRE/SIRFLOX/FOXFIRE-Global trial investigators. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-1171. Epub 2017 Aug 3. link to original article contains dosing details in manuscript link to PMC article PubMed ISRCTN83867919
  8. 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 dosing details in manuscript link to PMC article PubMed NCT01721954
  9. ECTX: NCT01460589

mFOLFOX6 (L-Leucovorin)

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Maughan et al. 2011 (UK MRC COIN) 2005-2008 Phase 3 (C) 1a. CapeOx & Cetuximab
1b. mFOLFOX6 & Cetuximab 		Did not meet primary endpoint of OS1
Wasan et al. 2017 (FOXFIRE) 2009-2014 Phase 3 (C) OxMdG plus SIRT Did not meet primary endpoint of OS

1Reported efficacy for UK MRC COIN is as reported for KRAS wild-type patients.

Chemotherapy

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 dosing details in manuscript PubMed NCT00182715
    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: 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 dosing details in manuscript link to PMC article PubMed ISRCTN83867919
  3. 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 dosing details in manuscript link to PMC article PubMed NCT01721954

FOLFOX 7/sLV5FU2

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

Protocol

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tournigand et al. 2006 (OPTIMOX1) 2000-2002 Phase 3 (E-switch-ic) FOLFOX4 Did not meet primary endpoint of DDC

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

Chemotherapy, FOLFOX 7 portion

14-day cycle for up to 6 cycles; then proceed to sLV5FU2:

Chemotherapy, sLV5FU2 portion

  • Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given first
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 1500 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 3000 mg/m2)

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

References

  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 dosing details in manuscript PubMed

FOLFOX 7/sLV5FU2 (L-Leucovorin)

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

Protocol

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tournigand et al. 2006 (OPTIMOX1) 2000-2002 Phase 3 (E-switch-ic) FOLFOX4 Did not meet primary endpoint of DDC

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

Chemotherapy, FOLFOX 7 portion

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 dosing details in manuscript PubMed

mFOLFOX7

mFOLFOX7: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Regimen

Study Dates of enrollment Evidence
Chibaudel et al. 2009 (OPTIMOX2) 2004-2006 Non-randomized part of phase 3 RCT

Chemotherapy

14-day cycle for 6 cycles

Subsequent 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 NCT00274872

mFOLFOX7 (L-Leucovorin)

mFOLFOX7: modified FOLinic acid (L-Leucovorin), Fluorouracil, OXaliplatin

Regimen

Study Dates of enrollment Evidence
Chibaudel et al. 2009 (OPTIMOX2) 2004-2006 Non-randomized part of phase 3 RCT

Chemotherapy

14-day cycle for 6 cycles

Subsequent 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 NCT00274872

FOLFOX4 & Bevacizumab

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Emmanouilides et al. 2007 2004-2005 Phase 2
Cassidy et al. 2008 (NO16966) 2003-2005 Phase 3 (E-RT-esc) 1. FOLFOX4
2. XELOX 		Superior PFS (primary endpoint)
3. XELOX & Bevacizumab Not reported

Chemotherapy

Targeted therapy

  • Bevacizumab (Avastin) 5 mg/kg IV once on day 1, given first
    • Infusion times are 2 hours for cycle 1, 1 hour for cycle 2, then 30 minutes for cycles 3 and later

14-day cycles

References

  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 dosing details in manuscript PubMed NCT00069095
    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 dosing details in manuscript 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-B

mFOLFOX6-B: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Bevacizumab
FOLFOX-B: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Bevacizumab

Example orders

Regimen variant #1, LCV 400 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Hochster et al. 2008 (TREE-2) 2003-11 to 2004-04 Phase 3 (E-switch-ic) 1. bFOL & Bevacizumab Did not meet secondary efficacy endpoints Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
2. CapeOx & Bevacizumab Did not meet secondary efficacy endpoints Similar grade 3/4 treatment-related adverse events during the first 12 weeks of treatment
Hecht et al. 2008 (PACCE) 2005-03 to 2006-10 Phase 3 (C) mFOLFOX6 & Bevacizumab & Panitumumab Superior OS
Median OS: 24.5 vs 19.4 mo
(HR 0.70, 95% CI 0.55-0.90)
Saltz et al. 2011 (USOR 05-041) 2005-NR Phase 3 (C) FOLF-CB Did not meet primary endpoint of PFS12
Schmoll et al. 2012 (HORIZON III) 2006-2009 Phase 3 (C) mFOLFOX6 & Cediranib Inconclusive whether non-inferior PFS
Yamazaki et al. 2016 (WJOG4407G) 2008-2012 Phase 3 (E-switch-ic) FOLFIRI & Bevacizumab Non-inferior PFS (primary endpoint)
Yamada et al. 2013 (SOFTCRC) 2009-2011 Phase 3 (C) SOX & Bevacizumab Seems to have non-inferior PFS
Aranda et al. 2020 (VISNU-1) 2012-2016 Phase 3 (C) FOLFOXIRI & Bevacizumab Inferior PFS
Wang et al. 2022 (VITALITY) 2017-2019 Phase 3 (C) 1a. mFOLFOX & high-dose vitamin C
1b. mFOLFOX-B & high-dose vitamin C 		Might have inferior PFS
Tabernero et al. 2024 (AGENT) 2018-12 to 2021-04 Phase 3 (C) Arfolitixorin, 5-FU, Oxaliplatin, Bevacizumab Did not meet primary endpoint of ORR

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

Chemotherapy

Targeted therapy

14-day cycles


Regimen variant #2, LCV 200 mg/m2

Study Dates of enrollment Evidence
Johnsson et al. 2013 (Nordic ACT) 2007-2009 Non-randomized part of phase 3 RCT

Chemotherapy

Targeted therapy

14-day cycle for 9 cycles

Subsequent treatment

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 dosing details in manuscript PubMed NCT00399750
  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 NCT00115765
  3. USOR 05-041: Saltz L, Badarinath S, Dakhil S, Bienvenu B, Harker WG, Birchfield G, Tokaz LK, Barrera D, Conkling PR, O'Rourke MA, Richards DA, Reidy D, Solit D, Vakiani E, Capanu M, Scales A, Zhan F, Boehm KA, Asmar L, Cohn A. Phase III trial of cetuximab, bevacizumab, and 5-fluorouracil/leucovorin vs FOLFOX-bevacizumab in colorectal cancer. Clin Colorectal Cancer. 2012 Jun;11(2):101-11. Epub 2011 Nov 4. link to original article contains dosing details in manuscript PubMed NCT00252564
  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 NCT00384176
  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 dosing details in manuscript PubMed NCT00598156
  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 JapicCTI-090699
    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 NCT00724503
  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 UMIN000001396
  10. VISNU-1: Aranda E, Viéitez JM, Gómez-España A, Gil Calle S, Salud-Salvia A, Graña B, Garcia-Alfonso P, Rivera F, Quintero-Aldana GA, Reina-Zoilo JJ, González-Flores E, Salgado Fernández M, Guillén-Ponce C, Garcia-Carbonero R, Safont MJ, La Casta Munoa A, García-Paredes B, López López R, Sastre J, Díaz-Rubio E; Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD). FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab for patients with metastatic colorectal cancer and ≥3 circulating tumour cells: the randomised phase III VISNÚ-1 trial. ESMO Open. 2020 Nov;5(6):e000944. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01640405
  11. VITALITY: Wang F, He MM, Xiao J, Zhang YQ, Yuan XL, Fang WJ, Zhang Y, Wang W, Hu XH, Ma ZG, Yao YC, Zhuang ZX, Zhou FX, Ying JE, Yuan Y, Zou QF, Guo ZQ, Wu XY, Jin Y, Mai ZJ, Wang ZQ, Qiu H, Guo Y, Shi SM, Chen SZ, Luo HY, Zhang DS, Wang FH, Li YH, Xu RH. A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study). Clin Cancer Res. 2022 Oct 3;28(19):4232-4239. link to original article contains dosing details in manuscript link to PMC article PubMed
  12. AGENT: Tabernero J, Yoshino T, Stintzing S, de Gramont A, Gibbs P, Jonker DJ, Nygren P, Papadimitriou C, Prager GW, Tell R, Lenz HJ. A Randomized Phase III Study of Arfolitixorin versus Leucovorin with 5-Fluorouracil, Oxaliplatin, and Bevacizumab for First-Line Treatment of Metastatic Colorectal Cancer: The AGENT Trial. Cancer Res Commun. 2024 Jan 4;4(1):28-37. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03750786

mFOLFOX6-B (L-Leucovorin)

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yamada et al. 2018 (TRICOLORE) 2012-2014 Phase 3 (C) IRIS & Bevacizumab Non-inferior PFS

Chemotherapy

Targeted therapy

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 dosing details in manuscript link to PMC article PubMed UMIN000007834

FUFOX

FUFOX: 5-FU, Folinic acid (Leucovorin), OXaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Porschen et al. 2007 2002-2004 Phase 3 (C) CapeOx Inconclusive whether non-inferior PFS (primary endpoint)

Chemotherapy

  • Fluorouracil (5-FU) 2000 mg/m2 IV continuous infusion over 22 hours, started on days 1, 8, 15, 22, given third (total dose per cycle: 8000 mg/m2)
  • Leucovorin (Folinic acid) 500 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22,, given second
  • Oxaliplatin (Eloxatin) 50 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, given first

35-day cycles

References

  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 dosing details in manuscript PubMed

FUIRI

FUIRI: 5-FU & IRInotecan

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Aranda et al. 2008 2001-2005 Phase 3 (E-de-esc) FOLFIRI Did not meet primary endpoint of ORR1

1Aranda et al. 2008 is described by the authors as a non-inferiority trial but the statistics used are superiority-based.

