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

Note: the page has systemic regimens for the more general category of RAS wild-type colorectal cancer. Also note that most of the regimens were evaluated on patients tested for KRAS mutations only, and that the definition of wild-type has evolved over time. See individual regimen biomarker eligibility criteria for more details.

See the main colorectal cancer page for general regimens.

See the RAS wild-type colon cancer page for adjuvant colon cancer regimens.

24 regimens on this page 36 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.

ESMO

Japanese Society for Cancer of the Colon and Rectum

2016: Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer PubMed

NCCN

NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Colon Cancer.

Perioperative therapy for oligometastatic disease

FOLFIRI

FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	2008-2011	Phase 3 (C)	1a. FOLFIRI & Cetuximab 1b. mFOLFOX6 & Cetuximab	Inferior OS

Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
Leucovorin (Folinic acid) 400 mg/m² IV once on day 1
Irinotecan (Camptosar) 180 mg/m² IV once on day 1

14-day cycles until lesions deemed resectable or up to 12 cycles

References

Fudan 2012-03: Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. link to original article contains dosing details in manuscript PubMed NCT01564810

FOLFIRI & Cetuximab

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

Regimen variant #1, weekly cetuximab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	2008-2011	Phase 3 (E-esc)	1a. FOLFIRI 1b. mFOLFOX6	Superior OS (secondary endpoint) Median OS: 30.9 vs 21 mo (HR 0.54, 95% CI 0.33-0.88) Superior rate of patients converted to resection for liver metastases (primary endpoint)

Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
Leucovorin (Folinic acid) 400 mg/m² IV once on day 1
Irinotecan (Camptosar) 180 mg/m² IV once on day 1

Targeted therapy

Cetuximab (Erbitux) as follows, given first:
- Cycle 1: 400 mg/m² IV once on day 1, then 250 mg/m² IV once on day 8
- Cycles 2 up to 12: 250 mg/m² IV once per day on days 1 & 8

14-day cycles until lesions deemed resectable or up to 12 cycles

Regimen variant #2, bi-weekly cetuximab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	2008-2011	Phase 3 (E-esc)	1a. FOLFIRI 1b. mFOLFOX6	Superior OS (secondary endpoint) Median OS: 30.9 vs 21 mo (HR 0.54, 95% CI 0.33-0.88)

Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
Leucovorin (Folinic acid) 400 mg/m² IV once on day 1
Irinotecan (Camptosar) 180 mg/m² IV once on day 1

Targeted therapy

Cetuximab (Erbitux) 500 mg/m² IV once on day 1, given first

14-day cycles until lesions deemed resectable or up to 12 cycles

References

Fudan 2012-03: Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. link to original article contains dosing details in manuscript PubMed NCT01564810

mFOLFOX6

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

Regimen variant #1, 400/2800/85, resectable or suboptimally resectable

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Primrose et al. 2014 (New EPOC)	2007-2012	Phase 3 (C)	mFOLFOX6 & Cetuximab	Did not meet primary endpoint of PFS¹ Median PFS: 22.2 vs 15.5 mo (HR 0.85, 95% CI 0.64-1.15)

¹Reported efficacy is based on the 2020 update.
Note: this trial was only open to KRAS wild-type patients with resectable or suboptimally resectable colorectal liver metastases.

Biomarker eligibility criteria

KRAS wild-type

Chemotherapy

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

14-day cycle for 6 cycles, then surgery, then 14-day cycle for 6 cycles

Regimen variant #2, 400/2800/85, unresectable

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	2008-2011	Phase 3 (C)	1a. FOLFIRI & Cetuximab 1b. mFOLFOX6 & Cetuximab	Inferior OS

Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.

Chemotherapy

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

14-day cycles until lesions deemed resectable or up to 12 cycles

References

Fudan 2012-03: Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. link to original article contains dosing details in manuscript PubMed NCT01564810
New EPOC: Primrose J, Falk S, Finch-Jones M, Valle J, O'Reilly D, Siriwardena A, Hornbuckle J, Peterson M, Rees M, Iveson T, Hickish T, Butler R, Stanton L, Dixon E, Little L, Bowers M, Pugh S, Garden OJ, Cunningham D, Maughan T, Bridgewater J. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol. 2014 May;15(6):601-11. Epub 2014 Apr 7. Erratum in: Lancet Oncol. 2014 Jun;15(7):e253. link to original article PubMed ISRCTN22944367
1. Update: Bridgewater JA, Pugh SA, Maishman T, Eminton Z, Mellor J, Whitehead A, Stanton L, Radford M, Corkhill A, Griffiths GO, Falk S, Valle JW, O'Reilly D, Siriwardena AK, Hornbuckle J, Rees M, Iveson TJ, Hickish T, Garden OJ, Cunningham D, Maughan TS, Primrose JN; New EPOC investigators. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Mar;21(3):398-411. Epub 2020 Jan 31. link to original article link to PMC article PubMed

mFOLFOX6 & Cetuximab

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

Regimen variant #1, weekly cetuximab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	2008-2011	Phase 3 (E-esc)	1a. FOLFIRI 1b. mFOLFOX6	Superior OS (secondary endpoint) Median OS: 30.9 vs 21 mo (HR 0.54, 95% CI 0.33-0.88)

Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

Chemotherapy

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

Targeted therapy

Cetuximab (Erbitux) as follows, given first:
- Cycle 1: 400 mg/m² IV once on day 1, then 250 mg/m² IV once on day 8
- Cycles 2 up to 12: 250 mg/m² IV once per day on days 1 & 8

14-day cycles until lesions deemed resectable or up to 12 cycles

Regimen variant #2, bi-weekly cetuximab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	2008-2011	Phase 3 (E-esc)	1a. FOLFIRI 1b. mFOLFOX6	Superior OS (secondary endpoint) Median OS: 30.9 vs 21 mo (HR 0.54, 95% CI 0.33-0.88)

Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.

Chemotherapy

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

Targeted therapy

Cetuximab (Erbitux) 500 mg/m² IV once on day 1, given first

14-day cycles until lesions deemed resectable or up to 12 cycles

References

Fudan 2012-03: Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. link to original article contains dosing details in manuscript PubMed NCT01564810

Advanced or metastatic disease, first-line

CapeOx & Panitumumab

CapeOx & Panitumumab: Capecitabine, Oxaliplatin, Panitumumab

Regimen

Study	Evidence
Papaxoinis et al. 2018 (HE 6A/09)	Phase 2

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

Chemotherapy

Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

Targeted therapy

Panitumumab (Vectibix) 9 mg/kg IV once on day 1

21-day cycles

References

HE 6A/09: Papaxoinis G, Kotoula V, Giannoulatou E, Koliou GA, Karavasilis V, Lakis S, Koureas A, Bobos M, Chalaralambous E, Daskalaki E, Chatzopoulos K, Tsironis G, Pazarli E, Chrisafi S, Samantas E, Kaklamanos IG, Varthalitis I, Konstantara A, Syrigos KN, Pentheroudakis G, Pectasides D, Fountzilas G. Phase II study of panitumumab combined with capecitabine and oxaliplatin as first-line treatment in metastatic colorectal cancer patients: clinical results including extended tumor genotyping. Med Oncol. 2018 May 31;35(7):101. link to original article contains dosing details in manuscript PubMed NCT01215539

FOLFIRI

FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan

Regimen

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

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

Biomarker eligibility criteria

CRYSTAL: none

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 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

References

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

FOLFIRI & Bevacizumab

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Heinemann et al. 2014 (FIRE-3)	2007-2012	Phase 3 (E-switch-ic)	FOLFIRI & Cetuximab	Did not meet primary endpoint of ORR

Chemotherapy

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

Targeted therapy

Bevacizumab (Avastin) 5 mg/kg IV once on day 1, given second
- In FIRE-3, initial infusion is over 90 minutes, next over 60 minutes, and subsequently over 30 minutes

14-day cycles

References

FIRE-3: Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31.link to original article PubMed NCT00433927

FOLFIRI & Cetuximab

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

Regimen variant #1, 200 LCV

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Pinto et al. 2024 (ERMES)	2015-05 to 2020-03	Phase 3 (C)	FOLFIRI & Cetuximab induction x 8, then Cetuximab maintenance	Inconclusive whether non-inferior PFS (co-primary endpoint) Median PFS: 12.2 vs 10 mo (HR 0.77, 95% CI 0.61-0.97)

Biomarker eligibility criteria

ERMES: Wild-type RAS, Wild-type BRAF

Chemotherapy

Leucovorin (Folinic acid) 200 mg/m² IV once on day 1
Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
Irinotecan (Camptosar) 180 mg/m² IV once on day 1

Targeted therapy

Cetuximab (Erbitux) as follows:
- Cycle 1: 400 mg/m² IV once on day 1, then 250 mg/m² IV once on day 8
- Cycle 2 onwards: 250 mg/m² IV once per day on days 1 & 8

14-day cycles

Regimen variant #2, 400 LCV

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Van Cutsem et al. 2009 (CRYSTAL)	2004-07 to 2005-11	Phase 3 (E-RT-esc)	FOLFIRI	Superior OS¹ (secondary endpoint) Median OS: 23.5 vs 19.5 mo (HR 0.81, 95% CI 0.69-0.94) Seems to have superior PFS (primary endpoint) Median PFS: 8.9 vs 8 mo (aHR 0.85, 95% CI 0.72-0.99)
Heinemann et al. 2014 (FIRE-3)	2007-2012	Phase 3 (E-switch-ooc)	FOLFIRI & Bevacizumab	Did not meet primary endpoint of ORR

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

Biomarker eligibility criteria

CRYSTAL: none
FIRE-3: Wild-type KRAS, Wild-type NRAS

Chemotherapy

Leucovorin (Folinic acid) 400 mg/m² IV over 2 hours once on day 1, given second, 1 hour after completion of cetuximab, 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 30 to 90 minutes once on day 1, given second, 1 hour after completion of cetuximab, with leucovorin

Targeted therapy

Cetuximab (Erbitux) as follows, given first and completed at least 1 hour before FOLFIRI begins:
- Cycle 1: 400 mg/m² IV over 2 hours once on day 1, then 250 mg/m² IV over 60 minutes once on day 8
- Cycle 2 onwards: 250 mg/m² IV over 60 minutes once per day on days 1 & 8

14-day cycles

References

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
FIRE-3: Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31. link to original article contains dosing details on CT.gov PubMed NCT00433927
ERMES: Pinto C, Orlandi A, Normanno N, Maiello E, Calegari MA, Antonuzzo L, Bordonaro R, Zampino MG, Pini S, Bergamo F, Tonini G, Avallone A, Latiano TP, Rosati G, Cogoni AA, Ballestrero A, Zaniboni A, Roselli M, Tamberi S, Barone C. Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Versus Cetuximab as Maintenance Therapy in First-Line Therapy for RAS and BRAF Wild-Type Metastatic Colorectal Cancer: Phase III ERMES Study. J Clin Oncol. 2024 Apr 10;42(11):1278-1287. Epub 2024 Jan 5. link to original article contains dosing details in manuscript PubMed NCT02484833

FOLFIRI & Cetuximab (L-Leucovorin)

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

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Van Cutsem et al. 2009 (CRYSTAL)	2004-07 to 2005-11	Phase 3 (E-RT-esc)	FOLFIRI	Superior OS¹ (secondary endpoint) Median OS: 23.5 vs 19.5 mo (HR 0.81, 95% CI 0.69-0.94)

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

Biomarker eligibility criteria

CRYSTAL: none

Chemotherapy

Levoleucovorin (Fusilev) 200 mg/m² IV over 2 hours once on day 1, given second, 1 hour after completion of cetuximab, 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 30 to 90 minutes once on day 1, given second, 1 hour after completion of cetuximab, with L-leucovorin

Targeted therapy

Cetuximab (Erbitux) as follows, given first and completed at least 1 hour before FOLFIRI begins:
- Cycle 1: 400 mg/m² IV over 2 hours once on day 1, then 250 mg/m² IV over 60 minutes once on day 8
- Cycle 2 onwards: 250 mg/m² IV over 60 minutes once per day on days 1 & 8

14-day cycles

References

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

FOLFIRINOX

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Modest et al. 2019 (VOLFI)	2011-2016	Randomized Phase 2 (C)	FOLFOXIRI & Panitumumab	Inferior ORR

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

Chemotherapy

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

14-day cycle until POD or resectability or to max 12 cycles

References

VOLFI: Modest DP, Martens UM, Riera-Knorrenschild J, Greeve J, Florschütz A, Wessendorf S, Ettrich T, Kanzler S, Nörenberg D, Ricke J, Seidensticker M, Held S, Buechner-Steudel P, Atzpodien J, Heinemann V, Seufferlein T, Tannapfel A, Reinacher-Schick AC, Geissler M. FOLFOXIRI Plus Panitumumab As First-Line Treatment of RAS Wild-Type Metastatic Colorectal Cancer: The Randomized, Open-Label, Phase II VOLFI Study (AIO KRK0109). J Clin Oncol. 2019 Dec 10;37(35):3401-3411. Epub 2019 Oct 14. link to original article contains dosing details in manuscript PubMed NCT01328171

FOLFOX4

FOLFOX4: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
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 inferior PFS²
Qin et al. 2018 (TAILOR-CRC)	2010-NR	Phase 3 (C)	FOLFOX4 & Cetuximab	Seems to have inferior OS

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: TAILOR required RAS wild-type (not just KRAS). Note that there is another trial named TAILOR in non-small cell lung cancer, so this one has been dubbed TAILOR-CRC.

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

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
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
TAILOR-CRC: Qin S, Li J, Wang L, Xu J, Cheng Y, Bai Y, Li W, Xu N, Lin LZ, Wu Q, Li Y, Yang J, Pan H, Ouyang X, Qiu W, Wu K, Xiong J, Dai G, Liang H, Hu C, Zhang J, Tao M, Yao Q, Wang J, Chen J, Eggleton SP, Liu T. Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer: the open-label, randomized, phase III TAILOR trial. J Clin Oncol. 2018 Oct 20;36(30):3031-9. Epub 2018 Sep 10. link to original article contains dosing details in abstract link to PMC article PubMed NCT01228734

FOLFOX4 & Cetuximab

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bokemeyer et al. 2008 (OPUS)	2005-2006	Randomized Phase 2 (E-esc)	FOLFOX4	Superior OS¹ (secondary endpoint) Median OS: 23.5 vs 19.5 mo (HR 0.81, 95% CI 0.69-0.94) Might have superior ORR (primary endpoint)
Qin et al. 2018 (TAILOR-CRC)	2010-NR	Phase 3 (E-esc)	FOLFOX4	Seems to have superior OS (secondary endpoint) Median OS: 20.7 vs 17.8 mo (HR 0.76, 95% CI 0.61-0.96) Superior PFS (primary endpoint) Median PFS: 9.2 vs 7.4 mo (HR 0.69, 95% CI 0.54-0.89)

¹Reported efficacy for OPUS is based on the 2012 pooled update and is only for KRAS wild-type tumors.
TAILOR required RAS wild-type (not just KRAS). Note that there is another trial named TAILOR in non-small cell lung cancer, so this one has been dubbed TAILOR-CRC.

Biomarker eligibility criteria

OPUS: none
TAILOR-CRC: Wild-type KRAS, Wild-type NRAS

Chemotherapy

Leucovorin (Folinic acid) 200 mg/m² IV over 2 hours once per day on days 1 & 2, given second, 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 third (total dose per cycle: 2000 mg/m²)
Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1, given second

Targeted therapy

Cetuximab (Erbitux) given first, as follows:
- Cycle 1: 400 mg/m² IV over 2 hours once on day 1, then 250 mg/m² IV over 60 minutes once on day 8
- Cycle 2 onwards: 250 mg/m² IV over 60 minutes once per day on days 1 & 8

14-day cycles

References

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
TAILOR-CRC: Qin S, Li J, Wang L, Xu J, Cheng Y, Bai Y, Li W, Xu N, Lin LZ, Wu Q, Li Y, Yang J, Pan H, Ouyang X, Qiu W, Wu K, Xiong J, Dai G, Liang H, Hu C, Zhang J, Tao M, Yao Q, Wang J, Chen J, Eggleton SP, Liu T. Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer: the open-label, randomized, phase III TAILOR trial. J Clin Oncol. 2018 Oct 20;36(30):3031-9. Epub 2018 Sep 10. link to original article contains dosing details in abstract link to PMC article PubMed NCT01228734

FOLFOX4 & Panitumumab

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Douillard et al. 2010 (PRIME)	2006-2008	Phase 3 (E-RT-esc)	FOLFOX4	Seems to have superior PFS (primary endpoint) Median PFS: 9.6 vs 8 mo (HR 0.80, 95% CI 0.66-0.97) Seems to have superior OS¹ (secondary endpoint) Median OS: 23.8 vs 19.4 mo (HR 0.83, 95% CI 0.70-0.98)

¹In KRAS wild-type patients, this regimen seems to have superior OS, based on the exploratory analysis in the 2014 update.