Chemotherapy

  • Fluorouracil (5-FU) 1125 mg/m2/day IV continuous infusion over 48 hours, started on day 1, given second (total dose per cycle: 2250 mg/m2)
  • Irinotecan (Camptosar) 80 mg/m2 IV over 30 minutes once on day 1, given first

7-day cycles

References

  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; TTD. Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study. Ann Oncol. 2009 Feb;20(2):251-7. Epub 2008 Aug 20. link to original article contains dosing details in manuscript PubMed

FULV

FULV: 5-FU & LeucoVorin
LV5FU2: LeucoVorin and 5-FU, two days out of the month
sLV5FU2: simplified LeucoVorin and 5-FU, two days out of the month

Example orders

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

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Verwaal et al. 2003 1998-2001 Phase 3 (C) HIPEC Seems to have inferior OS

Chemotherapy

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


Regimen variant #2, 450/200

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kosmidis et al. 1996 NR Phase 3 (C) FULV & IFN alfa-2b Superior OS

Chemotherapy

7-day cycles


Regimen variant #3, 500/20

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jäger et al. 1996 1989-1994 Phase 3 (C) FULV; high-dose Did not meet primary endpoint of ORR

Chemotherapy

7-day cycles


Regimen variant #4, 500/200, 6 out of 8 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Blanke et al. 2002 1995-1999 Phase 3 (C) FULV & Trimetrexate Did not meet primary endpoint of PFS

Chemotherapy

8-week cycles


Regimen variant #5, 600/25, 6 out of 8 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Heys et al. 1995 NR Phase 3 (C) FULV & rIL2 Might have inferior OS

Chemotherapy

8-week cycle for up to 3 cycles


Regimen variant #6, 600/500 ("Roswell Park regimen")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Petrelli et al. 1987 NR Phase 3 (E-esc) 1. 5-FU
2. 5-FU & MTX 		Superior ORR
Petrelli et al. 1989 NR Phase 3 (E-esc) 1. 5-FU
2. FULV; LDLV 		Might have superior OS
Buroker et al. 1994 1988-1990 Phase 3 (E-esc) FULV; Mayo Clinic regimen Did not meet primary endpoint of OS50%
Jones et al. 1995 1988-1991 Phase 3 (C) MFL Did not meet primary endpoint of ORR
Kabbinavar et al. 2005 (AVF0780g) 2000-08 to 2002-07 Randomized Phase 2 (C) FULV & Bevacizumab Did not meet primary endpoint of OS

Note: the original 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
  • Leucovorin (Folinic acid) 500 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, given first

8-week cycles


Regimen variant #7, 1500/400

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gamelin et al. 2008 NR Phase 3 (C) FULV; PK-guided Might have inferior OS

Chemotherapy

7-day cycles


Regimen variant #8, 1850/1000

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Man et al. 1995 (Corfu-A) 1990-01 to 1991-04 Phase 3 (E-switch-ooc) 5-FU & IFN alfa-2a Did not meet primary endpoint of ORR
Goldberg et al. 1997 1990-1995 Phase 3 (E-esc) 1. FULV; LDLV
2. FULV; oral LV 		Did not meet primary endpoint of OS
Bobbio-Pallavicini et al. 1993 NR in abstract Phase 3 (E-esc) 5-FU Seems to have superior OS

Note: Bobbio-Pallavicini et al. 1993 does not report spacing out the timing after the first 2 cycles, in the abstract.

Chemotherapy

28-day cycle for 2 cycles, then 35-day cycles (see note)


Regimen variant #9, 2000/100

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Borner et al. 1998 1991-1995 Phase 3 (E-esc) 5-FU Seems to have superior OS

Chemotherapy

1-month cycles


Regimen variant #10, 2000/400 (LV5FU2 aka "de Gramont regimen")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
de Gramont et al. 1997 (FFCD 9101) 1991-1994 Phase 3 (E-esc) FULV; Mayo Clinic regimen Superior PFS
Kerr et al. 2003 1994-2000 Phase 3 (C) FULV; IHA LV5FU2 Did not meet primary endpoint of OS
de Gramont et al. 2000 1995-1997 Phase 3 (C) FOLFOX4 Inferior PFS
Maughan et al. 2002 (MRC CR06) 1996-1998 Phase 3 (C) 1. Lokich regimen Did not meet primary endpoint of OS
2. Raltitrexed Did not meet primary endpoint of OS
Maughan et al. 2003 1996-2000 Phase 3 (C) FULV; intermittent LV5FU2 Did not meet primary endpoint of OS
Douillard et al. 2000 1997-05 to 1998-02 Phase 3 (C) 1a. IFL
1b. FOLFIRI 		Seems to have inferior OS
Ducreux et al. 2006 (FFCD 9601) 1997-2001 Phase 3 (C) 1. FULV; ldLV5FU2
2. 5-FU 		Did not meet primary endpoint of PFS
3. Raltitrexed Seems to have superior PFS
Cunningham et al. 2008 2000-NR Phase 3b (C) FOLFOX4 Did not meet primary endpoint of OS
Aparicio et al. 2015 (FFCD 2001-02) 2003-2010 Phase 3 (C) 1. FOLFIRI; "classic"
2. FOLFIRI; "simplified" 		Did not meet primary endpoint of PFS
3. FULV; sLV5FU2 Did not meet primary endpoint of PFS

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

Chemotherapy

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

14-day cycles (see note)


Regimen variant #11, 2000/500

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Scheithauer et al. 1997 1991-1994 Phase 3 (C) FULV (L-Leucovorin) Did not meet primary endpoint of OS12

Chemotherapy

28-day cycle for up to 6 cycles


Regimen variant #12, 2000/1000

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Labianca et al. 1991 1987-1989 Phase 3 (E-esc) 5-FU Seems to have superior ORR
Cocconi et al. 1998 1995-07 to 1996-02 Phase 3 (C) Raltitrexed Superior TTP (primary endpoint)
Median TTP: 5.1 vs 3.9 mo
(HR 0.75, 95% CI 0.62-0.92)

Chemotherapy

28-day cycles


Regimen variant #13, 2125/100 ("Mayo Clinic regimen")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
O'Connell 1989 NR Phase 3 (E-RT-esc) 1. 5-FU Seems to have superior OS
2. FULV; HDLV Did not meet primary efficacy endpoint
Poon et al. 1989 1984-1987 Phase 3 (E-RT-esc) 5-FU Seems to have superior OS
Buroker et al. 1994 1988-1990 Phase 3 (E-de-esc) FULV; Roswell Park regimen Did not meet primary endpoint of OS50%
de Gramont et al. 1997 (FFCD 9101) 1991-1994 Phase 3 (C) FULV; LV5FU2 Inferior PFS
Cunningham et al. 1995 1993-11 to 1994-06 Phase 3 (C) Raltitrexed Did not meet primary endpoint of TTP
Aranda et al. 1998 1994-1996 Phase 3 (C) 5-FU; high-dose Seems to have inferior ORR
Douillard et al. 2002 1995-1997 Phase 3 (C) UFT & Leucovorin Seems to have equivalent OS (primary endpoint)
Köhne et al. 2003 (EORTC 40952) 1995-1998 Phase 3 (C) 1. FU24h
2. FU24h + LV 		Did not meet primary endpoint of OS
Carmichael et al. 2002 1996-05 to 1997-07 Phase 3 (C) UFT & Leucovorin Did not meet primary endpoint of TTP
Saltz et al. 2000 1996-1998 Phase 3 (C) 1. IFL Seems to have inferior OS
2. Irinotecan Did not meet primary endpoint of PFS
Hoff et al. 2001 (SO14695) 1996-1998 Phase 3 (C) Capecitabine Inferior ORR
Van Cutsem et al. 2001 (SO14796) 1996-1998 Phase 3 (C) Capecitabine Equivalent ORR
Schilsky et al. 2002 (FUMA3008) 1997-1999 Phase 3 (C) Eniluracil & 5-FU Inconclusive whether non-inferior OS
Chong et al. 2005 1998-2001 Phase 3 (C) FULV & 3H1 Did not meet primary endpoint of OS
Hospers et al. 2006 1999-2002 Phase 3 (C) FOLFOX6 Seems to have inferior PFS

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

Chemotherapy

28-day cycle for 3 cycles, then 35-day cycle for 3 cycles (see note)


Regimen variant #14, 2560/175 (reduced-dose sLV5FU2)

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Seymour et al. 2011 (MRC FOCUS2) Phase 3 (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

14-day cycles


Regimen variant #15, 2600/500, weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Douillard et al. 2000 1997-05 to 1998-02 Phase 3 (C) 1a. IFL
1b. FOLFIRI 		Seems to have inferior OS

Chemotherapy

7-day cycles


Regimen variant #16, 2600/500, 6 out of 8 weeks ("AIO regimen")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Köhne et al. 2005 (EORTC 40986) 1999-2001 Phase 3 (C) FOLFIRI Inferior PFS

Chemotherapy

  • Fluorouracil (5-FU) 2600 mg/m2 IV continuous infusion over 24 hours, started on days 1, 8, 15, 22, 29, 36 (total dose per cycle: 15,600 mg/m2)
  • Leucovorin (Folinic acid) 500 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36

8-week cycles


Regimen variant #17, 2800/350 ("modified de Gramont regimen")

Study Evidence
Cheeseman et al. 2002 Non-randomized
Seymour et al. 2007 (MRC FOCUS) Phase 3 (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, given second, then 2400 mg/m2 IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m2)
  • Leucovorin (Folinic acid) 350 mg IV over 2 hours once on day 1, given first

Supportive therapy

14-day cycles


Regimen variant #18, 2800/400 (sLV5FU2)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ducreux et al. 2011 (FFCD 2000-05) 2002-2006 Phase 3 (C) See link See link

Chemotherapy

14-day cycles

Subsequent treatment

  • FFCD 2000-05, upon progression: mFOLFOX6


Regimen variant #19, other

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hausmaninger et al. 1999 1991-1995 Phase 3 (C) FULV & IFN alfa-2c Did not meet primary endpoint of ORR
Giacchetti et al. 2000 1994-1996 Phase 3 (C) Chronomodulated FOLFOX Seems to have inferior PFS

Note: See papers for details.

Chemotherapy

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 dosing details in manuscript PubMed
  2. O'Connell MJ; North Central Cancer Treatment Group. A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer: a Mayo Clinic/North Central Cancer Treatment Group study. Cancer. 1989 Mar 15;63(6 Suppl):1026-30. link to original article 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; NCCTG. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol. 1989 Oct;7(10):1407-18. link to original article 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 dosing details in abstract 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; GISCAD. Folinic acid + 5-fluorouracil (5-FU) versus equidose 5-FU in advanced colorectal cancer: phase III study of 'GISCAD' (Italian Group for the Study of Digestive Tract Cancer). Ann Oncol. 1991 Oct;2(9):673-9. link to original article contains dosing details in abstract PubMed
  6. Bobbio-Pallavicini E, Porta C, Moroni M, Spaghi A, Casagranda I, Nastasi G. Folinic acid does improve 5-fluorouracil activity in vivo: results of a phase III study comparing 5-fluorouracil to 5-fluorouracil and folinic acid in advanced colon cancer patients. J Chemother. 1993 Feb;5(1):52-5. link to original article contains dosing details in abstract PubMed
  7. 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 dosing details in abstract PubMed
  8. 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 dosing details in abstract PubMed
  9. 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
  10. Cunningham D, Zalcberg JR, Rath U, Olver I, Van Cutsem E, Svensson C, Seitz JF, Harper P, Kerr D, Perez-Manga G, Azab M, Seymour L, Lowery K; The 'Tomudex' Colorectal Cancer Study Group. 'Tomudex' (ZD1694): results of a randomised trial in advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopenia. Eur J Cancer. 1995 Nov;31A(12):1945-54. link to original article contains dosing details in manuscript PubMed
    1. Update: Cunningham D, Zalcberg JR, Rath U, Oliver I, van Cutsem E, Svensson C, Seitz JF, Harper P, Kerr D, Perez-Manga G; "Tomudex" Colorectal Cancer Study Group. Final results of a randomised trial comparing 'Tomudex' (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. Ann Oncol. 1996 Nov;7(9):961-5. Erratum in: Ann Oncol 1997 Apr;8(4):407. link to original article PubMed
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  12. Jäger E, Heike M, Bernhard H, Klein O, Bernhard G, Lautz D, Michaelis J, Meyer zum Büschenfelde KH, Knuth Al; Study Group for Palliative Treatment of Metastatic Colorectal Cancer. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. J Clin Oncol. 1996 Aug;14(8):2274-9. link to original article contains dosing details in manuscript PubMed
  13. 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 dosing details in abstract PubMed
  14. 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 dosing details in manuscript PubMed
  15. Scheithauer W, Kornek G, Marczell A, Salem G, Karner J, Kovats E, Burger D, Greiner R, Pidlich J, Schneeweiss B, Raderer M, Rosen H, Depisch D. Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study. J Clin Oncol. 1997 Mar;15(3):908-14. link to original article contains dosing details in abstract PubMed
  16. Goldberg RM, Hatfield AK, Kahn M, Sargent DJ, Knost JA, O'Connell MJ, Krook JE, Maillard JA, Wiesenfeld M, Schaefer PL, Tirona MT, Moertel CG; North Central Cancer Treatment Group. Prospectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. J Clin Oncol. 1997 Nov;15(11):3320-9. link to original article contains dosing details in abstract PubMed
  17. Borner MM, Castiglione M, Bacchi M, Weber W, Herrmann R, Fey MF, Pagani O, Leyvraz S, Morant R, Pestalozzi B, Hanselmann S, Goldhirsch A; Swiss Group for Clinical Cancer Research. The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: results of a phase III trial. Ann Oncol. 1998 May;9(5):535-41. link to original article contains dosing details in abstract PubMed
  18. Aranda E, Díaz-Rubio E, Cervantes A, Antón-Torres A, Carrato A, Massutí T, Tabernero JM, Sastre J, Trés A, Aparicio J, López-Vega JM, Barneto I, García-Conde J; TTD. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol. 1998 Jul;9(7):727-31. link to original article contains dosing details in abstract PubMed
  19. Cocconi G, Cunningham D, Van Cutsem E, Francois E, Gustavsson B, van Hazel G, Kerr D, Possinger K, Hietschold SM; Tomudex Colorectal Cancer Study Group. Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. J Clin Oncol. 1998 Sep;16(9):2943-52. link to original article contains dosing details in manuscript PubMed
  20. 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
  21. 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
  22. 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 dosing details in manuscript PubMed
  23. 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 dosing details in manuscript PubMed
  24. 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 dosing details in manuscript PubMed
  25. SO14695: Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001 Apr 15;19(8):2282-92. link to original article contains dosing details in manuscript 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
  26. SO14796: Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P; Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001 Nov 1;19(21):4097-106. link to original article contains dosing details in manuscript 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
  27. 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 dosing details in abstract PubMed
  28. 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 dosing details in abstract PubMed
  29. MRC CR06: Maughan TS, James RD, Kerr DJ, Ledermann JA, McArdle C, Seymour MT, Cohen D, Hopwood P, Johnston C, Stephens RJ; British MRC Colorectal Cancer Working Party. Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2002 May 4;359(9317):1555-63. link to original article PubMed NCT00002893
  30. 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 dosing details in manuscript link to PMC article PubMed
  31. 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 dosing details in abstract PubMed
  32. 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 dosing details in abstract PubMed
  33. Kerr DJ, McArdle CS, Ledermann J, Taylor I, Sherlock DJ, Schlag PM, Buckels J, Mayer D, Cain D, Stephens RJ; Medical Research Council's colorectal cancer study group; EORTC colorectal cancer study group. Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. Lancet. 2003 Feb 1;361(9355):368-73. link to original article contains dosing details in abstract PubMed
  34. 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
  35. EORTC 40952: Köhne CH, Wils J, Lorenz M, Schöffski P, Voigtmann R, Bokemeyer C, Lutz M, Kleeberg C, Ridwelski K, Souchon R, El-Serafi M, Weiss U, Burkhard O, Rückle H, Lichnitser M, Langenbuch T, Scheithauer W, Baron B, Couvreur ML, Schmoll HJ; European Organization of Research and Treatment of Cancer Gastrointestinal Group. Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952. J Clin Oncol. 2003 Oct 15;21(20):3721-8. Epub 2003 Sep 8. link to original article contains dosing details in abstract PubMed
  36. 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
  37. AVF0780g: Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, Mass R, Perrou B, Nelson B, Novotny WF. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005 Jun 1;23(16):3697-705. Epub 2005 Feb 28. link to original article PubMed
  38. EORTC 40986: Köhne CH, van Cutsem E, Wils J, Bokemeyer C, El-Serafi M, Lutz MP, Lorenz M, Reichardt P, Rückle-Lanz H, Frickhofen N, Fuchs R, Mergenthaler HG, Langenbuch T, Vanhoefer U, Rougier P, Voigtmann R, Müller L, Genicot B, Anak O, Nordlinger B; EORTC Gastrointestinal Group. Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol. 2005 Aug 1;23(22):4856-65. Epub 2005 Jun 6. link to original article contains dosing details in manuscript PubMed NCT00004885
  39. 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 dosing details in manuscript PubMed
  40. 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 dosing details in abstract PubMed
  41. FFCD 9601: Ducreux M, Bouche O, Pignon JP, Mousseau M, Raoul JL, Cassan P, Leduc B, Berger C, Dunant A, Fournet J, Bedenne L; FFCD. Randomised trial comparing three different schedules of infusional 5FU and raltitrexed alone as first-line therapy in metastatic colorectal cancer: final results of the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 trial. Oncology. 2006;70(3):222-30. Epub 2006 Jun 30. link to original article PubMed
  42. 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 NCT00008060
  43. 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 dosing details in manuscript PubMed
  44. 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 dosing details in abstract PubMed
  45. 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 dosing details in manuscript PubMed NCT00070213
  46. FFCD 2000-05: Ducreux M, Malka D, Mendiboure J, Etienne PL, Texereau P, Auby D, Rougier P, Gasmi M, Castaing M, Abbas M, Michel P, Gargot D, Azzedine A, Lombard-Bohas C, Geoffroy P, Denis B, Pignon JP, Bedenne L, Bouché O; Fédération Francophone de Cancérologie Digestive. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol. 2011 Oct;12(11):1032-44. Epub 2011 Sep 6. link to original article contains dosing details in abstract PubMed NCT00126256
  47. FFCD 2001-02: Aparicio T, Lavau-Denes S, Phelip JM, Maillard E, Jouve JL, Gargot D, Gasmi M, Locher C, Adhoute X, Michel P, Khemissa F, Lecomte T, Provençal J, Breysacher G, Legoux JL, Lepère C, Charneau J, Cretin J, Chone L, Azzedine A, Bouché O, Sobhani I, Bedenne L, Mitry E; FFCD. Randomized phase III trial in elderly patients comparing LV5FU2 with or without irinotecan for first-line treatment of metastatic colorectal cancer (FFCD 2001-02). Ann Oncol. 2016 Jan;27(1):121-7. Epub 2015 Oct 20. link to original article contains dosing details in supplement PubMed NCT00303771