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

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) 200 mg/m² IV over 2 hours once per day on days 1 & 2
Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1

Targeted therapy

Panitumumab (Vectibix) 6 mg/kg IV once on day 1, given first
- Infusion times are 1 hour for cycle 1, then if tolerated, 30 minutes for cycle 2 and later

14-day cycles

References

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

mFOLFOX6-B

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Venook et al. 2017 (CALGB 80405)	2005-2012	Phase 3 (E-switch-ic)	1a. mFOLFOX6 & Cetuximab 1b. FOLFIRI & Cetuximab	Did not meet primary endpoint of OS
Venook et al. 2017 (CALGB 80405)	2005-2012	Phase 3 (E-switch-ic)	2a. mFOLFOX6, Bevacizumab, Cetuximab 2b. FOLFIRI, Bevacizumab, Cetuximab	Not reported
Schwartzberg et al. 2014 (PEAK)	2009-2011	Randomized Phase 2 (C)	mFOLFOX6 & Panitumumab	Seems to have inferior PFS¹
Watanabe et al. 2023 (PARADIGM_CRC)	2015-05 to 2022-01	Phase 3 (C)	mFOLFOX6 & Panitumumab	Seems to have inferior OS

¹Reported efficacy for PEAK is based on the 2017 update.
Note: In CALGB 80405, the arm receiving bevacizumab and cetuximab was terminated early.

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
Leucovorin (Folinic acid) 200 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1

Targeted therapy

Bevacizumab (Avastin) 5 mg/kg IV once on day 1

14-day cycles

References

CALGB 80405: Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O'Neil BH, Atkins JN, Berry S, Polite BN, O'Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, El-Khoueiry AB, Watson P, Benson AB 3rd, Mulkerin DL, Mayer RJ, Blanke C. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2017 Jun 20;317(23):2392-2401. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00265850
PEAK: Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, Yu H, Oliner KS, Go WY. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014 Jul 20;32(21):2240-7. Epub 2014 Mar 31. link to original article PubMed NCT00819780
1. Update: Rivera F, Karthaus M, Hecht JR, Sevilla I, Forget F, Fasola G, Canon JL, Guan X, Demonty G, Schwartzberg LS. Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma. Int J Colorectal Dis. 2017 Aug;32(8):1179-1190. Epub 2017 Apr 19. link to original article link to PMC article PubMed
PARADIGM_CRC: Watanabe J, Muro K, Shitara K, Yamazaki K, Shiozawa M, Ohori H, Takashima A, Yokota M, Makiyama A, Akazawa N, Ojima H, Yuasa Y, Miwa K, Yasui H, Oki E, Sato T, Naitoh T, Komatsu Y, Kato T, Hihara M, Soeda J, Misumi T, Yamamoto K, Akagi K, Ochiai A, Uetake H, Tsuchihara K, Yoshino T. Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2023 Apr 18;329(15):1271-1282. Erratum in: JAMA. 2023 Jun 27;329(24):2196. link to original article link to PMC article PubMed NCT02394795

mFOLFOX6 & Cetuximab

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Venook et al. 2017 (CALGB 80405)	2005-2012	Phase 3 (E-switch-ic)	1a. mFOLFOX6-B 1b. FOLFIRI & Bevacizumab	Did not meet primary endpoint of OS
Venook et al. 2017 (CALGB 80405)	2005-2012	Phase 3 (E-switch-ic)	2a. mFOLFOX6, Bevacizumab, Cetuximab 2b. FOLFIRI, Bevacizumab, Cetuximab	Not reported
Aranda et al. 2018 (MACRO-2)	2010-NR	Non-randomized part of phase 2 RCT

Note: In CALGB 80405, the arm receiving bevacizumab and cetuximab was terminated early.

Biomarker eligibility criteria

CALGB 80405: Wild-type KRAS (codons 12 & 13)
MACRO-2: Wild-type KRAS (exons 3 & 4), Wild-type NRAS (exons 2 to 4)

Chemotherapy

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

Targeted therapy

Cetuximab (Erbitux) as follows, given first:
- Cycle 1: 400 mg/m² IV once on day 1, then 250 mg/m² IV once on day 8
- Cycle 2 onwards: 250 mg/m² IV once per day on days 1 & 8

14-day cycles (see below)

Subsequent treatment

MACRO-2, after 8 cycles: continued mFOLFOX6 & Cetuximab until progression versus cetuximab maintenance

References

CALGB 80405: Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O'Neil BH, Atkins JN, Berry S, Polite BN, O'Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, El-Khoueiry AB, Watson P, Benson AB 3rd, Mulkerin DL, Mayer RJ, Blanke C. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2017 Jun 20;317(23):2392-2401. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00265850
MACRO-2: Aranda E, García-Alfonso P, Benavides M, Sánchez Ruiz A, Guillén-Ponce C, Safont MJ, Alcaide J, Gómez A, López R, Manzano JL, Méndez Ureña M, Sastre J, Rivera F, Grávalos C, García T, Martín-Valadés JI, Falcó E, Navalón M, González Flores E, Ma García Tapiador A, Ma López Muñoz A, Barrajón E, Reboredo M, García Teijido P, Viudez A, Cárdenas N, Díaz-Rubio E; Spanish Cooperative Group for the Treatment of Digestive Tumours. First-line mFOLFOX plus cetuximab followed by mFOLFOX plus cetuximab or single-agent cetuximab as maintenance therapy in patients with metastatic colorectal cancer: phase II randomised MACRO2 TTD study. Eur J Cancer. 2018 Sep;101:263-272. Epub 2018 Jul 24. link to original article PubMed NCT01161316

mFOLFOX6 & Panitumumab

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Schwartzberg et al. 2014 (PEAK)	2009-2011	Randomized Phase 2 (E-switch-ooc)	mFOLFOX6-B	Seems to have superior PFS¹ (primary endpoint) Median PFS: 12.8 vs 10.1 mo (HR 0.68, 95% CI 0.48-0.96) Did not meet secondary endpoint of OS¹ Median OS: 36.9 vs 28.9 mo (HR 0.76, 95% CI 0.53-1.11)
Watanabe et al. 2023 (PARADIGM_CRC)	2015-05 to 2022-01	Phase 3 (E-switch-ooc)	mFOLFOX6-B	Seems to have superior OS² (primary endpoint) Median OS: 37.9 vs 34.3 mo (HR 0.82, 95.798% CI 0.68-0.99)
Rossini et al. 2022 (TRIPLETE)	2017-2021	Phase 3 (C)	mFOLFOXIRI & Panitumumab	Did not meet primary endpoint of ORR

¹Reported efficacy for PEAK is based on the 2017 update.
²Reported efficacy is for patients with left-sided primary tumors, which was the primary analysis; efficacy results for the overall population were similar.

Biomarker eligibility criteria

TRIPLETE: Wild-type KRAS (exons 2 to 4), wild-type NRAS (exons 2 to 4), wild-type BRAF codon 600

Chemotherapy

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

Targeted therapy

Panitumumab (Vectibix) 6 mg/kg IV over 30 to 60 minutes once on day 1, given first

14-day cycles

References

PEAK: Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, Yu H, Oliner KS, Go WY. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014 Jul 20;32(21):2240-7. Epub 2014 Mar 31. link to original article PubMed NCT00819780
1. Update: Rivera F, Karthaus M, Hecht JR, Sevilla I, Forget F, Fasola G, Canon JL, Guan X, Demonty G, Schwartzberg LS. Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma. Int J Colorectal Dis. 2017 Aug;32(8):1179-1190. Epub 2017 Apr 19. link to original article link to PMC article PubMed
TRIPLETE: Rossini D, Antoniotti C, Lonardi S, Pietrantonio F, Moretto R, Antonuzzo L, Boccaccino A, Morano F, Brugia M, Pozzo C, Marmorino F, Bergamo F, Tamburini E, Passardi A, Randon G, Murgioni S, Borelli B, Buonadonna A, Giordano M, Fontanini G, Conca V, Formica V, Aglietta M, Bordonaro R, Aprile G, Masi G, Boni L, Cremolini C. Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO. J Clin Oncol. 2022 Sep 1;40(25):2878-2888. Epub 2022 Jun 6. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03231722
PARADIGM_CRC: Watanabe J, Muro K, Shitara K, Yamazaki K, Shiozawa M, Ohori H, Takashima A, Yokota M, Makiyama A, Akazawa N, Ojima H, Yuasa Y, Miwa K, Yasui H, Oki E, Sato T, Naitoh T, Komatsu Y, Kato T, Hihara M, Soeda J, Misumi T, Yamamoto K, Akagi K, Ochiai A, Uetake H, Tsuchihara K, Yoshino T. Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2023 Apr 18;329(15):1271-1282. Erratum in: JAMA. 2023 Jun 27;329(24):2196. link to original article link to PMC article PubMed NCT02394795

mFOLFOXIRI & Cetuximab (L-Leucovorin)

mFOLFOXIRI & Cetuximab: modified L-FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, IRInotecan, Cetuximab

Regimen

Study	Evidence
Cremolini et al. 2018 (MACBETH)	Non-randomized part of phase 2 RCT

Note: 5-FU instructions are unusual in that no bolus is given.

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

Chemotherapy

Fluorouracil (5-FU) 1200 mg/m²/day IV continuous infusion over 48 hours, started on day 1, given fourth (total dose per cycle: 2400 mg/m²)
Levoleucovorin (Fusilev) 200 mg/m² IV over 2 hours once on day 1, given third, with oxaliplatin
Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1, given third, with L-leucovorin
Irinotecan (Camptosar) 130 mg/m² IV over 60 minutes once on day 1, given second

Targeted therapy

Cetuximab (Erbitux) 500 mg/m² IV over 60 minutes once on day 1, given first

14-day cycle for 8 cycles

Subsequent treatment

MACBETH, if deemed resectable: Surgery
MACBETH, if deemed unresectable: Cetuximab versus bevacizumab maintenance

References

MACBETH: Cremolini C, Antoniotti C, Lonardi S, Aprile G, Bergamo F, Masi G, Grande R, Tonini G, Mescoli C, Cardellino GG, Coltelli L, Salvatore L, Corsi DC, Lupi C, Gemma D, Ronzoni M, Dell'Aquila E, Marmorino F, Di Fabio F, Mancini ML, Marcucci L, Fontanini G, Zagonel V, Boni L, Falcone A. Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial. JAMA Oncol. 2018 Apr 1;4(4):529-536. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02295930

FOLFOXIRI & Panitumumab

FOLFOXIRI & Panitumumab: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, IRInotecan, Panitumumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Modest et al. 2019 (VOLFI)	2011-2016	Randomized Phase 2 (E-esc)	FOLFOXIRI	Superior ORR (primary endpoint)

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

Chemotherapy

Fluorouracil (5-FU) 1500 mg/m²/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 3000 mg/m²)
Leucovorin (Folinic acid) 200 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1
Irinotecan (Camptosar) 150 mg/m² IV once on day 1

Targeted therapy

Panitumumab (Vectibix) 6 mg/kg IV once on day 1

14-day cycle until POD or resectability or to max 12 cycles

References

VOLFI: Modest DP, Martens UM, Riera-Knorrenschild J, Greeve J, Florschütz A, Wessendorf S, Ettrich T, Kanzler S, Nörenberg D, Ricke J, Seidensticker M, Held S, Buechner-Steudel P, Atzpodien J, Heinemann V, Seufferlein T, Tannapfel A, Reinacher-Schick AC, Geissler M. FOLFOXIRI Plus Panitumumab As First-Line Treatment of RAS Wild-Type Metastatic Colorectal Cancer: The Randomized, Open-Label, Phase II VOLFI Study (AIO KRK0109). J Clin Oncol. 2019 Dec 10;37(35):3401-3411. Epub 2019 Oct 14. link to original article contains dosing details in manuscript PubMed NCT01328171

Maintenance after first-line therapy

Bevacizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hagman et al. 2015 (Nordic ACT2)	2010-2012	Phase 3 (C)	Erlotinib & Bevacizumab	Did not meet primary endpoint of PFS

Biomarker eligibility criteria

Wild-type KRAS

Targeted therapy

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

21-day cycles

References

Nordic ACT2: Hagman H, Frödin JE, Berglund Å, Sundberg J, Vestermark LW, Albertsson M, Fernebro E, Johnsson A. A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial. Ann Oncol. 2016 Jan;27(1):140-7. Epub 2015 Oct 19. link to original article contains dosing details in manuscript PubMed NCT01229813

Cetuximab monotherapy

Regimen variant #1, 250 mg/m² weekly

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Aranda et al. 2018 (MACRO-2)	2010-NR	Randomized Phase 2 (E-de-esc)	mFOLFOX6 & Cetuximab	Non-inferior PFS9 (primary endpoint)

Note: regimen details are from ClinicalTrials.gov; they were not present in the abstract or the manuscript.

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

Preceding treatment

First-line mFOLFOX6 & Cetuximab x 8

Targeted therapy

Cetuximab (Erbitux) 250 mg/m² IV once on day 1

7-day cycles

Regimen variant #2, 500 mg/m² q2wk

Study	Evidence
Cremolini et al. 2018 (MACBETH)	Randomized Phase 2

Note: this was a non-comparative study.

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

Preceding treatment

First-line mFOLFOXIRI & Cetuximab x 8

Targeted therapy

Cetuximab (Erbitux) 500 mg/m² IV once on day 1

14-day cycles

References

MACBETH: Cremolini C, Antoniotti C, Lonardi S, Aprile G, Bergamo F, Masi G, Grande R, Tonini G, Mescoli C, Cardellino GG, Coltelli L, Salvatore L, Corsi DC, Lupi C, Gemma D, Ronzoni M, Dell'Aquila E, Marmorino F, Di Fabio F, Mancini ML, Marcucci L, Fontanini G, Zagonel V, Boni L, Falcone A. Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial. JAMA Oncol. 2018 Apr 1;4(4):529-536. link to original article link to PMC article PubMed NCT02295930
MACRO-2: Aranda E, García-Alfonso P, Benavides M, Sánchez Ruiz A, Guillén-Ponce C, Safont MJ, Alcaide J, Gómez A, López R, Manzano JL, Méndez Ureña M, Sastre J, Rivera F, Grávalos C, García T, Martín-Valadés JI, Falcó E, Navalón M, González Flores E, Ma García Tapiador A, Ma López Muñoz A, Barrajón E, Reboredo M, García Teijido P, Viudez A, Cárdenas N, Díaz-Rubio E; Spanish Cooperative Group for the Treatment of Digestive Tumours. First-line mFOLFOX plus cetuximab followed by mFOLFOX plus cetuximab or single-agent cetuximab as maintenance therapy in patients with metastatic colorectal cancer: phase II randomised MACRO2 TTD study. Eur J Cancer. 2018 Sep;101:263-272. Epub 2018 Jul 24. link to original article PubMed NCT01161316

Advanced or metastatic disease, second-line

FOLFIRI

FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Peeters et al. 2010 (20050181)	2006-2008	Phase 3 (C)	FOLFIRI & Panitumumab	Seems to have inferior PFS¹

¹Reported efficacy is for wild-type KRAS, only, and is based on the 2014 update.

Biomarker eligibility criteria

None

Prior treatment criteria

First-line fluoropyrimidine-based chemotherapy, with progression

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

References

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

FOLFIRI & Panitumumab

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Peeters et al. 2010 (20050181)	2006-2008	Phase 3 (E-esc)	FOLFIRI	Seems to have superior PFS¹ (co-primary endpoint) Median PFS: 6.7 vs 4.9 mo (HR 0.82, 95% CI 0.69-0.97)

¹Reported efficacy is for wild-type KRAS, only, and is based on the 2014 update.

Biomarker eligibility criteria

None

Prior treatment criteria

First-line fluoropyrimidine-based chemotherapy, with progression

Chemotherapy

Leucovorin (Folinic acid) 400 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 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 second, with leucovorin

Targeted therapy

Panitumumab (Vectibix) 6 mg/kg IV over 60 minutes once on day 1, given first

14-day cycles

References

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

Irinotecan monotherapy

Example orders

Example orders for Irinotecan (Camptosar) in colon cancer

Regimen variant #1, 180 mg/m² q2wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shi et al. 2019 (CRC009)	2009-2011	Phase 3 (C)	Irinotecan & CMAB009	Inferior PFS50%

Prior treatment criteria

Exposure to FOLFOX, with progression or discontinuation due to toxicity

Chemotherapy

Irinotecan (Camptosar) 180 mg/m² IV over 90 minutes once on day 1

14-day cycles

Regimen variant #2, 300 mg/m² q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Seymour et al. 2013 (PICCOLO)	2006-12-04 to 2008-08-31	Phase 3 (C)	1. Irinotecan & Panitumumab	Did not meet primary endpoint of OS Median OS: 10.9 vs 10.4 mo (HR 0.99, 95% CI 0.81-1.20)
Seymour et al. 2013 (PICCOLO)	2006-12-04 to 2008-08-31	Phase 3 (C)	2. Irinotecan & Cyclosporine	Not reported

Note: In some trials, this starting dose was intended for patients who were at least 70 years old, had ECOG performance status 2 or more, or had prior pelvic radiation.