FULV (L-Leucovorin)

FULV (L-Leucovorin): 5-FU & L-LeucoVorin

Regimen variant #1, 1870/50

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Labianca et al. 1997 1991-1994 Phase 3 (C) FULV; HDLV Did not meet primary endpoint of ORR

Chemotherapy

28-day cycles


Regimen variant #2, 1875/500

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Colucci et al. 1999 1991-1993 Phase 3 (C) FULV & IFN alfa-2b Did not meet primary efficacy endpoints

Chemotherapy

21-day cycles


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

Study Evidence
Cheeseman et al. 2002 Non-randomized
Seymour et al. 2007 (MRC FOCUS) Phase 3 (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, given second, 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, given first

Supportive therapy

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 dosing details in abstract PubMed
  2. Colucci G, Maiello E, Gebbia V, Giuliani F, Serravezza G, Lelli G, Leo S, Filippelli G, Nicolella G, Brandi M; SICOG. 5-fluorouracil and levofolinic acid with or without recombinant interferon-2b in patients with advanced colorectal carcinoma: a randomized multicenter study with stratification for tumor burden and liver involvement by the Southern Italy Oncology Group. Cancer. 1999 Feb 1;85(3):535-45. link to original article contains dosing details in abstract 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 dosing details in manuscript 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 NCT00008060

FULV & Bevacizumab

FULV & Bevacizumab: 5-FU, LeucoVorin, Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kabbinavar et al. 2005 (AVF0780g) 2000-08 to 2002-07 Randomized Phase 2 (E-RT-esc) FULV Did not meet primary endpoint of OS

Note: This regimen was intended for patients who were felt to be nonoptimal candidates for first-line irinotecan.

Chemotherapy

Targeted therapy

56-day cycle for up to 12 cycles

References

  1. AVF0780g: Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, Mass R, Perrou B, Nelson B, Novotny WF. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005 Jun 1;23(16):3697-705. Epub 2005 Feb 28. link to original article contains dosing details in manuscript PubMed

FUOX

FUOX: 5-FU & OXaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Díaz-Rubio et al. 2007 (03-TTD-01) 2002-2004 Phase 3 (C) CapeOx Did not meet primary endpoint of TTP

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

Chemotherapy

14-day cycle for 18 cycles

References

  1. 03-TTD-01: Díaz-Rubio E, Tabernero J, Gómez-España A, Massutí B, Sastre J, Chaves M, Abad A, Carrato A, Queralt B, Reina JJ, Maurel J, González-Flores E, Aparicio J, Rivera F, Losa F, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol. 2007 Sep 20;25(27):4224-30. Epub 2007 Jun 4. link to original article contains dosing details in manuscript PubMed NCT00202774

IFL

IFL: Irinotecan, Fluorouracil, Leucovorin
mIFL: modified Irinotecan, Fluorouracil, Leucovorin

Regimen variant #1, q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Stathopoulos et al. 2010 2004-2008 Phase 3 (C) IFL & Bevacizumab Did not meet primary endpoint of OS36

Chemotherapy

21-day cycles


Regimen variant #2, 4 out of 6 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Saltz et al. 2000 1996-1998 Phase 3 (E-RT-esc) 1. FULV Seems to have superior OS
2. Irinotecan Might have superior OS
Goldberg et al. 2003 (NCCTG N9741) 1999-2001 Phase 3 (C) 1. FOLFOX4 Inferior OS
2. IROX Seems to have inferior OS
Hurwitz et al. 2004 (AVF2107g) 2000-2002 Phase 3 (C) 1. FULV & Bevacizumab Did not meet primary endpoint of OS1
2. IFL & Bevacizumab Inferior OS
Fuchs et al. 2007 (BICC-C) 2003-02 to 2004-12 Phase 3 (E-switch-ic) 1. CapeIRI Did not meet primary endpoint of PFS
2. FOLFIRI Inferior PFS (primary endpoint)
Guan et al. 2011 (ARTISTCRC) 2007-07-20 to 2008-08-07 Phase 3 (C) mIFL & Bevacizumab Inferior OS

1Reported efficacy for this arm of AVF2107g is based on the 2005 update.
Note: 5-FU in ARTIST was given over 6 to 8 hours. ARTIST should not be confused for the trial with the same name in gastric cancer.

Chemotherapy

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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00003594
    1. Toxicity analysis: Delaunoit T, Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Findlay BP, Thomas SP, Salim M, Schaefer PL, Stella PJ, Green E, Mailliard JA. Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup Trial N9741. Cancer. 2004 Nov 15;101(10):2170-6. link to original article 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 dosing details in manuscript PubMed NCT00109070
    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 dosing details in manuscript 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 dosing details in manuscript PubMed
  6. ARTISTCRC: Guan ZZ, Xu JM, Luo RC, Feng FY, Wang LW, Shen L, Yu SY, Ba Y, Liang J, Wang D, Qin SK, Wang JJ, He J, Qi C, Xu RH. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer. 2011 Oct;30(10):682-9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00642577

IFL & Bevacizumab

IFL & Bevacizumab: Irinotecan, Fluorouracil, Leucovorin, Bevacizumab
mIFL & Bevacizumab: modified Irinotecan, Fluorouracil, Leucovorin, Bevacizumab

Regimen variant #1, IFL

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hurwitz et al. 2004 (AVF2107g) 2000-2002 Phase 3 (E-RT-esc) 1. FL & Bevacizumab Not reported
2. IFL Superior OS (primary endpoint)
Median OS: 20.3 vs 15.6 mo
(HR 0.66)
Fuchs et al. 2007 (BICC-C) 2003-02 to 2004-12 Phase 3 (E-switch-ic) FOLFIRI+Bev Seems to have inferior OS (secondary endpoint)

Chemotherapy

Targeted therapy

21-day cycles


Regimen variant #2, mIFL

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Guan et al. 2011 (ARTISTCRC) 2007-07-20 to 2008-08-07 Phase 3 (E-esc) mIFL Superior OS (secondary endpoint)
Median OS: 18.7 vs 13.4 mo
(HR 0.62, 95% CI 0.41-0.95)

Superior PFS (co-primary endpoint)

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

Chemotherapy

Targeted therapy

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 NCT00109070
    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
  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 dosing details in manuscript 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. ARTISTCRC: Guan ZZ, Xu JM, Luo RC, Feng FY, Wang LW, Shen L, Yu SY, Ba Y, Liang J, Wang D, Qin SK, Wang JJ, He J, Qi C, Xu RH. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer. 2011 Oct;30(10):682-9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00642577

Irinotecan monotherapy

Example orders

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Saltz et al. 2000 1996-1998 Phase 3 (E-de-esc) 1. FULV Did not meet primary endpoint of PFS
2. IFL Might have inferior OS (secondary endpoint)

Chemotherapy

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 dosing details in manuscript PubMed

IRIS & Bevacizumab

IRIS & Bevacizumab: IRInotecan, S-1, Bevacizumab

Regimen variant #1, q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yamada et al. 2018 (TRICOLORE) 2012-2014 Phase 3 (E-switch-ic) 1a. CapeOx & Bevacizumab
1b. mFOLFOX6-B 		Non-inferior PFS (primary endpoint)
Median PFS: 14 vs 10.8 mo
(HR 0.84, 95% CI 0.70-1.02)

Chemotherapy

Targeted therapy

21-day cycles


Regimen variant #2, q4wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yamada et al. 2018 (TRICOLORE) 2012-2014 Phase 3 (E-switch-ic) 1a. CapeOx & Bevacizumab
1b. mFOLFOX6-B 		Non-inferior PFS (primary endpoint)
Median PFS: 14 vs 10.8 mo
(HR 0.84, 95% CI 0.70-1.02)

Chemotherapy

Targeted therapy

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 dosing details in manuscript link to PMC article PubMed UMIN000007834

IROX

IROX: IRinotecan & OXaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Goldberg et al. 2003 (NCCTG N9741) 1999-2001 Phase 3 (E-RT-switch-ic) 1. FOLFOX4 Did not meet primary endpoint of TTP
2. IFL Seems to have superior OS (secondary endpoint)

Chemotherapy

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 dosing details in manuscript PubMed NCT00003594
    1. Toxicity analysis: Delaunoit T, Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Findlay BP, Thomas SP, Salim M, Schaefer PL, Stella PJ, Green E, Mailliard JA. Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup Trial N9741. Cancer. 2004 Nov 15;101(10):2170-6. link to original article PubMed

Nordic FLOX

FLOX: Fluorouracil, Leucovorin, OXaliplatin

Example orders

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sørbye et al. 2004 2000-2001 Phase 2
Tveit et al. 2012 (NORDIC-VII) 2005-2007 Phase 3 (C) Nordic FLOX & Cetuximab Did not meet primary endpoint of PFS

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

Chemotherapy

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 dosing details in abstract 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 dosing details in manuscript PubMed NCT00145314
    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 original article link to PMC article PubMed

OXAFAFU

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Comella et al. 2005 2001-2003 Phase 3 (E-switch-ic) IRIFAFU Seems to have superior OS (secondary endpoint)
Median OS: 18.9 vs 15.6 mo

Chemotherapy

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; SICOG. Oxaliplatin plus high-dose folinic acid and 5-fluorouracil IV bolus (OXAFAFU) versus irinotecan plus high-dose folinic acid and 5-fluorouracil IV bolus (IRIFAFU) in patients with metastatic colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase III trial. Ann Oncol. 2005 Jun;16(6):878-86. Epub 2005 Apr 18. link to original article contains dosing details in abstract PubMed

S-1 monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Kwakman et al. 2017 (SALTO) 2014-01 to 2015-07 Phase 3 (E-switch-ic) Capecitabine Did not meet secondary efficacy endpoints1 Lower incidence of hand-foot syndrome

1Reported efficacy is based on the 2019 update.
Note: this trial had a primary toxicity endpoint.