Prior treatment criteria

First-line fluoropyrimidine-based chemotherapy, with progression

Chemotherapy

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

21-day cycles

Regimen variant #3, 350 mg/m² q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Seymour et al. 2013 (PICCOLO)	2006-12-04 to 2008-08-31	Phase 3 (C)	1. Irinotecan & Panitumumab	Did not meet primary endpoint of OS Median OS: 10.9 vs 10.4 mo (HR 0.99, 95% CI 0.81-1.20)
Seymour et al. 2013 (PICCOLO)	2006-12-04 to 2008-08-31	Phase 3 (C)	2. Irinotecan & Cyclosporine	Not reported

Prior treatment criteria

First-line fluoropyrimidine-based chemotherapy, with progression

Chemotherapy

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

Supportive therapy

(varied depending on reference):
"Standard regimens of antiemetics, Atropine (Atropen), and intensive Loperamide (Imodium)," but no prophylactic Atropine (Atropen) allowed on cycle 1 day 1

21-day cycles

References

PICCOLO: Seymour MT, Brown SR, Middleton G, Maughan T, Richman S, Gwyther S, Lowe C, Seligmann JF, Wadsley J, Maisey N, Chau I, Hill M, Dawson L, Falk S, O'Callaghan A, Benstead K, Chambers P, Oliver A, Marshall H, Napp V, Quirke P. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013 Jul;14(8):749-59. Epub 2013 May 29. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00389870
CRC009: Shi Y, Li J, Xu J, Sun Y, Wang L, Cheng Y, Liu W, Sun G, Chen Y, Bai L, Zhang Y, He X, Luo Y, Wang Z, Liu Y, Yao Q, Li Y, Qin S, Hu X, Bi F, Zheng R, Ouyang X. CMAB009 plus irinotecan versus irinotecan-only as second-line treatment after fluoropyrimidine and oxaliplatin failure in KRAS wild-type metastatic colorectal cancer patients: promising findings from a prospective, open-label, randomized, phase III trial. Cancer Commun (Lond). 2019 May 24;39(1):28. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01550055

Irinotecan & Cetuximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sobrero et al. 2008 (EPIC)	2003-2006	Phase 3 (E-esc)	Irinotecan	Did not meet primary endpoint of OS

Prior treatment criteria

First-line fluoropyrimidine and oxaliplatin treatment, with progression or discontinuation due to toxicity

Chemotherapy

Irinotecan (Camptosar) by the following criteria:
- Standard patients: 350 mg/m² IV over 90 minutes once on day 1
- If aged 70 years old or more, ECOG performance status 2 or more, or prior pelvic radiation: 300 mg/m² IV over 90 minutes once on day 1

Targeted therapy

Cetuximab (Erbitux) as follows:
- Cycle 1: 400 mg/m² IV over 2 hours once on day 1, then 250 mg/m² IV over 60 minutes once per day on days 8 & 15
- Cycle 2 onwards: 250 mg/m² IV over 60 minutes once per day on days 1, 8, 15

Supportive therapy

Antihistamine prior to at least the first infusion of cetuximab

21-day cycles

References

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

Advanced or metastatic disease, subsequent lines of therapy

Cetuximab monotherapy

Example orders

Example orders for Cetuximab (Erbitux) in colon cancer

Regimen variant #1, weekly

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Saltz et al. 2004	2001	Phase 2 (RT)
Cunningham et al. 2004 (BOND)	2001-07 to 2002-05	Phase 3 (C)	Irinotecan & Cetuximab	Inferior TTP
Lenz et al. 2006 (SALVAGE)	NR	Phase 2
Jonker et al. 2007 (NCIC-CTG CO.17)	2003-2005	Phase 3 (E-RT-esc)	Best supportive care	Superior OS (primary endpoint) Median OS: 6.1 vs 4.6 mo (HR 0.77, 95% CI 0.64-0.92)
Siu et al. 2013 (NCIC-CTG/AGITG CO.20)	2008-2011	Phase 3 (C)	Brivanib & Cetuximab	Did not meet primary endpoint of OS
Price et al. 2014 (ASPECCT)	2010-2012	Phase 3 (C)	Panitumumab	Non-inferior OS

Prior treatment criteria

Saltz et al. 2004: Exposure to irinotecan-containing therapy, with clinical failure
BOND: Exposure to irinotecan-containing therapy, with progression
SALVAGE: Exposure to irinotecan, oxaliplatin, and a fluoropyrimidine
NCIC-CTG CO.17: Exposure to irinotecan, oxaliplatin, and a fluoropyrimidine or contraindication to these drugs
NCIC-CTG/AGITG CO.20: Exposure to a fluoropyrimidine and exposure to irinotecan and oxaliplatin or contraindication to these drugs

Targeted therapy

Cetuximab (Erbitux) as follows:
- Cycle 1: 400 mg/m² IV over 2 hours once on day 1
- Cycle 2 onwards: 250 mg/m² IV over 60 minutes once on day 1

Supportive therapy

Varies depending on reference
Antihistamine (such as Diphenhydramine (Benadryl) 50 mg IV) prior to at least the first infusion of cetuximab

7-day cycles

Regimen variant #2, bi-weekly

Study	Evidence
Tabernero et al. 2009	Phase 1

Note: no primary reference could be found for this exact dosing in monotherapy; in the phase I trial it is described as "the most convenient and feasible dose".

Targeted therapy

Cetuximab (Erbitux) 500 mg/m² IV over 2 hours once on day 1
- If tolerated, subsequent doses can be given over 1 hour

Supportive therapy

Antihistamine prior to cetuximab

14-day cycles

References

Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004 Apr 1;22(7):1201-8. Epub 2004 Mar 1. link to original article PubMed
BOND: Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22;351(4):337-45. link to original article contains dosing details in manuscript PubMed
SALVAGE: Lenz HJ, Van Cutsem E, Khambata-Ford S, Mayer RJ, Gold P, Stella P, Mirtsching B, Cohn AL, Pippas AW, Azarnia N, Tsuchihashi Z, Mauro DJ, Rowinsky EK. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol. 2006 Oct 20;24(30):4914-21. link to original article contains dosing details in manuscript PubMed
NCIC-CTG CO.17: Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007 Nov 15;357(20):2040-8. link to original article contains dosing details in manuscript PubMed NCT00079066
1. Subgroup analysis: Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008 Oct 23;359(17):1757-65. link to original article PubMed
2. Subgroup analysis: Asmis TR, Powell E, Karapetis CS, Jonker DJ, Tu D, Jeffery M, Pavlakis N, Gibbs P, Zhu L, Dueck DA, Whittom R, Langer C, O'Callaghan CJ. Comorbidity, age and overall survival in cetuximab-treated patients with advanced colorectal cancer (ACRC)--results from NCIC-CTG CO.17: a phase III trial of cetuximab versus best supportive care. Ann Oncol. 2011 Jan;22(1):118-26. Epub 2010 Jul 5. link to original article contains dosing details in manuscript PubMed
Phase I: Tabernero J, Ciardiello F, Rivera F, Rodriguez-Braun E, Ramos FJ, Martinelli E, Vega-Villegas ME, Roselló S, Liebscher S, Kisker O, Macarulla T, Baselga J, Cervantes A. Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/pharmacodynamic phase I dose-escalation study. Ann Oncol. 2010 Jul;21(7):1537-45. Epub 2009 Nov 25. link to original article PubMed
NCIC-CTG/AGITG CO.20: Siu LL, Shapiro JD, Jonker DJ, Karapetis CS, Zalcberg JR, Simes J, Couture F, Moore MJ, Price TJ, Siddiqui J, Nott LM, Charpentier D, Liauw W, Sawyer MB, Jefford M, Magoski NM, Haydon A, Walters I, Ringash J, Tu D, O'Callaghan CJ. Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: the NCIC Clinical Trials Group and AGITG CO.20 Trial. J Clin Oncol. 2013 Jul 1;31(19):2477-84. Epub 2013 May 20. link to original article contains dosing details in manuscript PubMed NCT00640471
ASPECCT: Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Zhang K, Murugappan S, Sidhu R. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014 May;15(6):569-79. Epub 2014 Apr 14. link to original article PubMed NCT01001377
1. Update: Price T, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Guan X, Peeters M. Final results and outcomes by prior bevacizumab exposure, skin toxicity, and hypomagnesaemia from ASPECCT: randomized phase 3 non-inferiority study of panitumumab versus cetuximab in chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer. Eur J Cancer. 2016 Nov;68:51-59. Epub 2016 Oct 5. link to original article PubMed

Irinotecan & Cetuximab

Regimen variant #1, 125/250, irinotecan 2 weeks on, 1 week off

FDA-recommended dose

Note: In contrast to BOND, some guidelines list irinotecan as being given on days 1 & 8 of a 21-day cycle. No primary reference could be found for this. Note also that the FDA-recommended dosing is for the cetuximab component; no comment is made about irinotecan dosing.

Chemotherapy

Irinotecan (Camptosar) 125 mg/m² IV over 90 minutes once per day on days 1 & 8

Targeted therapy

Cetuximab (Erbitux) as follows:
- Cycle 1: 400 mg/m² IV over 2 hours once on day 1, then 250 mg/m² IV over 60 minutes once per day on days 8 & 15
- Cycle 2 onwards: 250 mg/m² IV over 60 minutes once per day on days 1, 8, 15

Supportive therapy

Antihistamine prior to at least the first infusion of cetuximab

21-day cycles

Regimen variant #2, 125/250, irinotecan 4 weeks on, 2 weeks off

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cunningham et al. 2004 (BOND)	2001-07 to 2002-05	Phase 3 (E-RT-esc)	Cetuximab	Superior TTP (secondary endpoint) Superior ORR (primary endpoint)

Note that the FDA-recommended dosing is for the cetuximab component; no comment is made about irinotecan dosing.

Prior treatment criteria

BOND: Exposure to irinotecan-containing therapy, with progression

Chemotherapy

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

Targeted therapy

Cetuximab (Erbitux) as follows:
- Cycle 1: 400 mg/m² IV over 2 hours once on day 1, then 250 mg/m² IV over 60 minutes once per day on days 8, 15, 22, 29, 36
- Cycle 2 onwards: 250 mg/m² IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36

Supportive therapy

Antihistamine prior to at least the first infusion of cetuximab

42-day cycles

Regimen variant #3, 150/500, bi-weekly

Study	Dates of enrollment	Evidence
Osumi et al. 2018	2011-2014	Phase 2

Prior treatment criteria

Exposure to fluoropyrimidine‐ and oxaliplatin‐based chemotherapy, with treatment failure

Chemotherapy

Irinotecan (Camptosar) 150 mg/m² IV once on day 1

Targeted therapy

Cetuximab (Erbitux) 500 mg/m² IV over 2 hours once on day 1
- Subsequent doses are given over 60 minutes

Supportive therapy

Antihistamine prior to cetuximab

14-day cycles

Regimen variant #4, 180/250, bi-weekly, with response adaptation

Study	Dates of enrollment	Evidence
Van Cutsem et al. 2012 (EVEREST)	2004-2005	Non-randomized part of phase 1/2 RCT

Prior treatment criteria

Exposure to irinotecan-containing chemotherapy

Chemotherapy

Irinotecan (Camptosar) 180 mg/m² IV over 30 minutes once per day on days 1 & 15

Targeted therapy

Cetuximab (Erbitux) 400 mg/m² IV once on day 1, then 250 mg/m² IV once per day on days 8 & 15

21-day course

Subsequent treatment

EVEREST, grade 0 or 1 skin reaction: Standard-dose Irinotecan & Cetuximab continuation vs escalate to Irinotecan & Cetuximab; cetuximab 500 mg/m²
EVEREST, grade 2 or worse skin reaction: Continue standard-dose Irinotecan & Cetuximab

Regimen variant #5, 180/500, bi-weekly

Study	Dates of enrollment	Evidence
Martín-Martorell et al. 2008	2005-2007	Phase 2

Prior treatment criteria

One previous line of chemotherapy

Chemotherapy

Irinotecan (Camptosar) 180 mg/m² IV over 30 minutes once on day 1

Targeted therapy

Cetuximab (Erbitux) 500 mg/m² IV over 2 hours once on day 1
- If tolerated, subsequent doses can be given over 1 hour

Supportive therapy

Antihistamine prior to cetuximab
Dexamethasone (Decadron) & Ondansetron (Zofran) prior to irinotecan

14-day cycles

Regimen variant #6, 350/250, q3wk irinotecan

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cunningham et al. 2004 (BOND)	2001-07 to 2002-05	Phase 3 (E-RT-esc)	Cetuximab	Superior TTP (secondary endpoint) Superior ORR (primary endpoint)

Note that the FDA-recommended dosing is for the cetuximab component; no comment is made about irinotecan dosing.

Prior treatment criteria

BOND: Exposure to irinotecan-containing therapy, with progression

Chemotherapy

Irinotecan (Camptosar) by the following criteria:
- Standard patients: 350 mg/m² IV over 90 minutes once on day 1
- If aged 70 years old or more, ECOG performance status 2 or more, or prior pelvic radiation: 300 mg/m² IV over 90 minutes once on day 1

Targeted therapy

Cetuximab (Erbitux) as follows:
- Cycle 1: 400 mg/m² IV over 2 hours once on day 1, then 250 mg/m² IV over 60 minutes once per day on days 8 & 15
- Cycle 2 onwards: 250 mg/m² IV over 60 minutes once per day on days 1, 8, 15

Supportive therapy

Antihistamine prior to at least the first infusion of cetuximab

21-day cycles

References

BOND: Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22;351(4):337-45. link to original article contains dosing details in manuscript PubMed
Martín-Martorell P, Roselló S, Rodríguez-Braun E, Chirivella I, Bosch A, Cervantes A. Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial. Br J Cancer. 2008 Aug 5;99(3):455-8. link to original article contains dosing details in manuscript link to PMC article PubMed
EVEREST: Van Cutsem E, Tejpar S, Vanbeckevoort D, Peeters M, Humblet Y, Gelderblom H, Vermorken JB, Viret F, Glimelius B, Gallerani E, Hendlisz A, Cats A, Moehler M, Sagaert X, Vlassak S, Schlichting M, Ciardiello F. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol. 2012 Aug 10;30(23):2861-8. Epub 2012 Jul 2. link to original article contains dosing details in abstract PubMed
Osumi H, Shinozaki E, Mashima T, Wakatsuki T, Suenaga M, Ichimura T, Ogura M, Ota Y, Nakayama I, Takahari D, Chin K, Miki Y, Yamaguchi K. Phase II trial of biweekly cetuximab and irinotecan as third-line therapy for pretreated KRAS exon 2 wild-type colorectal cancer. Cancer Sci. 2018 Aug;109(8):2567-2575. Epub 2018 Jul 13. link to original article link to PMC article contains dosing details in manuscript PubMed UMIN000019893

Panitumumab monotherapy

Example orders

Example orders for Panitumumab (Vectibix) in colon cancer

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Van Cutsem et al. 2007 (20020408)	2004-01 to 2005-06	Phase 3 (E-RT-esc)	Best supportive care	Superior PFS (primary endpoint) Median PFS: 8 vs 7.3 wks (HR 0.54, 95% CI 0.44-0.66)
Price et al. 2014 (ASPECCT)	2010-2012	Phase 3 (E-RT-switch-ic)	Cetuximab	Non-inferior OS (primary endpoint) Median OS: 10.4 vs 10 mo (HR 0.97, 95% CI 0.84-1.11)
Kim et al. 2016 (20100007)	2011-2013	Phase 3 (E-RT-esc)	Best supportive care	Superior OS (primary endpoint)¹ Median OS: 10 vs 6.9 mo (HR 0.72, 95% CI 0.55-0.94)

¹Reported efficacy for 20100007 is based on the 2018 update.

Prior treatment criteria

20020408 & 20100007: Exposure to irinotecan, oxaliplatin, and a fluoropyrimidine

Targeted therapy

Panitumumab (Vectibix) 6 mg/kg IV over 60 minutes once on day 1

14-day cycles

References

20020408: Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1;25(13):1658-64. link to original article contains dosing details in manuscript PubMed NCT00113763
ASPECCT: Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Zhang K, Murugappan S, Sidhu R. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014 May;15(6):569-79. Epub 2014 Apr 14. link to original article PubMed NCT01001377
1. Update: Price T, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Guan X, Peeters M. Final results and outcomes by prior bevacizumab exposure, skin toxicity, and hypomagnesaemia from ASPECCT: randomized phase 3 non-inferiority study of panitumumab versus cetuximab in chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer. Eur J Cancer. 2016 Nov;68:51-59. Epub 2016 Oct 5. link to original article PubMed
20100007: Kim TW, Elme A, Kusic Z, Park JO, Udrea AA, Kim SY, Ahn JB, Valencia RV, Krishnan S, Bilic A, Manojlovic N, Dong J, Guan X, Lofton-Day C, Jung AS, Vrdoljak E. A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer. Br J Cancer. 2016 Nov 8;115(10):1206-1214. Epub 2016 Oct 13. link to original article link to PMC article PubMed NCT01412957
1. Update: Kim TW, Elme A, Park JO, Udrea AA, Kim SY, Ahn JB, Valencia RV, Krishnan S, Manojlovic N, Guan X, Lofton-Day C, Jung AS, Vrdoljak E. Final Analysis of Outcomes and RAS/BRAF Status in a Randomized Phase 3 Study of Panitumumab and Best Supportive Care in Chemorefractory Wild Type KRAS Metastatic Colorectal Cancer. Clin Colorectal Cancer. 2018 Sep;17(3):206-214. Epub 2018 Mar 21. link to original article PubMed