Chemotherapy

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; Dutch Colorectal Cancer Group. Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group. Ann Oncol. 2017 Jun 1;28(6):1288-1293. link to original article contains dosing details in abstract PubMed NCT01918852
    1. Update: Kwakman JJM, van Werkhoven E, Simkens LHJ, van Rooijen JM, van de Wouw YAJ, ten Tije AJ, Creemers GM, Hendriks MP, Los M, van Alphen RJ, Polée MB, Muller EW, van der Velden AMT, van Voorthuizen T, Koopman M, Mol L, Punt CJA; Dutch Colorectal Cancer Group. Updated Survival Analysis of the Randomized Phase III Trial of S-1 Versus Capecitabine in the First-Line Treatment of Metastatic Colorectal Cancer by the Dutch Colorectal Cancer Group. Clin Colorectal Cancer. 2019 Jun;18(2):e229-e230. Epub 2019 Jan 29. link to original article PubMed

SOX

SOX: S-1 & OXaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hong et al. 2012 (SMC 2008-03-012) 2008-05-14 to 2009-09-23 Phase 3 (E-switch-ic) CapeOX Non-inferior PFS (primary endpoint)
Median PFS: 8.5 vs 6.7 mo
(HR 0.79, 95% CI 0.60-1.04)

Chemotherapy

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 dosing details in abstract PubMed NCT00677443
    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

SOX & Bevacizumab: S-1, OXaliplatin, Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yamada et al. 2013 (SOFTCRC) 2009-2011 Phase 3 (E-switch-ic) mFOLFOX6-B Seems to have non-inferior PFS

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

Chemotherapy

  • Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
    • Less than 1.25 m2: 40 mg PO twice per day on days 1 to 14 (see note)
    • Between 1.25 m2 and 1.5 m2: 50 mg PO twice per day on days 1 to 14 (see note)
    • 1.5 m2 or more: 60 mg PO twice per day on days 1 to 14 (see note)
  • Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1, given second

Targeted therapy

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 JapicCTI-090699
    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 dosing details in manuscript PubMed

Maintenance after first-line therapy

Bevacizumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Johnsson et al. 2013 (Nordic ACT) 2007-2009 Phase 3 (C) Erlotinib & Bevacizumab Did not meet primary endpoint of PFS
Tournigand et al. 2015 (OPTIMOX3) 2007-2011 Phase 3 (C) Erlotinib & Bevacizumab Might have inferior PFS
Koeberle et al. 2015 (SAKK 41/06) 2007-2012 Phase 3 (E-esc) No further treatment Inconclusive whether non-inferior TTP (primary endpoint)
Hegewisch-Becker et al. 2015 (AIO KRK 0207) 2009-2013 Phase 3 (E-esc) 1. No further treatment Not reported
2. Fluoropyrimidine & Bevacizumab Non-inferior TTF (primary endpoint)
Aparicio et al. 2018 (PRODIGE 9) 2010-2013 Phase 3 (E-esc) No further treatment Did not meet primary endpoint of TCD

Preceding treatment

Targeted therapy

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 dosing details in manuscript PubMed NCT00598156
  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 dosing details in manuscript PubMed NCT00544700
  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 NCT00973609
  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 dosing details in abstract PubMed NCT00265824
  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 NCT00952029

Capecitabine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hong et al. 2012 (SMC 2008-03-012) 2008-05-14 to 2009-09-23 Non-randomized part of phase 3 RCT
Luo et al. 2016 2010-2013 Phase 3 (E-esc) Observation Superior PFS (primary endpoint)
Median PFS: 6.4 vs 3.4 mo
(HR 0.54, 95% CI 0.42-0.70)
Adams et al. 2021 (FOCUS4-N) 2014-2020 Phase 3 (E-esc) Observation Superior PFS (primary endpoint)
Median PFS: 3.9 vs 1.9 mo
(HR 0.44, 95% CI 0.33-0.57)

Note: In FOCUS4-N, capecitabine was dosed "according to standard guidelines".

Preceding treatment

Chemotherapy

21-day cycles

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 dosing details in abstract PubMed NCT00677443
  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 dosing details in manuscript PubMed NCT02027363
  3. FOCUS4-N: Adams RA, Fisher DJ, Graham J, Seligmann JF, Seymour M, Kaplan R, Yates E, Parmar M, Richman SD, Quirke P, Butler R, Brown E, Collinson F, Falk S, Wasan H, Shiu KK, Middleton G, Samuel L, Wilson RH, Brown LC, Maughan TS; FOCUS4 Trial Investigators. Capecitabine Versus Active Monitoring in Stable or Responding Metastatic Colorectal Cancer After 16 Weeks of First-Line Therapy: Results of the Randomized FOCUS4-N Trial. J Clin Oncol. 2021 Nov 20;39(33):3693-3704. Epub 2021 Sep 13. link to original article link to PMC article PubMed ISRCTN90061546

Capecitabine & Bevacizumab

CAP-B: CAPecitabine & Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yalcin et al. 2013 (Stop and Go) 2008-04 to 2009-07 Phase 3 (E-de-esc) XELOX-B; continued Superior PFS (primary endpoint)
Median PFS: 11 vs 8.3 mo
(HR 0.6, 95% CI 0.43-0.83)
Simkens et al. 2015 (CAIRO3) 2007-2012 Phase 3 (E-esc) Observation Superior PFS-2 (primary endpoint)
Median PFS: 11.7 vs 8.5 mo
(HR 0.67, 95% CI 0.56-0.81)

Preceding treatment

Chemotherapy

Targeted therapy

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; Turkish Oncology Group. Bevacizumab + capecitabine as maintenance therapy after initial bevacizumab + XELOX treatment in previously untreated patients with metastatic colorectal cancer: phase III 'Stop and Go' study results--a Turkish Oncology Group trial. Oncology. 2013;85(6):328-35. Epub 2013 Nov 12. link to original article PubMed NCT00623805
  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; Dutch Colorectal Cancer Group. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015 May 9;385(9980):1843-52. Epub 2015 Apr 7. link to original article contains dosing details in manuscript PubMed NCT00442637
    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

Fluorouracil & Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (LYNK-003) 2020-ongoing Phase 3 (C) Fluorouracil, Olaparib, Bevacizumab Ongoing

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. Dosing details are from CT.gov.

Preceding treatment

Chemotherapy

  • Fluorouracil (5-FU) 2400 mg/m2 IV continuous infusion over 46 to 48 hours (total dose per cycle: 2400 mg/m2)

Targeted therapy

14-day cycles

References

  1. LYNK-003: NCT04456699

FULV & Bevacizumab (L-Leucovorin)

FULV & Bevacizumab: 5-FU, LevoleucoVorin, Bevacizumab

Regimen

Study Dates of enrollment Evidence
Loupakis et al. 2014 (TRIBE) 2008-2011 Non-randomized part of phase 3 RCT

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

Preceding treatment

Chemotherapy

Targeted therapy

14-day cycles

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 dosing details in manuscript PubMed NCT00719797
    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. Epub 2015 Aug 31. link to original article PubMed

S-1 monotherapy

Regimen

Study Dates of enrollment Evidence
Hong et al. 2012 (SMC 2008-03-012) 2008-05-14 to 2009-09-23 Non-randomized part of phase 3 RCT

Preceding treatment

  • First-line SOX x 9

Chemotherapy

21-day cycles

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 dosing details in abstract PubMed NCT00677443

Advanced or metastatic disease, second-line therapy

CapeOx

CapeOx: Capecitabine & Oxaliplatin
XELOX: XELoda & OXaliplatin

Example orders

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Koopman et al. 2007 (CAIRO) 2003-01 to 2004-12 Phase 3 (E-switch-ic) See link See link
Rothenberg et al. 2008 (NO16967) 2003-2005 Phase 3 (E-switch-ic) FOLFOX4 Non-inferior PFS (primary endpoint)

Preceding treatment

  • CAIRO: First-line CAPIRI, with progression

Chemotherapy

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; Dutch Colorectal Cancer Group. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article contains dosing details in manuscript PubMed NCT00312000
  2. NO16967: Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, Gollins S, Siu LL, Laguerre S, Cunningham D. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008 Oct;19(10):1720-6. Epub 2008 Jun 10. link to original article contains dosing details in manuscript PubMed

CapeOx & Erlotinib

CapeOx & Erlotinib: Capecitabine, OXaliplatin, Erlotinib

Regimen

Study Dates of enrollment Evidence
Meyerhardt et al. 2006 2003-2004 Phase 2

Chemotherapy

Targeted therapy

21-day cycles

References

  1. Meyerhardt JA, Zhu AX, Enzinger PC, Ryan DP, Clark JW, Kulke MH, Earle CC, Vincitore M, Michelini A, Sheehan S, Fuchs CS. Phase II study of capecitabine, oxaliplatin, and erlotinib in previously treated patients with metastastic colorectal cancer. J Clin Oncol. 2006 Apr 20;24(12):1892-7. link to original article PubMed

CAPIRI

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

Regimen variant #1, "standard"

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lim et al. 2015 (SMC 2009-11-017) 2010-2013 Phase 3 (C) 1a. FOLFIRI & Simvastatin
1b. XELIRI & Simvastatin 		Did not meet primary endpoint of PFS

Chemotherapy

21-day cycles


Regimen variant #2, "modified"