@@ Line 3: / Line 3: @@
 [[#top|Back to Top]]
 </div>
-{{#lst:Section editor transclusions|gi}}
+{{#lst:Editorial board transclusions|gi}}
 <big>Note: the page has systemic regimens for the more general category of RAS wild-type colorectal cancer. Also note that most of the regimens were evaluated on patients tested for KRAS mutations only, and that the definition of wild-type has evolved over time. See individual regimen biomarker eligibility criteria for more details.
 *See the [[Colorectal_cancer|'''main colorectal cancer page''']] for general regimens.
@@ Line 14: / Line 14: @@
 {{TOC limit|limit=3}}
 =Guidelines=
-==[http://www.esmo.org/ ESMO]==
+'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
+==[https://www.esmo.org/ ESMO]==
 *'''2016:''' [http://annonc.oxfordjournals.org/content/27/8/1386.full.pdf+html ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.] [https://pubmed.ncbi.nlm.nih.gov/27380959/ PubMed]
 *'''2013:''' [http://annonc.oxfordjournals.org/content/24/suppl_6/vi73.full.pdf+html Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines.] [https://pubmed.ncbi.nlm.nih.gov/23813931/ PubMed]
 ==[http://www.jsccr.jp/en/index.html Japanese Society for Cancer of the Colon and Rectum]==
 *'''2016:''' [https://doi.org/10.1007/s10147-017-1101-6 Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer] [https://pubmed.ncbi.nlm.nih.gov/28349281/ PubMed]
-==[https://www.nccn.org/ NCCN]==
+==NCCN==
-*[https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf NCCN Guidelines - Colon Cancer]
+*''NCCN does not currently have guidelines at this granular level; please see [https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428 NCCN Guidelines - Colon Cancer].''
 =Perioperative therapy for oligometastatic disease=
 ==FOLFIRI {{#subobject:a051ec|Regimen=1}}==
-FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
+FOLFIRI: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:49d215|Variant=1}}===
@@ Line 34: / Line 36: @@
 |-
 |[https://doi.org/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]
-|2008-2011 (NR)
+|2008-2011
 | style="background-color:#1a9851" |Phase 3 (C)
 |1a. [[#FOLFIRI_.26_Cetuximab|FOLFIRI & Cetuximab]]<br>1b. [[#mFOLFOX6_.26_Cetuximab|mFOLFOX6 & Cetuximab]]
@@ Line 44: / Line 46: @@
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
 *[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1
 '''14-day cycles until lesions deemed resectable or up to 12 cycles'''
 </div></div>
 ===References===
-#'''Fudan 2012-03:''' Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. [https://doi.org/10.1200/JCO.2012.44.8308 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23569301/ PubMed] [https://clinicaltrials.gov/study/NCT01564810 Clinical Trial Registry]
+#'''Fudan 2012-03:''' Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. [https://doi.org/10.1200/JCO.2012.44.8308 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23569301/ PubMed] [https://clinicaltrials.gov/study/NCT01564810 NCT01564810]
 ==FOLFIRI & Cetuximab {{#subobject:a051ec|Regimen=1}}==
-FOLFIRI & Cetuximab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Cetuximab
+FOLFIRI & Cetuximab: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Cetuximab
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #1, weekly cetuximab {{#subobject:8f47f9|Variant=1}}===
@@ Line 62: / Line 64: @@
 |-
 |[https://doi.org/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]
-|2008-2011 (NR)
+|2008-2011
 | style="background-color:#1a9851" |Phase 3 (E-esc)
 |1a. [[#FOLFIRI|FOLFIRI]]<br>1b. [[#mFOLFOX6|mFOLFOX6]]
-| style="background-color:#1a9850" |Superior OS<br>Median OS: 30.9 vs 21 mo<br>(HR 0.54, 95% CI 0.33-0.88)
+| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>Median OS: 30.9 vs 21 mo<br>(HR 0.54, 95% CI 0.33-0.88)<br><br>Superior rate of patients converted to resection for liver metastases (primary endpoint)
 |-
 |}
@@ Line 76: / Line 78: @@
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
 *[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1
 ====Targeted therapy====
@@ Line 85: / Line 87: @@
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2, bi-weekly cetuximab {{#subobject:49d215|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
@@ Line 94: / Line 97: @@
 |-
 |[https://doi.org/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]
-|2008-2011 (NR)
+|2008-2011
 | style="background-color:#1a9851" |Phase 3 (E-esc)
 |1a. [[#FOLFIRI|FOLFIRI]]<br>1b. [[#mFOLFOX6|mFOLFOX6]]
-| style="background-color:#1a9850" |Superior OS<br>Median OS: 30.9 vs 21 mo<br>(HR 0.54, 95% CI 0.33-0.88)
+| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>Median OS: 30.9 vs 21 mo<br>(HR 0.54, 95% CI 0.33-0.88)
 |-
 |}
@@ Line 104: / Line 107: @@
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
 *[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1
 ====Targeted therapy====
@@ Line 111: / Line 114: @@
 </div></div>
 ===References===
-#'''Fudan 2012-03:''' Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. [https://doi.org/10.1200/JCO.2012.44.8308 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23569301/ PubMed] [https://clinicaltrials.gov/study/NCT01564810 Clinical Trial Registry]
+#'''Fudan 2012-03:''' Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. [https://doi.org/10.1200/JCO.2012.44.8308 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23569301/ PubMed] [https://clinicaltrials.gov/study/NCT01564810 NCT01564810]
 ==mFOLFOX6 {{#subobject:8fcd39|Regimen=1}}==
-mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
+mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #1, 400/2800/85, resectable or suboptimally resectable {{#subobject:17252e|Variant=1}}===
@@ Line 124: / Line 127: @@
 |-
 |[https://doi.org/10.1016/S1470-2045(14)70105-6 Primrose et al. 2014 (New EPOC)]
-|2007-2012 (F)
+|2007-2012
 | style="background-color:#1a9851" |Phase 3 (C)
 |[[#mFOLFOX6_.26_Cetuximab|mFOLFOX6 & Cetuximab]]
@@ Line 138: / Line 141: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
@@ Line 153: / Line 156: @@
 |-
 |[https://doi.org/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]
-|2008-2011 (NR)
+|2008-2011
 | style="background-color:#1a9851" |Phase 3 (C)
 |1a. [[#FOLFIRI_.26_Cetuximab|FOLFIRI & Cetuximab]]<br>1b. [[#mFOLFOX6_.26_Cetuximab|mFOLFOX6 & Cetuximab]]
@@ Line 162: / Line 165: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
@@ Line 168: / Line 171: @@
 </div></div>
 ===References===
-#'''Fudan 2012-03:''' Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. [https://doi.org/10.1200/JCO.2012.44.8308 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23569301/ PubMed] [https://clinicaltrials.gov/study/NCT01564810 Clinical Trial Registry]
+#'''Fudan 2012-03:''' Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. [https://doi.org/10.1200/JCO.2012.44.8308 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23569301/ PubMed] [https://clinicaltrials.gov/study/NCT01564810 NCT01564810]
 #'''New EPOC:''' Primrose J, Falk S, Finch-Jones M, Valle J, O'Reilly D, Siriwardena A, Hornbuckle J, Peterson M, Rees M, Iveson T, Hickish T, Butler R, Stanton L, Dixon E, Little L, Bowers M, Pugh S, Garden OJ, Cunningham D, Maughan T, Bridgewater J. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol. 2014 May;15(6):601-11. Epub 2014 Apr 7. Erratum in: Lancet Oncol. 2014 Jun;15(7):e253. [https://doi.org/10.1016/S1470-2045(14)70105-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24717919/ PubMed] ISRCTN22944367
 ##'''Update:''' Bridgewater JA, Pugh SA, Maishman T, Eminton Z, Mellor J, Whitehead A, Stanton L, Radford M, Corkhill A, Griffiths GO, Falk S, Valle JW, O'Reilly D, Siriwardena AK, Hornbuckle J, Rees M, Iveson TJ, Hickish T, Garden OJ, Cunningham D, Maughan TS, Primrose JN; New EPOC investigators. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Mar;21(3):398-411. Epub 2020 Jan 31. [https://doi.org/10.1016/s1470-2045(19)30798-3 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7052737/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32014119/ PubMed]
 ==mFOLFOX6 & Cetuximab {{#subobject:8fcd39|Regimen=1}}==
-mFOLFOX6 & Cetuximab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Cetuximab
+mFOLFOX6 & Cetuximab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Cetuximab
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #1, weekly cetuximab {{#subobject:dcf5ee|Variant=1}}===
@@ Line 183: / Line 186: @@
 |-
 |[https://doi.org/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]
-|2008-2011 (NR)
+|2008-2011
 | style="background-color:#1a9851" |Phase 3 (E-esc)
 |1a. [[#FOLFIRI|FOLFIRI]]<br>1b. [[#mFOLFOX6|mFOLFOX6]]
-| style="background-color:#1a9850" |Superior OS<br>Median OS: 30.9 vs 21 mo<br>(HR 0.54, 95% CI 0.33-0.88)
+| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>Median OS: 30.9 vs 21 mo<br>(HR 0.54, 95% CI 0.33-0.88)
 |-
 |}
@@ Line 197: / Line 200: @@
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
 ====Targeted therapy====
@@ Line 215: / Line 218: @@
 |-
 |[https://doi.org/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]
-|2008-2011 (NR)
+|2008-2011
 | style="background-color:#1a9851" |Phase 3 (E-esc)
 |1a. [[#FOLFIRI|FOLFIRI]]<br>1b. [[#mFOLFOX6|mFOLFOX6]]
-| style="background-color:#1a9850" |Superior OS<br>Median OS: 30.9 vs 21 mo<br>(HR 0.54, 95% CI 0.33-0.88)
+| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>Median OS: 30.9 vs 21 mo<br>(HR 0.54, 95% CI 0.33-0.88)
 |-
 |}
@@ Line 225: / Line 228: @@
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
 ====Targeted therapy====
@@ Line 232: / Line 235: @@
 </div></div>
 ===References===
-#'''Fudan 2012-03:''' Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. [https://doi.org/10.1200/JCO.2012.44.8308 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23569301/ PubMed] [https://clinicaltrials.gov/study/NCT01564810 Clinical Trial Registry]
+#'''Fudan 2012-03:''' Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. [https://doi.org/10.1200/JCO.2012.44.8308 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23569301/ PubMed] [https://clinicaltrials.gov/study/NCT01564810 NCT01564810]
 =Advanced or metastatic disease, first-line=
 ==CapeOx & Panitumumab {{#subobject:22cf7b|Regimen=1}}==
@@ Line 259: / Line 262: @@
 </div></div>
 ===References===
-#'''HE 6A/09:''' Papaxoinis G, Kotoula V, Giannoulatou E, Koliou GA, Karavasilis V, Lakis S, Koureas A, Bobos M, Chalaralambous E, Daskalaki E, Chatzopoulos K, Tsironis G, Pazarli E, Chrisafi S, Samantas E, Kaklamanos IG, Varthalitis I, Konstantara A, Syrigos KN, Pentheroudakis G, Pectasides D, Fountzilas G. Phase II study of panitumumab combined with capecitabine and oxaliplatin as first-line treatment in metastatic colorectal cancer patients: clinical results including extended tumor genotyping. Med Oncol. 2018 May 31;35(7):101. [https://doi.org/10.1007/s12032-018-1160-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29855806/ PubMed] [https://clinicaltrials.gov/study/NCT01215539 Clinical Trial Registry]
+#'''HE 6A/09:''' Papaxoinis G, Kotoula V, Giannoulatou E, Koliou GA, Karavasilis V, Lakis S, Koureas A, Bobos M, Chalaralambous E, Daskalaki E, Chatzopoulos K, Tsironis G, Pazarli E, Chrisafi S, Samantas E, Kaklamanos IG, Varthalitis I, Konstantara A, Syrigos KN, Pentheroudakis G, Pectasides D, Fountzilas G. Phase II study of panitumumab combined with capecitabine and oxaliplatin as first-line treatment in metastatic colorectal cancer patients: clinical results including extended tumor genotyping. Med Oncol. 2018 May 31;35(7):101. [https://doi.org/10.1007/s12032-018-1160-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29855806/ PubMed] [https://clinicaltrials.gov/study/NCT01215539 NCT01215539]
 ==FOLFIRI {{#subobject:11cf4b|Regimen=1}}==
-FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
+FOLFIRI: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:64dac6|Variant=1}}===
@@ Line 272: / Line 275: @@
 |-
 |[https://doi.org/10.1056/NEJMoa0805019 Van Cutsem et al. 2009 (CRYSTAL)]
-|2004-2005
+|2004-07 to 2005-11
 | style="background-color:#1a9851" |Phase 3 (C)
 |[[#FOLFIRI_.26_Cetuximab_2|FOLFIRI & Cetuximab]]
@@ Line 285: / Line 288: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
 *[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first, with leucovorin'''
@@ Line 291: / Line 294: @@
 </div></div>
 ===References===
-#'''CRYSTAL:''' Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. [https://doi.org/10.1056/NEJMoa0805019 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19339720/ PubMed] [https://clinicaltrials.gov/study/NCT00154102 Clinical Trial Registry]
+#'''CRYSTAL:''' Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. [https://doi.org/10.1056/NEJMoa0805019 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19339720/ PubMed] [https://clinicaltrials.gov/study/NCT00154102 NCT00154102]
 <!-- ## '''Update: Abstract:''' E. Van Cutsem, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D. Cunningham, I. Celik, C. Kohne. Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome. 2010 ASCO Annual Meeting abstract 3570. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=54429 link to abstract] -->
 ##'''Update:''' Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. [https://doi.org/10.1200/jco.2010.33.5091 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21502544/ PubMed]
@@ Line 297: / Line 300: @@
 ##'''Biomarker analysis:''' Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. [https://doi.org/10.1200/JCO.2014.59.4812 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25605843/ PubMed]
 ==FOLFIRI & Bevacizumab {{#subobject:80d6b8|Regimen=1}}==
-FOLFIRI & Bevacizumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Bevacizumab
+FOLFIRI & Bevacizumab: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Bevacizumab
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:28b67a|Variant=1}}===
@@ Line 308: / Line 311: @@
 |-
 |[https://doi.org/10.1016/S1470-2045(14)70330-4 Heinemann et al. 2014 (FIRE-3)]
-|2007-2012 (C)
+|2007-2012
 | style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 |[[#FOLFIRI_.26_Cetuximab_2|FOLFIRI & Cetuximab]]
@@ Line 316: / Line 319: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
 *[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first, with leucovorin'''
@@ Line 325: / Line 328: @@
 </div></div>
 ===References===
-#'''FIRE-3:''' Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31.[https://doi.org/10.1016/S1470-2045(14)70330-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25088940/ PubMed] [https://clinicaltrials.gov/study/NCT00433927 Clinical Trial Registry]
+#'''FIRE-3:''' Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31.[https://doi.org/10.1016/S1470-2045(14)70330-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25088940/ PubMed] [https://clinicaltrials.gov/study/NCT00433927 NCT00433927]
 ==FOLFIRI & Cetuximab {{#subobject:11cf7b|Regimen=1}}==
-FOLFIRI & Cetuximab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Cetuximab
+FOLFIRI & Cetuximab: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Cetuximab
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 200 LCV {{#subobject:92lcv6|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/jco.23.01021 Pinto et al. 2024 (ERMES)]
+|2015-05 to 2020-03
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#FOLFIRI_.26_Cetuximab_2|FOLFIRI & Cetuximab]] induction x 8, then [[#Cetuximab_monotherapy|Cetuximab]] maintenance
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS (co-primary endpoint)<br>Median PFS: 12.2 vs 10 mo<br>(HR 0.77, 95% CI 0.61-0.97)
+|-
+|}
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*ERMES: Wild-type RAS, Wild-type BRAF
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV once on day 1
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1
+====Targeted therapy====
+*[[Cetuximab (Erbitux)]] as follows:
+**Cycle 1: 400 mg/m<sup>2</sup> IV once on day 1, then 250 mg/m<sup>2</sup> IV once on day 8
+**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV once per day on days 1 & 8
+'''14-day cycles'''
+</div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:921ac6|Variant=1}}===
+===Regimen variant #2, 400 LCV {{#subobject:921ac6|Variant=1}}===
 {| class="wikitable" style="color:white; background-color:#404040"
 |<small>'''FDA-recommended dose'''</small>
-|-
-|}
-{| class="wikitable" style="color:white; background-color:#1B4F26"
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-17-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
 |-
 |}
@@ Line 346: / Line 376: @@
 |-
 |[https://doi.org/10.1056/NEJMoa0805019 Van Cutsem et al. 2009 (CRYSTAL)]
-|2004-2005
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-17-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+|-
+|} -->
+|2004-07 to 2005-11
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 |[[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#1a9850" |Superior OS<sup>1</sup><br>Median OS: 23.5 vs 19.5 mo<br>(HR 0.81, 95% CI 0.69-0.94)
+| style="background-color:#1a9850" |Superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: 23.5 vs 19.5 mo<br>(HR 0.81, 95% CI 0.69-0.94)<br><br>Seems to have superior PFS (primary endpoint)<br>Median PFS: 8.9 vs 8 mo<br>(aHR 0.85, 95% CI 0.72-0.99)
 |-
 |[https://doi.org/10.1016/S1470-2045(14)70330-4 Heinemann et al. 2014 (FIRE-3)]
@@ Line 366: / Line 400: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, 1 hour after completion of cetuximab, with irinotecan'''
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, 1 hour after completion of cetuximab, with irinotecan'''
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
 *[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given second, 1 hour after completion of cetuximab, with leucovorin'''
@@ Line 375: / Line 409: @@
 '''14-day cycles'''
 </div></div>
 ===References===
-#'''CRYSTAL:''' Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. [https://doi.org/10.1056/NEJMoa0805019 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19339720/ PubMed] [https://clinicaltrials.gov/study/NCT00154102 Clinical Trial Registry]
+#'''CRYSTAL:''' Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. [https://doi.org/10.1056/NEJMoa0805019 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19339720/ PubMed] [https://clinicaltrials.gov/study/NCT00154102 NCT00154102]
 <!-- ## '''Update: Abstract:''' E. Van Cutsem, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D. Cunningham, I. Celik, C. Kohne. Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome. 2010 ASCO Annual Meeting abstract 3570. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=54429 link to abstract] -->
 ##'''Update:''' Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. [https://doi.org/10.1200/jco.2010.33.5091 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21502544/ PubMed]
 ##'''Pooled update:''' Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://doi.org/10.1016/j.ejca.2012.02.057 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22446022/ PubMed]
 ##'''Biomarker analysis:''' Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. [https://doi.org/10.1200/JCO.2014.59.4812 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25605843/ PubMed]
-#'''FIRE-3:''' Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31. [https://doi.org/10.1016/S1470-2045(14)70330-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25088940/ PubMed] [https://clinicaltrials.gov/study/NCT00433927 Clinical Trial Registry]
+#'''FIRE-3:''' Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31. [https://doi.org/10.1016/S1470-2045(14)70330-4 link to original article] '''contains dosing details on CT.gov''' [https://pubmed.ncbi.nlm.nih.gov/25088940/ PubMed] [https://clinicaltrials.gov/study/NCT00433927 NCT00433927]
+#'''ERMES:''' Pinto C, Orlandi A, Normanno N, Maiello E, Calegari MA, Antonuzzo L, Bordonaro R, Zampino MG, Pini S, Bergamo F, Tonini G, Avallone A, Latiano TP, Rosati G, Cogoni AA, Ballestrero A, Zaniboni A, Roselli M, Tamberi S, Barone C. Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Versus Cetuximab as Maintenance Therapy in First-Line Therapy for RAS and BRAF Wild-Type Metastatic Colorectal Cancer: Phase III ERMES Study. J Clin Oncol. 2024 Apr 10;42(11):1278-1287. Epub 2024 Jan 5. [https://doi.org/10.1200/jco.23.01021 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/38181312/ PubMed] [https://clinicaltrials.gov/study/NCT02484833 NCT02484833]
 ==FOLFIRI & Cetuximab (L-Leucovorin) {{#subobject:22bf7b|Regimen=1}}==
-FOLFIRI & Cetuximab: L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Cetuximab
+FOLFIRI & Cetuximab: L-'''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Cetuximab
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:8ugac6|Variant=1}}===
 {| class="wikitable" style="color:white; background-color:#404040"
 |<small>'''FDA-recommended dose'''</small>
-|-
-|}
-{| class="wikitable" style="color:white; background-color:#1B4F26"
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-17-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
 |-
 |}
@@ Line 402: / Line 435: @@
 |-
 |[https://doi.org/10.1056/NEJMoa0805019 Van Cutsem et al. 2009 (CRYSTAL)]
-|2004-2005
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-17-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+|-
+|} -->
+|2004-07 to 2005-11
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 |[[#FOLFIRI_2|FOLFIRI]]
-| style="background-color:#1a9850" |Superior OS<sup>1</sup><br>Median OS: 23.5 vs 19.5 mo<br>(HR 0.81, 95% CI 0.69-0.94)
+| style="background-color:#1a9850" |Superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: 23.5 vs 19.5 mo<br>(HR 0.81, 95% CI 0.69-0.94)
-|-
-|[https://doi.org/10.1016/S1470-2045(14)70330-4 Heinemann et al. 2014 (FIRE-3)]
-|2007-2012
-| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
-|[[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
 |}
@@ Line 418: / Line 449: @@
 ====Biomarker eligibility criteria====
 *CRYSTAL: none
-*FIRE-3: Wild-type KRAS, Wild-type NRAS
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
@@ Line 432: / Line 462: @@
 </div></div>
 ===References===
-#'''CRYSTAL:''' Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. [https://doi.org/10.1056/NEJMoa0805019 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19339720/ PubMed] [https://clinicaltrials.gov/study/NCT00154102 Clinical Trial Registry]
+#'''CRYSTAL:''' Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. [https://doi.org/10.1056/NEJMoa0805019 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19339720/ PubMed] [https://clinicaltrials.gov/study/NCT00154102 NCT00154102]
 <!-- ## '''Update: Abstract:''' E. Van Cutsem, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D. Cunningham, I. Celik, C. Kohne. Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome. 2010 ASCO Annual Meeting abstract 3570. [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=54429 link to abstract] -->
 ##'''Update:''' Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. [https://doi.org/10.1200/jco.2010.33.5091 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21502544/ PubMed]
 ##'''Pooled update:''' Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://doi.org/10.1016/j.ejca.2012.02.057 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22446022/ PubMed]
 ##'''Biomarker analysis:''' Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. [https://doi.org/10.1200/JCO.2014.59.4812 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25605843/ PubMed]
-#'''FIRE-3:''' Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31. [https://doi.org/10.1016/S1470-2045(14)70330-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25088940/ PubMed] [https://clinicaltrials.gov/study/NCT00433927 Clinical Trial Registry]
+==FOLFIRINOX {{#subobject:9bf7dc|Regimen=1}}==
+FOLFIRINOX: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, '''<u>OX</u>'''aliplatin
+<br>FOLFOXIRI: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>IRI</u>'''notecan
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:19365x|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/JCO.19.01340 Modest et al. 2019 (VOLFI)]
+|2011-2016
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
+|[[#FOLFOXIRI_.26_Panitumumab|FOLFOXIRI & Panitumumab]]
+| style="background-color:#d73027" |Inferior ORR
+|-
+|}
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*Wild-type KRAS, Wild-type NRAS
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 1600 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 3200 mg/m<sup>2</sup>)
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV once on day 1
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
+*[[Irinotecan (Camptosar)]] 165 mg/m<sup>2</sup> IV once on day 1
+'''14-day cycle until POD or resectability or to max 12 cycles'''
+</div></div>
+===References===
+#'''VOLFI:''' Modest DP, Martens UM, Riera-Knorrenschild J, Greeve J, Florschütz A, Wessendorf S, Ettrich T, Kanzler S, Nörenberg D, Ricke J, Seidensticker M, Held S, Buechner-Steudel P, Atzpodien J, Heinemann V, Seufferlein T, Tannapfel A, Reinacher-Schick AC, Geissler M. FOLFOXIRI Plus Panitumumab As First-Line Treatment of RAS Wild-Type Metastatic Colorectal Cancer: The Randomized, Open-Label, Phase II VOLFI Study (AIO KRK0109). J Clin Oncol. 2019 Dec 10;37(35):3401-3411. Epub 2019 Oct 14. [https://doi.org/10.1200/JCO.19.01340 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31609637/ PubMed] [https://clinicaltrials.gov/study/NCT01328171 NCT01328171]
 ==FOLFOX4 {{#subobject:7239a0|Regimen=1}}==
-FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
+FOLFOX4: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:ab483a|Variant=1}}===
@@ Line 473: / Line 536: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given first, with oxaliplatin on day 1'''
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given second''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
@@ Line 479: / Line 542: @@
 </div></div>
 ===References===
-#'''OPUS:''' Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29. [https://doi.org/10.1200/JCO.2008.20.8397 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19114683/ PubMed] [https://clinicaltrials.gov/study/NCT00125034 Clinical Trial Registry]
+#'''OPUS:''' Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29. [https://doi.org/10.1200/JCO.2008.20.8397 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19114683/ PubMed] [https://clinicaltrials.gov/study/NCT00125034 NCT00125034]
 ##'''Update:''' Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011 Jul;22(7):1535-46. Epub 2011 Jan 12. [https://doi.org/10.1093/annonc/mdq632 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21228335/ PubMed]
 ##'''Pooled update:''' Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://doi.org/10.1016/j.ejca.2012.02.057 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22446022/ PubMed]
-#'''PRIME:''' Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010 Nov 1;28(31):4697-705. Epub 2010 Oct 4. [https://doi.org/10.1200/jco.2009.27.4860 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20921465/ PubMed] [https://clinicaltrials.gov/study/NCT00364013 Clinical Trial Registry]
+#'''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. [https://doi.org/10.1200/jco.2009.27.4860 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20921465/ PubMed] [https://clinicaltrials.gov/study/NCT00364013 NCT00364013]
 ##'''Biomarker analysis:''' Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013 Sep 12;369(11):1023-34. [https://doi.org/10.1056/NEJMoa1305275 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24024839/ PubMed]
 ##'''Update:''' Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jul;25(7):1346-55. Epub 2014 Apr 8. [https://doi.org/10.1093/annonc/mdu141 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24718886/ PubMed]
-#'''TAILOR-CRC:''' Qin S, Li J, Wang L, Xu J, Cheng Y, Bai Y, Li W, Xu N, Lin LZ, Wu Q, Li Y, Yang J, Pan H, Ouyang X, Qiu W, Wu K, Xiong J, Dai G, Liang H, Hu C, Zhang J, Tao M, Yao Q, Wang J, Chen J, Eggleton SP, Liu T. Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer: the open-label, randomized, phase III TAILOR trial. J Clin Oncol. 2018 Oct 20;36(30):3031-9. Epub 2018 Sep 10. [https://doi.org/10.1200/JCO.2018.78.3183 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6324088/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30199311/ PubMed] [https://clinicaltrials.gov/study/NCT01228734 Clinical Trial Registry]
+#'''TAILOR-CRC:''' Qin S, Li J, Wang L, Xu J, Cheng Y, Bai Y, Li W, Xu N, Lin LZ, Wu Q, Li Y, Yang J, Pan H, Ouyang X, Qiu W, Wu K, Xiong J, Dai G, Liang H, Hu C, Zhang J, Tao M, Yao Q, Wang J, Chen J, Eggleton SP, Liu T. Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer: the open-label, randomized, phase III TAILOR trial. J Clin Oncol. 2018 Oct 20;36(30):3031-9. Epub 2018 Sep 10. [https://doi.org/10.1200/JCO.2018.78.3183 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6324088/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30199311/ PubMed] [https://clinicaltrials.gov/study/NCT01228734 NCT01228734]
 ==FOLFOX4 & Cetuximab {{#subobject:5e5bf3|Regimen=1}}==
-FOLFOX4 & Cetuximab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Cetuximab
+FOLFOX4 & Cetuximab: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Cetuximab
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:9ec84d|Variant=1}}===
@@ Line 501: / Line 565: @@
 | style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
 |[[#FOLFOX4|FOLFOX4]]
-| style="background-color:#1a9850" |Superior OS<sup>1</sup><br>Median OS: 23.5 vs 19.5 mo<br>(HR 0.81, 95% CI 0.69-0.94)
+| style="background-color:#1a9850" |Superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: 23.5 vs 19.5 mo<br>(HR 0.81, 95% CI 0.69-0.94)<br><br>Might have superior ORR (primary endpoint)
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6324088/ Qin et al. 2018 (TAILOR-CRC)]
@@ Line 507: / Line 571: @@
 | style="background-color:#1a9851" |Phase 3 (E-esc)
 |[[#FOLFOX4|FOLFOX4]]
-| style="background-color:#91cf60" |Seems to have superior OS<br>Median OS: 20.7 vs 17.8 mo<br>(HR 0.76, 95% CI 0.61-0.96)
+| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br>Median OS: 20.7 vs 17.8 mo<br>(HR 0.76, 95% CI 0.61-0.96)<br><br>Superior PFS (primary endpoint)<br>Median PFS: 9.2 vs 7.4 mo<br>(HR 0.69, 95% CI 0.54-0.89)
 |-
 |}
@@ Line 519: / Line 583: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given second, with oxaliplatin on day 1'''
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2, '''given second, with oxaliplatin on day 1'''
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus, '''given third''' (total dose per cycle: 2000 mg/m<sup>2</sup>)
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
@@ Line 528: / Line 592: @@
 '''14-day cycles'''
 </div></div>
 ===References===
-#'''OPUS:''' Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29. [https://doi.org/10.1200/JCO.2008.20.8397 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19114683/ PubMed] [https://clinicaltrials.gov/study/NCT00125034 Clinical Trial Registry]
+#'''OPUS:''' Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29. [https://doi.org/10.1200/JCO.2008.20.8397 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19114683/ PubMed] [https://clinicaltrials.gov/study/NCT00125034 NCT00125034]
 ##'''Update:''' Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011 Jul;22(7):1535-46. Epub 2011 Jan 12. [https://doi.org/10.1093/annonc/mdq632 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21228335/ PubMed]
 ##'''Pooled update:''' Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://doi.org/10.1016/j.ejca.2012.02.057 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22446022/ PubMed]
-#'''TAILOR-CRC:''' Qin S, Li J, Wang L, Xu J, Cheng Y, Bai Y, Li W, Xu N, Lin LZ, Wu Q, Li Y, Yang J, Pan H, Ouyang X, Qiu W, Wu K, Xiong J, Dai G, Liang H, Hu C, Zhang J, Tao M, Yao Q, Wang J, Chen J, Eggleton SP, Liu T. Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer: the open-label, randomized, phase III TAILOR trial. J Clin Oncol. 2018 Oct 20;36(30):3031-9. Epub 2018 Sep 10. [https://doi.org/10.1200/JCO.2018.78.3183 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6324088/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30199311/ PubMed] [https://clinicaltrials.gov/study/NCT01228734 Clinical Trial Registry]
+#'''TAILOR-CRC:''' Qin S, Li J, Wang L, Xu J, Cheng Y, Bai Y, Li W, Xu N, Lin LZ, Wu Q, Li Y, Yang J, Pan H, Ouyang X, Qiu W, Wu K, Xiong J, Dai G, Liang H, Hu C, Zhang J, Tao M, Yao Q, Wang J, Chen J, Eggleton SP, Liu T. Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer: the open-label, randomized, phase III TAILOR trial. J Clin Oncol. 2018 Oct 20;36(30):3031-9. Epub 2018 Sep 10. [https://doi.org/10.1200/JCO.2018.78.3183 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6324088/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30199311/ PubMed] [https://clinicaltrials.gov/study/NCT01228734 NCT01228734]
 ==FOLFOX4 & Panitumumab {{#subobject:486271|Regimen=1}}==
-FOLFOX4 & Panitumumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Panitumumab
+FOLFOX4 & Panitumumab: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Panitumumab
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:d862a3|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#1B4F26"
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-15-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
-|-
-|}
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 549: / Line 611: @@
 |-
 |[https://doi.org/10.1200/jco.2009.27.4860 Douillard et al. 2010 (PRIME)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-15-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+|-
+|} -->
 |2006-2008
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
@@ Line 563: / Line 629: @@
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
 ====Targeted therapy====
@@ Line 572: / Line 638: @@
 ===References===
 <!-- Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL; the 2008 Gastrointestinal Cancers Symposium, January 25-27, 2008, Orlando, FL; the joint 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology, September 20-24, 2009, Berlin, Germany; the 6th Annual Meeting of the International Society of Gastrointestinal Oncology, October 1-3, 2009, Philadelphia, PA; the 2009 National Cancer Research Institute Cancer Conference, October 4-7, 2009, Birmingham, United Kingdom; and the 2010 Gastrointestinal Cancers Symposium, January 22-24, 2010, Orlando, FL. -->
-#'''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. [https://doi.org/10.1200/jco.2009.27.4860 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20921465/ PubMed] [https://clinicaltrials.gov/study/NCT00364013 Clinical Trial Registry]
+#'''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. [https://doi.org/10.1200/jco.2009.27.4860 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20921465/ PubMed] [https://clinicaltrials.gov/study/NCT00364013 NCT00364013]
 ##'''Biomarker analysis:''' Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013 Sep 12;369(11):1023-34. [https://doi.org/10.1056/NEJMoa1305275 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24024839/ PubMed]
 ##'''Update:''' Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jul;25(7):1346-55. Epub 2014 Apr 8. [https://doi.org/10.1093/annonc/mdu141 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24718886/ PubMed]
 ==mFOLFOX6-B {{#subobject:8ugz86|Regimen=1}}==
-mFOLFOX6-B: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
+mFOLFOX6-B: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:8baf2c|Variant=1}}===
@@ Line 602: / Line 668: @@
 | style="background-color:#fc8d59" |Seems to have inferior PFS<sup>1</sup>
 |-
-|[https://www.clinicaltrials.gov/study/NCT02394795 Awaiting publication (PARADIGM<sub>CRC</sub>)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10114040/ Watanabe et al. 2023 (PARADIGM<sub>CRC</sub>)]
-|2015-2022
+|2015-05 to 2022-01
 | style="background-color:#1a9851" |Phase 3 (C)
 |[[#mFOLFOX6_.26_Panitumumab|mFOLFOX6 & Panitumumab]]
@@ Line 614: / Line 680: @@
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV once on day 1
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
 ====Targeted therapy====
@@ Line 621: / Line 687: @@
 </div></div>
 ===References===
-#'''CALGB 80405:''' Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O'Neil BH, Atkins JN, Berry S, Polite BN, O'Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, El-Khoueiry AB, Watson P, Benson AB 3rd, Mulkerin DL, Mayer RJ, Blanke C. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2017 Jun 20;317(23):2392-2401. [https://jamanetwork.com/journals/jama/fullarticle/2632502 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545896/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28632865/ PubMed] [https://clinicaltrials.gov/study/NCT00265850 Clinical Trial Registry]
+#'''CALGB 80405:''' Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O'Neil BH, Atkins JN, Berry S, Polite BN, O'Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, El-Khoueiry AB, Watson P, Benson AB 3rd, Mulkerin DL, Mayer RJ, Blanke C. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2017 Jun 20;317(23):2392-2401. [https://jamanetwork.com/journals/jama/fullarticle/2632502 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545896/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28632865/ PubMed] [https://clinicaltrials.gov/study/NCT00265850 NCT00265850]
-#'''PEAK:''' Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, Yu H, Oliner KS, Go WY. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014 Jul 20;32(21):2240-7. Epub 2014 Mar 31. [https://doi.org/10.1200/jco.2013.53.2473 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24687833/ PubMed] [https://clinicaltrials.gov/study/NCT00819780 Clinical Trial Registry]
+#'''PEAK:''' Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, Yu H, Oliner KS, Go WY. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014 Jul 20;32(21):2240-7. Epub 2014 Mar 31. [https://doi.org/10.1200/jco.2013.53.2473 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24687833/ PubMed] [https://clinicaltrials.gov/study/NCT00819780 NCT00819780]
-##'''Update:''' Rivera F, Karthaus M, Hecht JR, Sevilla I, Forget F, Fasola G, Canon JL, Guan X, Demonty G, Schwartzberg LS. Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma. Int J Colorectal Dis. 2017 Aug;32(8):1179-1190. Epub 2017 Apr 19. [https://doi.org/10.1007/s00384-017-2800-1 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5522523/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28424871/ PubMed]
+##'''Update:''' Rivera F, Karthaus M, Hecht JR, Sevilla I, Forget F, Fasola G, Canon JL, Guan X, Demonty G, Schwartzberg LS. Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma. Int J Colorectal Dis. 2017 Aug;32(8):1179-1190. Epub 2017 Apr 19. [https://doi.org/10.1007/s00384-017-2800-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5522523/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28424871/ PubMed]
-#'''PARADIGM<sub>CRC</sub>:''' [https://clinicaltrials.gov/study/NCT02394795 Clinical Trial Registry]
+#'''PARADIGM<sub>CRC</sub>:''' Watanabe J, Muro K, Shitara K, Yamazaki K, Shiozawa M, Ohori H, Takashima A, Yokota M, Makiyama A, Akazawa N, Ojima H, Yuasa Y, Miwa K, Yasui H, Oki E, Sato T, Naitoh T, Komatsu Y, Kato T, Hihara M, Soeda J, Misumi T, Yamamoto K, Akagi K, Ochiai A, Uetake H, Tsuchihara K, Yoshino T. Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2023 Apr 18;329(15):1271-1282. Erratum in: JAMA. 2023 Jun 27;329(24):2196. [https://doi.org/10.1001/jama.2023.4428 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10114040/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37071094/ PubMed] [https://clinicaltrials.gov/study/NCT02394795 NCT02394795]
 ==mFOLFOX6 & Cetuximab {{#subobject:12d786|Regimen=1}}==
-mFOLFOX6 & Cetuximab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Cetuximab
+mFOLFOX6 & Cetuximab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Cetuximab
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:8baf2c|Variant=1}}===
@@ Line 662: / Line 728: @@
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
 ====Targeted therapy====
@@ Line 675: / Line 741: @@
 </div></div>
 ===References===
-#'''CALGB 80405:''' Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O'Neil BH, Atkins JN, Berry S, Polite BN, O'Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, El-Khoueiry AB, Watson P, Benson AB 3rd, Mulkerin DL, Mayer RJ, Blanke C. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2017 Jun 20;317(23):2392-2401. [https://jamanetwork.com/journals/jama/fullarticle/2632502 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545896/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28632865/ PubMed] [https://clinicaltrials.gov/study/NCT00265850 Clinical Trial Registry]
+#'''CALGB 80405:''' Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O'Neil BH, Atkins JN, Berry S, Polite BN, O'Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, El-Khoueiry AB, Watson P, Benson AB 3rd, Mulkerin DL, Mayer RJ, Blanke C. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2017 Jun 20;317(23):2392-2401. [https://jamanetwork.com/journals/jama/fullarticle/2632502 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545896/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28632865/ PubMed] [https://clinicaltrials.gov/study/NCT00265850 NCT00265850]
-#'''MACRO-2:''' Aranda E, García-Alfonso P, Benavides M, Sánchez Ruiz A, Guillén-Ponce C, Safont MJ, Alcaide J, Gómez A, López R, Manzano JL, Méndez Ureña M, Sastre J, Rivera F, Grávalos C, García T, Martín-Valadés JI, Falcó E, Navalón M, González Flores E, Ma García Tapiador A, Ma López Muñoz A, Barrajón E, Reboredo M, García Teijido P, Viudez A, Cárdenas N, Díaz-Rubio E; Spanish Cooperative Group for the Treatment of Digestive Tumours. First-line mFOLFOX plus cetuximab followed by mFOLFOX plus cetuximab or single-agent cetuximab as maintenance therapy in patients with metastatic colorectal cancer: phase II randomised MACRO2 TTD study. Eur J Cancer. 2018 Sep;101:263-272. Epub 2018 Jul 24. [https://doi.org/10.1016/j.ejca.2018.06.024 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30054049/ PubMed] [https://clinicaltrials.gov/study/NCT01161316 Clinical Trial Registry]
+#'''MACRO-2:''' Aranda E, García-Alfonso P, Benavides M, Sánchez Ruiz A, Guillén-Ponce C, Safont MJ, Alcaide J, Gómez A, López R, Manzano JL, Méndez Ureña M, Sastre J, Rivera F, Grávalos C, García T, Martín-Valadés JI, Falcó E, Navalón M, González Flores E, Ma García Tapiador A, Ma López Muñoz A, Barrajón E, Reboredo M, García Teijido P, Viudez A, Cárdenas N, Díaz-Rubio E; Spanish Cooperative Group for the Treatment of Digestive Tumours. First-line mFOLFOX plus cetuximab followed by mFOLFOX plus cetuximab or single-agent cetuximab as maintenance therapy in patients with metastatic colorectal cancer: phase II randomised MACRO2 TTD study. Eur J Cancer. 2018 Sep;101:263-272. Epub 2018 Jul 24. [https://doi.org/10.1016/j.ejca.2018.06.024 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30054049/ PubMed] [https://clinicaltrials.gov/study/NCT01161316 NCT01161316]
 ==mFOLFOX6 & Panitumumab {{#subobject:avn786|Regimen=1}}==
-mFOLFOX6 & Panitumumab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Panitumumab
+mFOLFOX6 & Panitumumab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Panitumumab
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:8bukqc|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#1B4F26"
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-16-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
-|-
-|}
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 698: / Line 760: @@
 | style="background-color:#91cf60" |Seems to have superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: 12.8 vs 10.1 mo<br>(HR 0.68, 95% CI 0.48-0.96)<br><br>Did not meet secondary endpoint of OS<sup>1</sup><br>Median OS: 36.9 vs 28.9 mo<br>(HR 0.76, 95% CI 0.53-1.11)
 |-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc9426812/ Rossini et al. 2022 (TRIPLETE)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10114040/ Watanabe et al. 2023 (PARADIGM<sub>CRC</sub>)]
+|2015-05 to 2022-01
+| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
+|[[#mFOLFOX6-B|mFOLFOX6-B]]
+| style="background-color:#91cf60" |Seems to have superior OS<sup>2</sup> (primary endpoint)<br>Median OS: 37.9 vs 34.3 mo<br>(HR 0.82, 95.798% CI 0.68-0.99)
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9426812/ Rossini et al. 2022 (TRIPLETE)]
 |2017-2021
 | style="background-color:#1a9851" |Phase 3 (C)
@@ Line 705: / Line 773: @@
 |-
 |}
-''<sup>1</sup>Reported efficacy for PEAK is based on the 2017 update.''
+''<sup>1</sup>Reported efficacy for PEAK is based on the 2017 update.''<br>
+''<sup>2</sup>Reported efficacy is for patients with left-sided primary tumors, which was the primary analysis; efficacy results for the overall population were similar.''
 <div class="toccolours" style="background-color:#fdcdac">
 ====Biomarker eligibility criteria====
@@ Line 713: / Line 782: @@
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, '''given third''', then 2400 mg/m<sup>2</sup> IV continuous infusion over 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1, '''given second'''
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV once on day 1, '''given second'''
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
 ====Targeted therapy====
@@ Line 721: / Line 790: @@
 ===References===
-#'''PEAK:''' Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, Yu H, Oliner KS, Go WY. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014 Jul 20;32(21):2240-7. Epub 2014 Mar 31. [https://doi.org/10.1200/jco.2013.53.2473 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24687833/ PubMed] [https://clinicaltrials.gov/study/NCT00819780 Clinical Trial Registry]
+#'''PEAK:''' Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, Yu H, Oliner KS, Go WY. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014 Jul 20;32(21):2240-7. Epub 2014 Mar 31. [https://doi.org/10.1200/jco.2013.53.2473 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24687833/ PubMed] [https://clinicaltrials.gov/study/NCT00819780 NCT00819780]
-##'''Update:''' Rivera F, Karthaus M, Hecht JR, Sevilla I, Forget F, Fasola G, Canon JL, Guan X, Demonty G, Schwartzberg LS. Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma. Int J Colorectal Dis. 2017 Aug;32(8):1179-1190. Epub 2017 Apr 19. [https://doi.org/10.1007/s00384-017-2800-1 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5522523/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28424871/ PubMed]
+##'''Update:''' Rivera F, Karthaus M, Hecht JR, Sevilla I, Forget F, Fasola G, Canon JL, Guan X, Demonty G, Schwartzberg LS. Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma. Int J Colorectal Dis. 2017 Aug;32(8):1179-1190. Epub 2017 Apr 19. [https://doi.org/10.1007/s00384-017-2800-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5522523/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28424871/ PubMed]
-#'''TRIPLETE:''' Rossini D, Antoniotti C, Lonardi S, Pietrantonio F, Moretto R, Antonuzzo L, Boccaccino A, Morano F, Brugia M, Pozzo C, Marmorino F, Bergamo F, Tamburini E, Passardi A, Randon G, Murgioni S, Borelli B, Buonadonna A, Giordano M, Fontanini G, Conca V, Formica V, Aglietta M, Bordonaro R, Aprile G, Masi G, Boni L, Cremolini C. Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO. J Clin Oncol. 2022 Sep 1;40(25):2878-2888. Epub 2022 Jun 6. [https://doi.org/10.1200/jco.22.00839 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc9426812/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35666229/ PubMed] [https://clinicaltrials.gov/study/NCT03231722 Clinical Trial Registry]
+#'''TRIPLETE:''' Rossini D, Antoniotti C, Lonardi S, Pietrantonio F, Moretto R, Antonuzzo L, Boccaccino A, Morano F, Brugia M, Pozzo C, Marmorino F, Bergamo F, Tamburini E, Passardi A, Randon G, Murgioni S, Borelli B, Buonadonna A, Giordano M, Fontanini G, Conca V, Formica V, Aglietta M, Bordonaro R, Aprile G, Masi G, Boni L, Cremolini C. Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO. J Clin Oncol. 2022 Sep 1;40(25):2878-2888. Epub 2022 Jun 6. [https://doi.org/10.1200/jco.22.00839 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9426812/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35666229/ PubMed] [https://clinicaltrials.gov/study/NCT03231722 NCT03231722]
+#'''PARADIGM<sub>CRC</sub>:''' Watanabe J, Muro K, Shitara K, Yamazaki K, Shiozawa M, Ohori H, Takashima A, Yokota M, Makiyama A, Akazawa N, Ojima H, Yuasa Y, Miwa K, Yasui H, Oki E, Sato T, Naitoh T, Komatsu Y, Kato T, Hihara M, Soeda J, Misumi T, Yamamoto K, Akagi K, Ochiai A, Uetake H, Tsuchihara K, Yoshino T. Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2023 Apr 18;329(15):1271-1282. Erratum in: JAMA. 2023 Jun 27;329(24):2196. [https://doi.org/10.1001/jama.2023.4428 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10114040/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37071094/ PubMed] [https://clinicaltrials.gov/study/NCT02394795 NCT02394795]
 ==mFOLFOXIRI & Cetuximab (L-Leucovorin){{#subobject:9bf7|Regimen=1}}==
-mFOLFOXIRI & Cetuximab: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>IRI</u>'''notecan, Cetuximab
+mFOLFOXIRI & Cetuximab: '''<u>m</u>'''odified L-'''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>IRI</u>'''notecan, Cetuximab
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:19365|Variant=1}}===
@@ Line 758: / Line 828: @@
 </div></div>
 ===References===
-#'''MACBETH:''' Cremolini C, Antoniotti C, Lonardi S, Aprile G, Bergamo F, Masi G, Grande R, Tonini G, Mescoli C, Cardellino GG, Coltelli L, Salvatore L, Corsi DC, Lupi C, Gemma D, Ronzoni M, Dell'Aquila E, Marmorino F, Di Fabio F, Mancini ML, Marcucci L, Fontanini G, Zagonel V, Boni L, Falcone A. Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial. JAMA Oncol. 2018 Apr 1;4(4):529-536. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2672387 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885260/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29450468/ PubMed] [https://clinicaltrials.gov/study/NCT02295930 Clinical Trial Registry]
+#'''MACBETH:''' Cremolini C, Antoniotti C, Lonardi S, Aprile G, Bergamo F, Masi G, Grande R, Tonini G, Mescoli C, Cardellino GG, Coltelli L, Salvatore L, Corsi DC, Lupi C, Gemma D, Ronzoni M, Dell'Aquila E, Marmorino F, Di Fabio F, Mancini ML, Marcucci L, Fontanini G, Zagonel V, Boni L, Falcone A. Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial. JAMA Oncol. 2018 Apr 1;4(4):529-536. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2672387 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885260/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29450468/ PubMed] [https://clinicaltrials.gov/study/NCT02295930 NCT02295930]
 ==FOLFOXIRI & Panitumumab {{#subobject:9bf7|Regimen=1}}==
-FOLFOXIRI & Panitumumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>IRI</u>'''notecan, Panitumumab
+FOLFOXIRI & Panitumumab: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>IRI</u>'''notecan, Panitumumab
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:19365|Variant=1}}===
@@ Line 774: / Line 844: @@
 | style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
 |[[#FOLFIRINOX|FOLFOXIRI]]
-| style="background-color:#1a9850" |Superior ORR
+| style="background-color:#1a9850" |Superior ORR (primary endpoint)
 |-
 |}
@@ Line 784: / Line 854: @@
 ====Chemotherapy====
 *[[Fluorouracil (5-FU)]] 1500 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 3000 mg/m<sup>2</sup>)
-*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV once on day 1
 *[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
 *[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV once on day 1
@@ Line 792: / Line 862: @@
 </div></div>
 ===References===
-#'''VOLFI:''' Modest DP, Martens UM, Riera-Knorrenschild J, Greeve J, Florschütz A, Wessendorf S, Ettrich T, Kanzler S, Nörenberg D, Ricke J, Seidensticker M, Held S, Buechner-Steudel P, Atzpodien J, Heinemann V, Seufferlein T, Tannapfel A, Reinacher-Schick AC, Geissler M. FOLFOXIRI Plus Panitumumab As First-Line Treatment of RAS Wild-Type Metastatic Colorectal Cancer: The Randomized, Open-Label, Phase II VOLFI Study (AIO KRK0109). J Clin Oncol. 2019 Dec 10;37(35):3401-3411. Epub 2019 Oct 14. [https://doi.org/10.1200/JCO.19.01340 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31609637/ PubMed] [https://clinicaltrials.gov/study/NCT01328171 Clinical Trial Registry]
+#'''VOLFI:''' Modest DP, Martens UM, Riera-Knorrenschild J, Greeve J, Florschütz A, Wessendorf S, Ettrich T, Kanzler S, Nörenberg D, Ricke J, Seidensticker M, Held S, Buechner-Steudel P, Atzpodien J, Heinemann V, Seufferlein T, Tannapfel A, Reinacher-Schick AC, Geissler M. FOLFOXIRI Plus Panitumumab As First-Line Treatment of RAS Wild-Type Metastatic Colorectal Cancer: The Randomized, Open-Label, Phase II VOLFI Study (AIO KRK0109). J Clin Oncol. 2019 Dec 10;37(35):3401-3411. Epub 2019 Oct 14. [https://doi.org/10.1200/JCO.19.01340 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31609637/ PubMed] [https://clinicaltrials.gov/study/NCT01328171 NCT01328171]
 =Maintenance after first-line therapy=
@@ Line 822: / Line 892: @@
 </div></div>
 ===References===
-#'''Nordic ACT2:''' Hagman H, Frödin JE, Berglund Å, Sundberg J, Vestermark LW, Albertsson M, Fernebro E, Johnsson A. A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial. Ann Oncol. 2016 Jan;27(1):140-7. Epub 2015 Oct 19. [https://doi.org/10.1093/annonc/mdv490 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26483047/ PubMed] [https://clinicaltrials.gov/study/NCT01229813 Clinical Trial Registry]
+#'''Nordic ACT2:''' Hagman H, Frödin JE, Berglund Å, Sundberg J, Vestermark LW, Albertsson M, Fernebro E, Johnsson A. A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial. Ann Oncol. 2016 Jan;27(1):140-7. Epub 2015 Oct 19. [https://doi.org/10.1093/annonc/mdv490 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26483047/ PubMed] [https://clinicaltrials.gov/study/NCT01229813 NCT01229813]
 ==Cetuximab monotherapy {{#subobject:afad4f|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
@@ Line 837: / Line 907: @@
 | style="background-color:#1a9851" |Randomized Phase 2 (E-de-esc)
 |[[#mFOLFOX6_.26_Cetuximab_2|mFOLFOX6 & Cetuximab]]
-| style="background-color:#eeee01" |Non-inferior PFS
+| style="background-color:#eeee01" |Non-inferior PFS9 (primary endpoint)
 |-
 |}
@@ Line 847: / Line 917: @@
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#mFOLFOX6_.26_Cetuximab_2|mFOLFOX6 & Cetuximab]] x 8