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2018 (AXEPT) 2013-2015 Phase 3 (E-switch-ic) 1a. FOLFIRI
1b. FOLFIRI & Bevacizumab 		Non-inferior OS (primary endpoint)
Median OS: 16.8 vs 15.4 mo
(HR 0.85, 95% CI 0.71-1.02)

Chemotherapy

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 dosing details in manuscript link to PMC article PubMed NCT01238094
  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 dosing details in manuscript PubMed NCT01996306

CAPIRI-Bev

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2018 (AXEPT) 2013-2015 Phase 3 (E-switch-ic) 1a. FOLFIRI
1b. FOLFIRI & Bevacizumab 		Non-inferior OS (primary endpoint)
Median OS: 16.8 vs 15.4 mo
(HR 0.85, 95% CI 0.71-1.02)

Chemotherapy

Targeted therapy

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 dosing details in manuscript PubMed NCT01996306

Fluorouracil monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rougier et al. 1998 (V302) 1995-1997 Phase 3 (C) Irinotecan Seems to have inferior OS

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

Chemotherapy

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 dosing details in manuscript PubMed

FOLFIRI

FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan

Example orders

Regimen variant #1, lower-dose leucovorin

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lim et al. 2015 (SMC 2009-11-017) 2010-2013 Phase 3 (C) 1a. FOLFIRI & Simvastatin
1b. XELIRI & Simvastatin 		Did not meet primary endpoint of PFS

Chemotherapy

14-day cycles


Regimen variant #2, higher-dose leucovorin

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tournigand et al. 2003 1997-1999 Phase 3 (E-switch-ic) mFOLFOX6 Did not meet primary endpoint of PFS15
Peeters et al. 2010 (20050181) 2006-2008 Phase 3 (C) FOLFIRI & Panitumumab Seems to have inferior PFS1
Bennouna et al. 2012 (ML18147) 2006-2010 Phase 3 (C) Second-line chemotherapy & Bevacizumab (see note) Inferior OS
Van Cutsem et al. 2012 (VELOUR) 2007-2010 Phase 3 (C) FOLFIRI & Ziv-aflibercept Inferior OS
Masi et al. 2015 (BEBYP) 2008-2012 Phase 3 (C) FOLFIRI & Bevacizumab Inferior PFS
Tabernero et al. 2015 (RAISE) 2010-2013 Phase 3 (C) FOLFIRI & Ramucirumab Seems to have inferior OS
Xu et al. 2018 (AXEPT) 2013-2015 Phase 3 (C) 1a. mXELIRI
1b. mXELIRI & Bevacizumab 		Non-inferior OS
Shah et al. 2023 (CanStem303C) 2016-08-31 to 2019-03-18 Phase 3 (C) FOLFIRI & Napabucasin Did not meet primary endpoint of OS

1Reported efficacy for 20050181 is for wild-type KRAS, only, and is based on the 2014 update.
Note: the abstract of ML18147 does not specify the exact second-line chemotherapy regimen; patients had to be previously bevacizumab-exposed. BEBYP does not provide dosing details; this is the most commonly used variant of FOLFIRI.

Chemotherapy

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

14-day cycles

Subsequent treatment

  • Tournigand et al. 2003, upon progression: mFOLFOX6

Dose and schedule modifications

  • In Tournigand et al. 2003, if no toxicity greater than grade 1 in cycles 1 & 2, fluorouracil increased to: 400 mg/m2 IV bolus once on day 1, then 3000 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 3400 mg/m2)

References

  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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00339183
    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. 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 dosing details in abstract PubMed NCT00126256
  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. Epub 2012 Sep 4. link to original article contains dosing details in manuscript PubMed NCT00561470
    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. Epub 2013 Oct 16. 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. 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 NCT00700102
  6. BEBYP: Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-30. Epub 2015 Jan 18. link to original article does not contain dosing details PubMed NCT00720512
  7. RAISE: Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F; RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 May;16(5):499-508. Epub 2015 Apr 12. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. link to original article contains dosing details in manuscript PubMed NCT01183780
    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
  8. 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 dosing details in manuscript link to PMC article PubMed NCT01238094
  9. 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 dosing details in manuscript PubMed NCT01996306
  10. CanStem303C: Shah MA, Yoshino T, Tebbutt NC, Grothey A, Tabernero J, Xu RH, Cervantes A, Oh SC, Yamaguchi K, Fakih M, Falcone A, Wu C, Chiu VK, Tomasek J, Bendell J, Fontaine M, Hitron M, Xu B, Taieb J, Van Cutsem E. Napabucasin Plus FOLFIRI in Patients With Previously Treated Metastatic Colorectal Cancer: Results From the Open-Label, Randomized Phase III CanStem303C Study. Clin Colorectal Cancer. 2023 Mar;22(1):100-110. Epub 2022 Nov 11. link to original article PubMed NCT02753127
  11. KRYSTAL-10: NCT04793958

FOLFIRI (L-Leucovorin)

FOLFIRI: FOLinic acid (L-Leucovorin), Fluorouracil, IRInotecan

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tournigand et al. 2003 1997-1999 Phase 3 (E-switch-ic) mFOLFOX6 Did not meet primary endpoint of PFS15
Xu et al. 2018 (AXEPT) 2013-2015 Phase 3 (C) 1a. mXELIRI
1b. 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 second (total dose per cycle: 2800 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1, given first, with levoleucovorin

14-day cycles

Subsequent treatment

  • Tournigand et al. 2003, upon progression: mFOLFOX6

Dose and schedule modifications

  • In Tournigand et al. 2003, if no toxicity greater than grade 1 in cycles 1 & 2, fluorouracil increased to: 400 mg/m2 IV bolus once on day 1, then 3000 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 3400 mg/m2)

References

  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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT01996306

FOLFIRI & Bevacizumab

FOLFIRI & Bevacizumab: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan, Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bennouna et al. 2012 (ML18147) 2006-2010 Phase 3 (E-RT-esc) Second-line chemotherapy (see note) Superior OS (primary endpoint)
Median OS: 11.2 vs 9.8 mo
(HR 0.81, 95% CI 0.69-0.94)
Masi et al. 2015 (BEBYP) 2008-2012 Phase 3 (E-esc) FOLFIRI Superior PFS (primary endpoint)
Median PFS: 6.8 vs 5 mo
(HR 0.70, 95% CI 0.52-0.95)
Xu et al. 2018 (AXEPT) 2013-2015 Phase 3 (C) 1a. mXELIRI
1b. mXELIRI & Bevacizumab 		Non-inferior OS

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

Chemotherapy

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

Targeted therapy

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 NCT00700102
  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 dosing details PubMed NCT00720512
  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 dosing details in manuscript PubMed NCT01996306

FOLFIRI & Bevacizumab (L-Leucovorin)

FOLFIRI & Bevacizumab: FOLinic acid (L-Leucovorin), Fluorouracil, IRInotecan, Bevacizumab

Regimen variant #1, 200/2800/150/5

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Iwamoto et al. 2015 (EAGLECRC) 2009-2012 Phase 3 (C) FOLFIRI & Bevacizumab; lower-dose bevacizumab (10 mg/kg) Did not meet primary endpoint of PFS

Note: this study should not be confused by the one of the same name for head & neck cancer.

Chemotherapy

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

Targeted therapy

14-day cycles


Regimen variant #2, 200/2800/180/5

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2018 (AXEPT) 2013-2015 Phase 3 (C) 1a. mXELIRI
1b. 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

Targeted therapy

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 dosing details in manuscript PubMed UMIN000002557
  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 dosing details in manuscript PubMed NCT01996306

FOLFIRI & Ramucirumab

FOLFIRI & Ramucirumab: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan & Ramucirumab

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tabernero et al. 2015 (RAISE) 2010-2013 Phase 3 (E-RT-esc) FOLFIRI Seems to have superior OS (primary endpoint)
Median OS: 13.3 vs 11.7 mo
(HR 0.84, 95% CI 0.73-0.98)

Chemotherapy

  • Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, either given third or concurrently with irinotecan
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 1200 mg/m2/day IV continuous infusion over 48 hours, given third (total dose per cycle: 2800 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 90 minutes once on day 1, given second

Targeted therapy

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. Epub 2015 Apr 12. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. link to original article contains dosing details in manuscript PubMed NCT01183780
    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

FOLFIRI & Ziv-aflibercept: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan, Ziv-aflibercept

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Van Cutsem et al. 2012 (VELOUR) 2007-2010 Phase 3 (E-RT-esc) FOLFIRI Superior OS (primary endpoint)
Median OS: 13.5 vs 12.1 mo
(HR 0.82, 95.34% CI 0.71-0.94)
Li et al. 2018 (AFLAME) 2012-2014 Phase 3 (E-esc) FOLFIRI Superior PFS (primary endpoint)
Median PFS: 6.9 vs 5.6 mo
(HR 0.63, 95% CI 0.49-0.81)

Chemotherapy

Targeted therapy

Supportive therapy

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. Epub 2012 Sep 4. link to original article PubMed NCT00561470
    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. Epub 2013 Oct 16. link to original article contains dosing details in manuscript 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 dosing details in manuscript PubMed NCT01661270

FOLFOX4

FOLFOX4: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rothenberg et al. 2003 (BRCC-00036) 2000-11 to 2001-09 Phase 3 (E-RT-esc) 1. LV5FU2
2. Oxaliplatin 		Superior TTP (secondary endpoint)

Superior ORR (primary endpoint)
Rothenberg et al. 2008 (NO16967) 2003-2005 Phase 3 (E-switch-ic) XELOX Non-inferior PFS (primary endpoint)