+*First-line [[#mFOLFOX6_.26_Cetuximab_2|mFOLFOX6 & Cetuximab]] x 8
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
@@ Line 871: / Line 941: @@
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#mFOLFOXIRI_.26_Cetuximab_.28L-Leucovorin.29|mFOLFOXIRI & Cetuximab]] x 8
+*First-line [[#mFOLFOXIRI_.26_Cetuximab_.28L-Leucovorin.29|mFOLFOXIRI & Cetuximab]] x 8
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
@@ Line 879: / Line 949: @@
 </div></div>
 ===References===
-#'''MACBETH:''' Cremolini C, Antoniotti C, Lonardi S, Aprile G, Bergamo F, Masi G, Grande R, Tonini G, Mescoli C, Cardellino GG, Coltelli L, Salvatore L, Corsi DC, Lupi C, Gemma D, Ronzoni M, Dell'Aquila E, Marmorino F, Di Fabio F, Mancini ML, Marcucci L, Fontanini G, Zagonel V, Boni L, Falcone A. Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial. JAMA Oncol. 2018 Apr 1;4(4):529-536. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2672387 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885260/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29450468/ PubMed] [https://clinicaltrials.gov/study/NCT02295930 Clinical Trial Registry]
+#'''MACBETH:''' Cremolini C, Antoniotti C, Lonardi S, Aprile G, Bergamo F, Masi G, Grande R, Tonini G, Mescoli C, Cardellino GG, Coltelli L, Salvatore L, Corsi DC, Lupi C, Gemma D, Ronzoni M, Dell'Aquila E, Marmorino F, Di Fabio F, Mancini ML, Marcucci L, Fontanini G, Zagonel V, Boni L, Falcone A. Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial. JAMA Oncol. 2018 Apr 1;4(4):529-536. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2672387 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885260/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29450468/ PubMed] [https://clinicaltrials.gov/study/NCT02295930 NCT02295930]
-#'''MACRO-2:''' Aranda E, García-Alfonso P, Benavides M, Sánchez Ruiz A, Guillén-Ponce C, Safont MJ, Alcaide J, Gómez A, López R, Manzano JL, Méndez Ureña M, Sastre J, Rivera F, Grávalos C, García T, Martín-Valadés JI, Falcó E, Navalón M, González Flores E, Ma García Tapiador A, Ma López Muñoz A, Barrajón E, Reboredo M, García Teijido P, Viudez A, Cárdenas N, Díaz-Rubio E; Spanish Cooperative Group for the Treatment of Digestive Tumours. First-line mFOLFOX plus cetuximab followed by mFOLFOX plus cetuximab or single-agent cetuximab as maintenance therapy in patients with metastatic colorectal cancer: phase II randomised MACRO2 TTD study. Eur J Cancer. 2018 Sep;101:263-272. Epub 2018 Jul 24. [https://doi.org/10.1016/j.ejca.2018.06.024 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30054049/ PubMed] [https://clinicaltrials.gov/study/NCT01161316 Clinical Trial Registry]
+#'''MACRO-2:''' Aranda E, García-Alfonso P, Benavides M, Sánchez Ruiz A, Guillén-Ponce C, Safont MJ, Alcaide J, Gómez A, López R, Manzano JL, Méndez Ureña M, Sastre J, Rivera F, Grávalos C, García T, Martín-Valadés JI, Falcó E, Navalón M, González Flores E, Ma García Tapiador A, Ma López Muñoz A, Barrajón E, Reboredo M, García Teijido P, Viudez A, Cárdenas N, Díaz-Rubio E; Spanish Cooperative Group for the Treatment of Digestive Tumours. First-line mFOLFOX plus cetuximab followed by mFOLFOX plus cetuximab or single-agent cetuximab as maintenance therapy in patients with metastatic colorectal cancer: phase II randomised MACRO2 TTD study. Eur J Cancer. 2018 Sep;101:263-272. Epub 2018 Jul 24. [https://doi.org/10.1016/j.ejca.2018.06.024 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30054049/ PubMed] [https://clinicaltrials.gov/study/NCT01161316 NCT01161316]
 =Advanced or metastatic disease, second-line=
 ==FOLFIRI {{#subobject:8c0ig3|Regimen=1}}==
-FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
+FOLFIRI: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:lxw6e5|Variant=1}}===
@@ Line 910: / Line 980: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
 *[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first, with leucovorin'''
@@ Line 916: / Line 986: @@
 </div></div>
 ===References===
-#'''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. [https://doi.org/10.1200/jco.2009.27.6055 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20921462/ PubMed] [https://clinicaltrials.gov/study/NCT00339183 Clinical Trial Registry]
+#'''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. [https://doi.org/10.1200/jco.2009.27.6055 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20921462/ PubMed] [https://clinicaltrials.gov/study/NCT00339183 NCT00339183]
 ##'''Update:''' Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tian Y, Sidhu R. Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jan;25(1):107-16. Erratum in: Ann Oncol. 2014 Mar;25(3):757. [https://doi.org/10.1093/annonc/mdt523 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24356622/ PubMed]
 ==FOLFIRI & Panitumumab {{#subobject:8c0093|Regimen=1}}==
-FOLFIRI & Panitumumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Panitumumab
+FOLFIRI & Panitumumab: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Panitumumab
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:ebf6e5|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#1B4F26"
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-20-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
-|-
-|}
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 934: / Line 1,000: @@
 |-
 |[https://doi.org/10.1200/jco.2009.27.6055 Peeters et al. 2010 (20050181)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-20-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
+|-
+|} -->
 |2006-2008
 | style="background-color:#1a9851" |Phase 3 (E-esc)
 |[[#FOLFIRI_3|FOLFIRI]]
-| style="background-color:#91cf60" |Seems to have superior PFS<sup>1</sup><br>Median PFS: 6.7 vs 4.9 mo<br>(HR 0.82, 95% CI 0.69-0.97)
+| style="background-color:#91cf60" |Seems to have superior PFS<sup>1</sup> (co-primary endpoint)<br>Median PFS: 6.7 vs 4.9 mo<br>(HR 0.82, 95% CI 0.69-0.97)
 |-
 |}
@@ Line 949: / Line 1,019: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, with irinotecan'''
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, with irinotecan'''
 *[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
 *[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given second, with leucovorin'''
@@ Line 957: / Line 1,027: @@
 </div></div>
 ===References===
-#'''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. [https://doi.org/10.1200/jco.2009.27.6055 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20921462/ PubMed] [https://clinicaltrials.gov/study/NCT00339183 Clinical Trial Registry]
+#'''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. [https://doi.org/10.1200/jco.2009.27.6055 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20921462/ PubMed] [https://clinicaltrials.gov/study/NCT00339183 NCT00339183]
 ##'''Update:''' Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tian Y, Sidhu R. Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jan;25(1):107-16. Erratum in: Ann Oncol. 2014 Mar;25(3):757. [https://doi.org/10.1093/annonc/mdt523 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24356622/ PubMed]
@@ Line 1,007: / Line 1,077: @@
 |-
 |}
-''Note: In some trials, this starting dose was intended for patients who were at least 70 years old, had [[Performance status|ECOG performance status]] 2 or more, or had prior pelvic radiation. Patients in N9841 had not previously received irinotecan or oxaliplatin.''
+''Note: In some trials, this starting dose was intended for patients who were at least 70 years old, had [[Performance status|ECOG performance status]] 2 or more, or had prior pelvic radiation.''
 <div class="toccolours" style="background-color:#fdcdac">
 ====Prior treatment criteria====
@@ Line 1,018: / Line 1,088: @@
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #3, 350 mg/m<sup>2</sup> q3wk {{#subobject:627110|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
@@ Line 1,049: / Line 1,120: @@
 </div></div>
 ===References===
-#'''PICCOLO:''' Seymour MT, Brown SR, Middleton G, Maughan T, Richman S, Gwyther S, Lowe C, Seligmann JF, Wadsley J, Maisey N, Chau I, Hill M, Dawson L, Falk S, O'Callaghan A, Benstead K, Chambers P, Oliver A, Marshall H, Napp V, Quirke P. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013 Jul;14(8):749-59. Epub 2013 May 29. [https://dx.doi.org/10.1016%2FS1470-2045(13)70163-3 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699713/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23725851/ PubMed] [https://clinicaltrials.gov/study/NCT00389870 Clinical Trial Registry]
+#'''PICCOLO:''' Seymour MT, Brown SR, Middleton G, Maughan T, Richman S, Gwyther S, Lowe C, Seligmann JF, Wadsley J, Maisey N, Chau I, Hill M, Dawson L, Falk S, O'Callaghan A, Benstead K, Chambers P, Oliver A, Marshall H, Napp V, Quirke P. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013 Jul;14(8):749-59. Epub 2013 May 29. [https://dx.doi.org/10.1016%2FS1470-2045(13)70163-3 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699713/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23725851/ PubMed] [https://clinicaltrials.gov/study/NCT00389870 NCT00389870]
-#'''CRC009:''' Shi Y, Li J, Xu J, Sun Y, Wang L, Cheng Y, Liu W, Sun G, Chen Y, Bai L, Zhang Y, He X, Luo Y, Wang Z, Liu Y, Yao Q, Li Y, Qin S, Hu X, Bi F, Zheng R, Ouyang X. CMAB009 plus irinotecan versus irinotecan-only as second-line treatment after fluoropyrimidine and oxaliplatin failure in KRAS wild-type metastatic colorectal cancer patients: promising findings from a prospective, open-label, randomized, phase III trial. Cancer Commun (Lond). 2019 May 24;39(1):28. [https://dx.doi.org/10.1186/s40880-019-0374-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534840/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31126331/ PubMed] [https://clinicaltrials.gov/study/NCT01550055 Clinical Trial Registry]
+#'''CRC009:''' Shi Y, Li J, Xu J, Sun Y, Wang L, Cheng Y, Liu W, Sun G, Chen Y, Bai L, Zhang Y, He X, Luo Y, Wang Z, Liu Y, Yao Q, Li Y, Qin S, Hu X, Bi F, Zheng R, Ouyang X. CMAB009 plus irinotecan versus irinotecan-only as second-line treatment after fluoropyrimidine and oxaliplatin failure in KRAS wild-type metastatic colorectal cancer patients: promising findings from a prospective, open-label, randomized, phase III trial. Cancer Commun (Lond). 2019 May 24;39(1):28. [https://dx.doi.org/10.1186/s40880-019-0374-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534840/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31126331/ PubMed] [https://clinicaltrials.gov/study/NCT01550055 NCT01550055]
 ==Irinotecan & Cetuximab {{#subobject:c912ee|Regimen=1}}==
@@ Line 1,075: / Line 1,146: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 350 mg/m<sup>2</sup> IV over 90 minutes once on day 1
+*[[Irinotecan (Camptosar)]] by the following criteria:
+**Standard patients: 350 mg/m<sup>2</sup> IV over 90 minutes once on day 1
 **If aged 70 years old or more, [[Performance status|ECOG performance status]] 2 or more, or prior pelvic radiation: 300 mg/m<sup>2</sup> IV over 90 minutes once on day 1
 ====Targeted therapy====
@@ Line 1,087: / Line 1,159: @@
 ===References===
 <!-- Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, June 2005; the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2006; safety and efficacy results from this study were presented at the Annual Meeting of the American Association for Cancer Research, April 14-18, 2007, Los Angeles, CA; and the quality of life results from this study were presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 2007. -->
-#'''EPIC:''' Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kröning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008 May 10;26(14):2311-9. Epub 2008 Apr 7. [https://doi.org/10.1200/jco.2007.13.1193 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18390971/ PubMed] [https://clinicaltrials.gov/study/NCT00063141 Clinical Trial Registry]
+#'''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. [https://doi.org/10.1200/jco.2007.13.1193 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18390971/ PubMed] [https://clinicaltrials.gov/study/NCT00063141 NCT00063141]
 =Advanced or metastatic disease, subsequent lines of therapy=
 ==Cetuximab monotherapy {{#subobject:a41ec2|Regimen=1}}==
@@ Line 1,096: / Line 1,168: @@
 {| class="wikitable" style="color:white; background-color:#404040"
 |<small>'''FDA-recommended dose'''</small>
-|-
-|}
-{| class="wikitable" style="color:white; background-color:#1B4F26"
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-18-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
 |-
 |}
@@ Line 1,116: / Line 1,184: @@
 |-
 |[https://doi.org/10.1056/NEJMoa033025 Cunningham et al. 2004 (BOND)]
-|2001-2002
+|2001-07 to 2002-05
 | style="background-color:#1a9851" |Phase 3 (C)
 |[[#Irinotecan_.26_Cetuximab_2|Irinotecan & Cetuximab]]
@@ Line 1,128: / Line 1,196: @@
 |-
 |[https://doi.org/10.1056/NEJMoa071834 Jonker et al. 2007 (NCIC-CTG CO.17)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-18-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+|-
+|} -->
 |2003-2005
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 |[[Colon_cancer_-_null_regimens#Best_supportive_care_2|Best supportive care]]
-| style="background-color:#1a9850" |Superior OS<br>Median OS: 6.1 vs 4.6 mo<br>(HR 0.77, 95% CI 0.64-0.92)
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 6.1 vs 4.6 mo<br>(HR 0.77, 95% CI 0.64-0.92)
 |-
 |[https://doi.org/10.1200/JCO.2012.46.0543 Siu et al. 2013 (NCIC-CTG/AGITG CO.20)]
 |2008-2011
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Brivanib_.26_Cetuximab_777|Brivanib & Cetuximab]]
+|[[#Brivanib_.26_Cetuximab_999|Brivanib & Cetuximab]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
@@ Line 1,157: / Line 1,229: @@
 ====Targeted therapy====
 *[[Cetuximab (Erbitux)]] as follows:
-**Cycle 1: 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, then 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 8, 15, 22
+**Cycle 1: 400 mg/m<sup>2</sup> IV over 2 hours once on day 1
-**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22
+**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 ====Supportive therapy====
 *Varies depending on reference
 *[[:Category:Antihistamines|Antihistamine]] (such as [[Diphenhydramine (Benadryl)]] 50 mg IV) prior to at least the first infusion of cetuximab
-'''28-day cycles'''
+'''7-day cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
@@ Line 1,188: / Line 1,260: @@
 #'''SALVAGE:''' Lenz HJ, Van Cutsem E, Khambata-Ford S, Mayer RJ, Gold P, Stella P, Mirtsching B, Cohn AL, Pippas AW, Azarnia N, Tsuchihashi Z, Mauro DJ, Rowinsky EK. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol. 2006 Oct 20;24(30):4914-21. [https://doi.org/10.1200/jco.2006.06.7595 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17050875/ PubMed]
 <!-- # Bristol-Myers Squibb and ImClone. A Phase III Randomized Study of Cetuximab (Erbitux, C225) and Best Supportive Care Versus Best Supportive Care in Patients with Pretreated Metastatic Epidermal Growth Factor Receptor (EGFR)-Positive Colorectal Carcinoma. Final Clinical Study Report for CA225025. 2007 Mar 5. [http://ctr.bms.com/pdf//CA225025.pdf link to original report] '''contains dosing details in manuscript''' -->
-#'''NCIC-CTG CO.17:''' Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007 Nov 15;357(20):2040-8. [https://doi.org/10.1056/NEJMoa071834 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18003960/ PubMed] [https://clinicaltrials.gov/study/NCT00079066 Clinical Trial Registry]
+#'''NCIC-CTG CO.17:''' Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007 Nov 15;357(20):2040-8. [https://doi.org/10.1056/NEJMoa071834 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18003960/ PubMed] [https://clinicaltrials.gov/study/NCT00079066 NCT00079066]
 ##'''Subgroup analysis:''' Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008 Oct 23;359(17):1757-65. [https://doi.org/10.1056/NEJMoa0804385 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18946061/ PubMed]
 ##'''Subgroup analysis:''' Asmis TR, Powell E, Karapetis CS, Jonker DJ, Tu D, Jeffery M, Pavlakis N, Gibbs P, Zhu L, Dueck DA, Whittom R, Langer C, O'Callaghan CJ. Comorbidity, age and overall survival in cetuximab-treated patients with advanced colorectal cancer (ACRC)--results from NCIC-CTG CO.17: a phase III trial of cetuximab versus best supportive care. Ann Oncol. 2011 Jan;22(1):118-26. Epub 2010 Jul 5. [https://doi.org/10.1093/annonc/mdq309 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20603436/ PubMed]
 #'''Phase I:''' Tabernero J, Ciardiello F, Rivera F, Rodriguez-Braun E, Ramos FJ, Martinelli E, Vega-Villegas ME, Roselló S, Liebscher S, Kisker O, Macarulla T, Baselga J, Cervantes A. Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/pharmacodynamic phase I dose-escalation study. Ann Oncol. 2010 Jul;21(7):1537-45. Epub 2009 Nov 25. [https://doi.org/10.1093/annonc/mdp549 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19940007/ PubMed]
-#'''NCIC-CTG/AGITG CO.20:''' Siu LL, Shapiro JD, Jonker DJ, Karapetis CS, Zalcberg JR, Simes J, Couture F, Moore MJ, Price TJ, Siddiqui J, Nott LM, Charpentier D, Liauw W, Sawyer MB, Jefford M, Magoski NM, Haydon A, Walters I, Ringash J, Tu D, O'Callaghan CJ. Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: the NCIC Clinical Trials Group and AGITG CO.20 Trial. J Clin Oncol. 2013 Jul 1;31(19):2477-84. Epub 2013 May 20. [https://doi.org/10.1200/JCO.2012.46.0543 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23690424/ PubMed] [https://clinicaltrials.gov/study/NCT00640471 Clinical Trial Registry]
+#'''NCIC-CTG/AGITG CO.20:''' Siu LL, Shapiro JD, Jonker DJ, Karapetis CS, Zalcberg JR, Simes J, Couture F, Moore MJ, Price TJ, Siddiqui J, Nott LM, Charpentier D, Liauw W, Sawyer MB, Jefford M, Magoski NM, Haydon A, Walters I, Ringash J, Tu D, O'Callaghan CJ. Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: the NCIC Clinical Trials Group and AGITG CO.20 Trial. J Clin Oncol. 2013 Jul 1;31(19):2477-84. Epub 2013 May 20. [https://doi.org/10.1200/JCO.2012.46.0543 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23690424/ PubMed] [https://clinicaltrials.gov/study/NCT00640471 NCT00640471]
-#'''ASPECCT:''' Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Zhang K, Murugappan S, Sidhu R. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014 May;15(6):569-79. Epub 2014 Apr 14. [https://doi.org/10.1016/S1470-2045(14)70118-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24739896/ PubMed] [https://clinicaltrials.gov/study/NCT01001377 Clinical Trial Registry]
+#'''ASPECCT:''' Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Zhang K, Murugappan S, Sidhu R. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014 May;15(6):569-79. Epub 2014 Apr 14. [https://doi.org/10.1016/S1470-2045(14)70118-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24739896/ PubMed] [https://clinicaltrials.gov/study/NCT01001377 NCT01001377]
 ##'''Update:''' Price T, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Guan X, Peeters M. Final results and outcomes by prior bevacizumab exposure, skin toxicity, and hypomagnesaemia from ASPECCT: randomized phase 3 non-inferiority study of panitumumab versus cetuximab in chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer. Eur J Cancer. 2016 Nov;68:51-59. Epub 2016 Oct 5. [https://doi.org/10.1016/j.ejca.2016.08.010 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27716478/ PubMed]
@@ Line 1,229: / Line 1,301: @@
 |-
 |[https://doi.org/10.1056/NEJMoa033025 Cunningham et al. 2004 (BOND)]
-|2001-2002
+|2001-07 to 2002-05
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 |[[#Cetuximab_monotherapy_2|Cetuximab]]
-| style="background-color:#1a9850" |Superior TTP
+| style="background-color:#1a9850" |Superior TTP (secondary endpoint)<br><br>Superior ORR (primary endpoint)
 |-
 |}
@@ Line 1,302: / Line 1,374: @@
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*EVEREST, grade 0 or 1 skin reaction: Continue standard dose versus escalate dose of cetuximab to 500 mg/m<sup>2</sup>
+*EVEREST, grade 0 or 1 skin reaction: Standard-dose [[#Irinotecan_.26_Cetuximab_2|Irinotecan & Cetuximab]] continuation vs escalate to [[#Irinotecan_.26_Cetuximab_2|Irinotecan & Cetuximab]]; cetuximab 500 mg/m<sup>2</sup>
-*EVEREST, grade 2 or worse skin reaction: Continue standard dose
+*EVEREST, grade 2 or worse skin reaction: Continue standard-dose [[#Irinotecan_.26_Cetuximab_2|Irinotecan & Cetuximab]]
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #5, 180/500, bi-weekly {{#subobject:3062ba|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
@@ Line 1,346: / Line 1,419: @@
 |-
 |[https://doi.org/10.1056/NEJMoa033025 Cunningham et al. 2004 (BOND)]
-|2001-2002
+|2001-07 to 2002-05
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 |[[#Cetuximab_monotherapy_2|Cetuximab]]
-| style="background-color:#1a9850" |Superior TTP
+| style="background-color:#1a9850" |Superior TTP (secondary endpoint)<br><br>Superior ORR (primary endpoint)
 |-
 |}
@@ Line 1,359: / Line 1,432: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Irinotecan (Camptosar)]] 350 mg/m<sup>2</sup> IV over 90 minutes once on day 1
+*[[Irinotecan (Camptosar)]] by the following criteria:
+**Standard patients: 350 mg/m<sup>2</sup> IV over 90 minutes once on day 1
 **If aged 70 years old or more, [[Performance status|ECOG performance status]] 2 or more, or prior pelvic radiation: 300 mg/m<sup>2</sup> IV over 90 minutes once on day 1
 ====Targeted therapy====
@@ Line 1,379: / Line 1,453: @@
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:fa978e|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#1B4F26"
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-23-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
-|-
-|}
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 1,391: / Line 1,461: @@
 |-
 |[https://doi.org/10.1200/jco.2006.08.1620 Van Cutsem et al. 2007 (20020408)]
-|2004-2005
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-23-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
+|-
+|} -->
+|2004-01 to 2005-06
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 |[[Colon_cancer_-_null_regimens#Best_supportive_care_2|Best supportive care]]
-| style="background-color:#1a9850" |Superior PFS<br>Median PFS: 8 vs 7.3 wks<br>(HR 0.54, 95% CI 0.44-0.66)
+| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 8 vs 7.3 wks<br>(HR 0.54, 95% CI 0.44-0.66)
 |-
 |[https://doi.org/10.1016/S1470-2045(14)70118-4 Price et al. 2014 (ASPECCT)]
@@ Line 1,400: / Line 1,474: @@
 | style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
 |[[#Cetuximab_monotherapy_2|Cetuximab]]
-| style="background-color:#eeee01" |Non-inferior OS<br>Median OS: 10.4 vs 10 mo<br>(HR 0.97, 95% CI 0.84-1.11)
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)<br>Median OS: 10.4 vs 10 mo<br>(HR 0.97, 95% CI 0.84-1.11)
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104888/ Kim et al. 2016 (20100007)]
@@ Line 1,406: / Line 1,480: @@
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 |[[Colon_cancer_-_null_regimens#Best_supportive_care_2|Best supportive care]]
-| style="background-color:#1a9850" |Superior OS<sup>1</sup><br>Median OS: 10 vs 6.9 mo<br>(HR 0.72, 95% CI 0.55-0.94)
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<sup>1</sup><br>Median OS: 10 vs 6.9 mo<br>(HR 0.72, 95% CI 0.55-0.94)
 |-
 |}
@@ Line 1,422: / Line 1,496: @@
 ===References===
 <!-- Presented at the 97th Annual Meeting of the American Association for Cancer Research, April 1-5, 2006, Washington, DC; 2nd Annual Conference of the Hematology/Oncology Pharmacy Association, June 15-18, 2006, Orlando, FL; 8th Annual Conference of the World Congress on Gastrointestinal Cancer, June 28-July 1, 2006, Barcelona, Spain; and at the 31st European Society of Medical Oncology Congress, September 29-October 3, 2006, Istanbul, Turkey. -->
-#'''20020408:''' Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1;25(13):1658-64. [https://doi.org/10.1200/jco.2006.08.1620 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17470858/ PubMed] [https://clinicaltrials.gov/study/NCT00113763 Clinical Trial Registry]
+#'''20020408:''' Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1;25(13):1658-64. [https://doi.org/10.1200/jco.2006.08.1620 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17470858/ PubMed] [https://clinicaltrials.gov/study/NCT00113763 NCT00113763]
-#'''ASPECCT:''' Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Zhang K, Murugappan S, Sidhu R. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014 May;15(6):569-79. Epub 2014 Apr 14. [https://doi.org/10.1016/S1470-2045(14)70118-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24739896/ PubMed] [https://clinicaltrials.gov/study/NCT01001377 Clinical Trial Registry]
+#'''ASPECCT:''' Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Zhang K, Murugappan S, Sidhu R. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014 May;15(6):569-79. Epub 2014 Apr 14. [https://doi.org/10.1016/S1470-2045(14)70118-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24739896/ PubMed] [https://clinicaltrials.gov/study/NCT01001377 NCT01001377]
 ##'''Update:''' Price T, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Guan X, Peeters M. Final results and outcomes by prior bevacizumab exposure, skin toxicity, and hypomagnesaemia from ASPECCT: randomized phase 3 non-inferiority study of panitumumab versus cetuximab in chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer. Eur J Cancer. 2016 Nov;68:51-59. Epub 2016 Oct 5. [https://doi.org/10.1016/j.ejca.2016.08.010 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27716478/ PubMed]
-#'''20100007:''' Kim TW, Elme A, Kusic Z, Park JO, Udrea AA, Kim SY, Ahn JB, Valencia RV, Krishnan S, Bilic A, Manojlovic N, Dong J, Guan X, Lofton-Day C, Jung AS, Vrdoljak E. A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer. Br J Cancer. 2016 Nov 8;115(10):1206-1214. Epub 2016 Oct 13. [https://doi.org/10.1038/bjc.2016.309 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104888/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27736842/ PubMed] [https://clinicaltrials.gov/study/NCT01412957 Clinical Trial Registry]
+#'''20100007:''' Kim TW, Elme A, Kusic Z, Park JO, Udrea AA, Kim SY, Ahn JB, Valencia RV, Krishnan S, Bilic A, Manojlovic N, Dong J, Guan X, Lofton-Day C, Jung AS, Vrdoljak E. A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer. Br J Cancer. 2016 Nov 8;115(10):1206-1214. Epub 2016 Oct 13. [https://doi.org/10.1038/bjc.2016.309 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104888/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27736842/ PubMed] [https://clinicaltrials.gov/study/NCT01412957 NCT01412957]
 ##'''Update:''' Kim TW, Elme A, Park JO, Udrea AA, Kim SY, Ahn JB, Valencia RV, Krishnan S, Manojlovic N, Guan X, Lofton-Day C, Jung AS, Vrdoljak E. Final Analysis of Outcomes and RAS/BRAF Status in a Randomized Phase 3 Study of Panitumumab and Best Supportive Care in Chemorefractory Wild Type KRAS Metastatic Colorectal Cancer. Clin Colorectal Cancer. 2018 Sep;17(3):206-214. Epub 2018 Mar 21. [https://doi.org/10.1016/j.clcc.2018.03.008 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29703606/ PubMed]
 [[Category:Colorectal cancer regimens]]
 [[Category:Biomarker-specific pages]]
 [[Category:Gastrointestinal cancers]]