Chemotherapy

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

14-day cycles

References

  1. BRCC-00036: Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, Hart LL, Gupta S, Garay CA, Burger BG, Le Bail N, Haller DG. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol. 2003 Jun 1;21(11):2059-69. link to original article contains dosing details in manuscript PubMed
  2. NO16967: Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, Gollins S, Siu LL, Laguerre S, Cunningham D. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008 Oct;19(10):1720-6. Epub 2008 Jun 10. link to original article refers to de Gramont et al. 2000 protocol PubMed

mFOLFOX6

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

Example orders

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Masi et al. 2015 (BEBYP) 2008-2012 Phase 3 (C) mFOLFOX6-B Inferior PFS

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

Chemotherapy

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 dosing details PubMed NCT00720512
  2. KRYSTAL-10: NCT04793958

mFOLFOX6-B

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Masi et al. 2015 (BEBYP) 2008-2012 Phase 3 (E-esc) mFOLFOX6 Superior PFS (primary endpoint)
Median PFS: 6.8 vs 5 mo
(HR 0.70, 95% CI 0.52-0.95)

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

Chemotherapy

Targeted therapy

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 dosing details PubMed NCT00720512

FULV

FULV: 5-FU & LeucoVorin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rothenberg et al. 2003 (BRCC-00036) 2000-11 to 2001-09 Phase 3 (C) 1. FOLFOX4 Inferior ORR
2. Oxaliplatin Did not meet primary endpoint of ORR

Chemotherapy

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

14-day cycles

References

  1. BRCC-00036: Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, Hart LL, Gupta S, Garay CA, Burger BG, Le Bail N, Haller DG. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol. 2003 Jun 1;21(11):2059-69. link to original article contains dosing details in manuscript PubMed

Irinotecan monotherapy

Example orders

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

Study Dates of enrollment Evidence
Rothenberg et al. 1999 1994 Phase 2 (RT)

Note: this was a mid-protocol dose amendment for excess toxicity.

Chemotherapy

42-day cycles


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

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rothenberg et al. 1996 NR Phase 2 (RT)
Pitot et al. 1997 1993-1994 Phase 2 (RT)
Fuchs et al. 2003 1998-2001 Phase 3 (E-switch-ic) Irinotecan; every 3 weeks Did not meet primary endpoint of OS
OS12: 46% vs 41%

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

Chemotherapy

42-day cycles


Regimen variant #3, 250 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Haller et al. 2008 (EFC4585) 2001-2004 Phase 3 (C) IROX Inferior OS

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

Chemotherapy

21-day cycles


Regimen variant #4, 300 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rougier et al. 1998 (V302) 1995-1997 Phase 3 (E-RT-switch-ic) CI 5-FU Seems to have superior OS
Median OS: 10.8 vs 8.5 mo
Fuchs et al. 2003 1998-2001 Phase 3 (E-switch-ic) Irinotecan; 4 weeks out of 6 Did not meet primary endpoint of OS
OS12: 41% vs 46%
Kim et al. 2009 (N9841) 1999-2003 Phase 3 (C) FOLFOX4 Non-inferior OS
Sobrero et al. 2008 (EPIC) 2003-2006 Phase 3 (C) Irinotecan & Cetuximab Did not meet primary endpoint of OS

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

Chemotherapy

21-day cycles


Regimen variant #5, 350 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rougier et al. 1997 1992-1993 Phase 2 (RT)
Rougier et al. 1998 (V302) 1995-1997 Phase 3 (E-RT-switch-ic) CI 5-FU Seems to have superior OS
Median OS: 10.8 vs 8.5 mo
Lal et al. 2004 1997-2002 Phase 3 (C) Irinotecan x 8 Did not meet primary endpoint of FFS
Fuchs et al. 2003 1998-2001 Phase 3 (E-switch-ic) Irinotecan; 4 weeks out of 6 Did not meet primary endpoint of OS
OS12: 41% vs 46%
Kim et al. 2009 (N9841) 1999-2003 Phase 3 (C) FOLFOX4 Non-inferior OS
Haller et al. 2008 (EFC4585) 2001-2004 Phase 3 (C) IROX Inferior OS
Koopman et al. 2007 (CAIRO) 2003-01 to 2004-12 Phase 3 (C) See link See link
Sobrero et al. 2008 (EPIC) 2003-2006 Phase 3 (C) Irinotecan & Cetuximab Did not meet primary endpoint of OS

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

Preceding treatment

Chemotherapy

Supportive therapy

21-day cycles

Subsequent treatment

  • CAIRO, with progression: Third-line 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 dosing details in abstract 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 dosing details in abstract 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 dosing details in abstract 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 dosing details in abstract 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 dosing details in manuscript 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 dosing details in abstract 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; Dutch Colorectal Cancer Group. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article contains dosing details in manuscript PubMed NCT00312000
  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 dosing details in manuscript PubMed NCT00063141
  10. EFC4585: Haller DG, Rothenberg ML, Wong AO, Koralewski PM, Miller WH Jr, Bodoky G, Habboubi N, Garay C, Olivatto LO. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008 Oct 1;26(28):4544-50. link to original article contains dosing details in manuscript PubMed NCT00012389
  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; NCCTG. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol. 2009 Jun 10;27(17):2848-54. Epub 2009 Apr 20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00005036

IRIS

IRIS: IRInotecan & S-1

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Muro et al. 2010 (FIRIS) 2006-2008 Phase 3 (E-switch-ic) FOLFIRI Non-inferior OS1 (secondary endpoint)

1Reported efficacy is based on the 2014 update.

Chemotherapy

  • Irinotecan (Camptosar) 125 mg/m2 IV once per day on days 1 & 15
  • Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
    • Less than 1.25 m2: 40 mg PO twice per day on days 1 to 14
    • Between 1.25 m2 and 1.5 m2: 50 mg PO twice per day on days 1 to 14
    • 1.5 m2 or more: 60 mg PO twice per day on days 1 to 14

28-day cycles

References

  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 original article contains dosing details in manuscript PubMed NCT00284258
    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

IROX: IRinotecan & OXaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Haller et al. 2008 (EFC4585) 2001-2004 Phase 3 (E-esc) Irinotecan Superior OS (primary endpoint)
Median OS: 13.4 vs 11.1 mo
(HR 0.78, 95% CI 0.65-0.94)

Chemotherapy

21-day cycles

References

  1. EFC4585: Haller DG, Rothenberg ML, Wong AO, Koralewski PM, Miller WH Jr, Bodoky G, Habboubi N, Garay C, Olivatto LO. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008 Oct 1;26(28):4544-50. link to original article contains dosing details in manuscript PubMed NCT00012389

Advanced or metastatic disease, third-line therapy

CapeOx

CapeOX: Capecitabine, OXaliplatin

Example orders

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Koopman et al. 2007 (CAIRO) 2003-01 to 2004-12 Phase 3 (C) See link See link

Preceding treatment

Chemotherapy

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; Dutch Colorectal Cancer Group. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article contains dosing details in manuscript PubMed NCT00312000

FOLFIRI

FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan

Example orders

Regimen

Study Dates of enrollment Evidence
André et al. 1999 1996-12 to 1997-11 Non-randomized

Chemotherapy

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

14-day cycles

Dose and schedule modifications

  • In André et al. 1999, the continuous 5-FU infusion dose could be increased from 1200 mg/m2/day to 1500 mg/m2/day if there were no toxicities higher than grade 1

References

  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 dosing details in manuscript PubMed

Regorafenib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Eng et al. 2019 (IMblaze370) 2016-07-27 to 2017-01-19 Phase 3 (C) 1. Atezolizumab
2. Cobimetinib & Atezolizumab 		Did not meet primary endpoint of OS

Targeted therapy

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 dosing details in abstract PubMed NCT02788279

Advanced or metastatic disease, subsequent lines of therapy

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

Capecitabine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (X-PECT) 2010-NR Phase 3 (C) Capecitabine & Perifosine Not reported

Note: this trial has not yet been published; dosing details are from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

21-day cycles

References

  1. X-PECT: NCT01097018

Durvalumab & Tremelimumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Chen et al. 2020 (NCIC-CTG CO.26) 2016-2017 Randomized Phase 2 (E-esc) Best supportive care Might have superior OS (primary endpoint)
Median OS: 6.6 vs 4.1 mo
(HR 0.72, 90% CI 0.54-0.97)

Eligibility criteria

  • Advanced CRC progressed on all available standard systemic therapies, ECOG PS 0-1. PD-L1, TMB, MSI status were NOT used as inclusion criteria

Immunotherapy

28-day cycles

References

  1. NCIC-CTG CO.26: Chen EX, Jonker DJ, Loree JM, Kennecke HF, Berry SR, Couture F, Ahmad CE, Goffin JR, Kavan P, Harb M, Colwell B, Samimi S, Samson B, Abbas T, Aucoin N, Aubin F, Koski S, Wei AC, Magoski NM, Tu D, O'Callaghan CJ. Effect of Combined Immune Checkpoint Inhibition vs Best Supportive Care Alone in Patients With Advanced Colorectal Cancer: The Canadian Cancer Trials Group CO.26 Study. JAMA Oncol. 2020;6(6):831–838. link to article contains dosing details in abstract link to PMC article PubMed NCT02870920

Fluorouracil monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hendlisz et al. 2010 (Sir-Spheres1) 2004-2007 Phase 3 (C) 5-FU & Radioembolization 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. Sir-Spheres1: Hendlisz A, Van den Eynde M, Peeters M, Maleux G, Lambert B, Vannoote J, De Keukeleire K, Verslype C, Defreyne L, Van Cutsem E, Delatte P, Delaunoit T, Personeni N, Paesmans M, Van Laethem JL, Flamen P. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol. 2010 Aug 10;28(23):3687-94. Epub 2010 Jun 21. link to original article contains dosing details in abstract PubMed NCT00199173

FOLFOX4

FOLFOX4: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Giantonio et al. 2007 (ECOG E3200) 2001-2003 Phase 3 (C) 1. FOLFOX4 & Bevacizumab Inferior OS
2. Bevacizumab Not reported
Kim et al. 2009 (N9841) 1999-2003 Phase 3 (E-esc) Irinotecan Non-inferior OS (primary endpoint)
Median OS: 13.8 vs 14.3 mo
(HR 0.92, 95% CI 0.80-1.10)
Van Cutsem et al. 2011 (CONFIRM 2) 2003-01 to 2004-10 Phase 3 (C) FOLFOX4 & Vatalanib Did not meet primary endpoint of OS

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

Chemotherapy

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

14-day cycles

References

  1. ECOG E3200: Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd; ECOG. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007 Apr 20;25(12):1539-44. link to original article contains dosing details in manuscript PubMed NCT00025337
  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; NCCTG. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol. 2009 Jun 10;27(17):2848-54. Epub 2009 Apr 20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00005036
  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 dosing details in manuscript PubMed NCT00056446

FOLFOX4 (L-Leucovorin)

FOLFOX4: FOLinic acid (L-Leucovorin), Fluorouracil, OXaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Van Cutsem et al. 2011 (CONFIRM 2) 2003-01 to 2004-10 Phase 3 (C) FOLFOX4 & Vatalanib Did not meet primary endpoint of OS

Note: these patients had not previously received oxaliplatin.

Chemotherapy

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

14-day cycles

References

  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 dosing details in manuscript PubMed NCT00056446

FOLFOX4 & Bevacizumab

FOLFOX4 & Bevacizumab: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Giantonio et al. 2007 (ECOG E3200) 2001-2003 Phase 3 (E-RT-esc) 1. FOLFOX4 Superior OS (primary endpoint)
Median OS: 12.9 vs 10.8 mo
(HR 0.75, 95% CI 0.63-0.89)
2. Bevacizumab Not reported

Chemotherapy

Targeted therapy

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; ECOG. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007 Apr 20;25(12):1539-44. link to original article contains dosing details in manuscript PubMed NCT00025337

Fruquintinib monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Li et al. 2018 (FRESCO) 2014-2016 Phase 3 (E-RT-esc) Placebo Superior OS (primary endpoint)
Median OS: 9.3 vs 6.6 mo
(HR 0.65, 95% CI 0.51-0.83)
Dasari et al. 2023 (FRESCO-2) 2020-08-12 to 2021-12-02 Phase 3 (E-RT-esc) Placebo Superior OS (primary endpoint)
Median OS: 7.4 vs 4.8 mo
(HR 0.66, 95% CI 0.55-0.80)

Prior treatment criteria

  • FRESCO: At least 2 lines of chemotherapy but no prior VEGFR inhibitor therapy, with progression
  • FRESCO-2: All current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil and/or regorafenib

Targeted therapy

28-day cycles

References

  1. 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 contains dosing details in abstract link to PMC article PubMed NCT02314819
  2. FRESCO-2: Dasari A, Lonardi S, Garcia-Carbonero R, Elez E, Yoshino T, Sobrero A, Yao J, García-Alfonso P, Kocsis J, Cubillo Gracian A, Sartore-Bianchi A, Satoh T, Randrian V, Tomasek J, Chong G, Paulson AS, Masuishi T, Jones J, Csőszi T, Cremolini C, Ghiringhelli F, Shergill A, Hochster HS, Krauss J, Bassam A, Ducreux M, Elme A, Faugeras L, Kasper S, Van Cutsem E, Arnold D, Nanda S, Yang Z, Schelman WR, Kania M, Tabernero J, Eng C; FRESCO-2 Study Investigators. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023 Jul 1;402(10395):41-53. Epub 2023 Jun 15. link to original article contains dosing details in abstract PubMed NCT04322539

FULV & Bevacizumab

FULV & Bevacizumab: 5-FU, LeucoVorin, Bevacizumab

Regimen variant #1, Roswell Park backbone

Study Dates of enrollment Evidence
Chen et al. 2006 (TRC-301) 2003 Phase 2 (RT)

Note: this is based on the Roswell Park regimen backbone.

Chemotherapy

Targeted therapy

56-day cycles


Regimen variant #2, de Gramont backbone

Study Dates of enrollment Evidence
Chen et al. 2006 (TRC-301) 2003 Phase 2 (RT)

Note: this is based on the de Gramont regimen backbone.

Chemotherapy

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

Targeted therapy

14-day cycles

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 contains dosing details in manuscript PubMed NCT00066846

Irinotecan monotherapy

Example orders

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cunningham et al. 1998 (V301) 1995-NR Phase 3 (E-RT-esc) Supportive care Superior OS

Chemotherapy

Supportive therapy

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 dosing details in manuscript PubMed

Regorafenib monotherapy

Regimen variant #1, Standard Dosing

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Grothey et al. 2012 (CORRECT) 2010-04-30 to 2011-03-22 Phase 3 (E-RT-esc) Placebo Superior OS (primary endpoint)
Median OS: 6.4 vs 5 mo
(HR 0.77, 95% CI 0.64-0.94)
Li et al. 2015 (CONCUR) 2012-04-29 to 2013-02-06 Phase 3 (E-esc) Placebo Superior OS (primary endpoint)
Median OS: 8.8 vs 6.3 mo
(HR 0.55, 95% CI 0.40-0.77)

Targeted therapy

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

28-day cycles


Regimen variant #2, Dose-escalation

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Bekaii-Saab et al. 2019 (ReDOS) 2015-2017 Randomized Phase 2 (E-esc) Regorafenib; standard dosing Seems to have superior OS (secondary endpoint) Superior rate of patients proceeding to cycle 3 (primary endpoint)

Targeted therapy

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

Supportive therapy

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

28-day cycles

References

  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. Epub 2012 Nov 22. link to original article contains dosing details in manuscript PubMed NCT01103323
    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 NCT01584830
  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 dosing details in abstract link to PMC article PubMed NCT02368886

Trifluridine and tipiracil monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yoshino et al. 2012 2009-08-25 to 2010-04-12 Randomized Phase 2 (E-esc) Placebo Superior OS (primary endpoint)
Median OS: 9 vs 6.6 mo
(HR 0.56, 95% CI 0.39-0.81)
Mayer et al. 2015 (RECOURSE) 2012-06-17 to 2013-10-08 Phase 3 (E-RT-esc) Placebo Superior OS (primary endpoint)
Median OS: 7.1 vs 5.3 mo
(HR 0.68, 95% CI 0.58-0.81)
Xu et al. 2017 (TERRA) 2013-2015 Phase 3 (E-esc) Placebo Seems to have superior OS (primary endpoint)
Median OS: 7.8 vs 7.1 mo
(HR 0.79, 95% CI 0.62-0.99)
Pfeiffer et al. 2020 2017-2018 Randomized Phase 2 (C) Trifluridine and tipiracil & Bevacizumab Inferior PFS
Prager et al. 2023 (SUNLIGHT) 2020-11-25 to 2022-02-18 Phase 3 (C) Trifluridine and tipiracil & Bevacizumab Inferior OS

Chemotherapy

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 dosing details in manuscript PubMed JapicCTI-090880
  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 dosing details in manuscript PubMed NCT01607957
    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 original article link to PMC 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 dosing details in manuscript PubMed NCT01955837
  4. Pfeiffer P, Yilmaz M, Möller S, Zitnjak D, Krogh M, Petersen LN, Poulsen LO, Winther SB, Thomsen KG, Qvortrup C. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol. 2020 Mar;21(3):412-420. Epub 2020 Jan 27. link to original article PubMed EudraCT 2016-005241-23
  5. SUNLIGHT: Prager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, Cruz FM, Wyrwicz L, Stroyakovskiy D, Pápai Z, Poureau PG, Liposits G, Cremolini C, Bondarenko I, Modest DP, Benhadji KA, Amellal N, Leger C, Vidot L, Tabernero J; SUNLIGHT Investigators. Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N Engl J Med. 2023 May 4;388(18):1657-1667. link to original article PubMed NCT04737187
  6. RAMTAS: NCT03520946

Trifluridine and tipiracil & Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pfeiffer et al. 2020 2017-2018 Randomized Phase 2 (E-esc) Trifluridine and tipiracil Superior PFS (primary endpoint)
Median PFS: 4.6 vs 2.6 mo
(HR 0.45, 95% CI 0.29-0.72)
Prager et al. 2023 (SUNLIGHT) 2020-11-25 to 2022-02-18 Phase 3 (E-esc) Trifluridine and tipiracil Superior OS (primary endpoint)
Median OS: 10.8 vs 7.5 mo
(HR 0.61, 95% CI 0.49-0.77)

Chemotherapy

Targeted therapy

28-day cycles

References

  1. Pfeiffer P, Yilmaz M, Möller S, Zitnjak D, Krogh M, Petersen LN, Poulsen LO, Winther SB, Thomsen KG, Qvortrup C. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol. 2020 Mar;21(3):412-420. Epub 2020 Jan 27. link to original article PubMed EudraCT 2016-005241-23
  2. SUNLIGHT: Prager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, Cruz FM, Wyrwicz L, Stroyakovskiy D, Pápai Z, Poureau PG, Liposits G, Cremolini C, Bondarenko I, Modest DP, Benhadji KA, Amellal N, Leger C, Vidot L, Tabernero J; SUNLIGHT Investigators. Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N Engl J Med. 2023 May 4;388(18):1657-1667. link to original article PubMed NCT04737187
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