Difference between revisions of "Colorectal cancer, RAS wild-type"

Revision as of 17:50, 23 June 2024

Guidelines

ESMO

Japanese Society for Cancer of the Colon and Rectum

NCCN

Perioperative therapy for oligometastatic disease

FOLFIRI

Regimen

Chemotherapy

References

FOLFIRI & Cetuximab

Regimen variant #1, weekly cetuximab

Biomarker eligibility criteria

Chemotherapy

Targeted therapy

Regimen variant #2, bi-weekly cetuximab

Chemotherapy

Targeted therapy

References

mFOLFOX6

Regimen variant #1, 400/2800/85, resectable or suboptimally resectable

Biomarker eligibility criteria

Chemotherapy

Regimen variant #2, 400/2800/85, unresectable

Chemotherapy

References

mFOLFOX6 & Cetuximab

Regimen variant #1, weekly cetuximab

Biomarker eligibility criteria

Chemotherapy

Targeted therapy

Regimen variant #2, bi-weekly cetuximab

Chemotherapy

Targeted therapy

References

Advanced or metastatic disease, first-line

CapeOx & Panitumumab

Regimen

Biomarker eligibility criteria

Chemotherapy

Targeted therapy

References

FOLFIRI

Regimen

Biomarker eligibility criteria

Chemotherapy

References

FOLFIRI & Bevacizumab

Regimen

Chemotherapy

Targeted therapy

References

FOLFIRI & Cetuximab

Regimen variant #1, 200 LCV

Biomarker eligibility criteria

Chemotherapy

Targeted therapy

Regimen variant #2, 400 LCV

Biomarker eligibility criteria

Chemotherapy

Targeted therapy

References

FOLFIRI & Cetuximab (L-Leucovorin)

Regimen

Biomarker eligibility criteria

Chemotherapy

Targeted therapy

References

FOLFIRINOX

Regimen

Biomarker eligibility criteria

Chemotherapy

References

FOLFOX4

Regimen

Chemotherapy

References

FOLFOX4 & Cetuximab

Regimen

Regimen variant #1, 250 mg/m² weekly

Regimen variant #2, 500 mg/m² q2wk