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Section editor transclusions 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.

35 regimens on this page 55 variants on this page

Guidelines

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 Guidelines - Colon Cancer

Perioperative therapy for oligometastatic disease

FOLFIRI

FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	2008-2011 (NR)	Phase 3 (C)	FOLFIRI & 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)
Folinic acid (Leucovorin) 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, Fluorouracil, IRInotecan, Cetuximab

Regimen variant #1, weekly cetuximab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	2008-2011 (NR)	Phase 3 (E-esc)	FOLFIRI	Superior OS 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)
Folinic acid (Leucovorin) 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	2008-2011 (NR)	Phase 3 (E-esc)	FOLFIRI	Superior OS 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)
Folinic acid (Leucovorin) 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, Fluorouracil, OXaliplatin

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Primrose et al. 2014 (New EPOC)	2007-2012 (F)	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

Folinic acid (Leucovorin) 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	2008-2011 (NR)	Phase 3 (C)	mFOLFOX6 & Cetuximab	Inferior OS

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

Chemotherapy

Folinic acid (Leucovorin) 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, Fluorouracil, OXaliplatin, Cetuximab

Regimen variant #1, weekly cetuximab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	2008-2011 (NR)	Phase 3 (E-esc)	mFOLFOX6	Superior OS 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)
Folinic acid (Leucovorin) 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	2008-2011 (NR)	Phase 3 (E-esc)	mFOLFOX6	Superior OS 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)
Folinic acid (Leucovorin) 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 & Bevacizumab

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

Regimen

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

Chemotherapy

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

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, Fluorouracil, IRInotecan, Cetuximab

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Van Cutsem et al. 2009 (CRYSTAL)	2004-2005 (C)	Phase 3 (E-RT-esc)	FOLFIRI	Superior OS¹ Median OS: 23.5 vs 19.5 mo (HR 0.81, 95% CI 0.69-0.94)
Heinemann et al. 2014 (FIRE-3)	2007-2012 (C)	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

Folinic acid (Leucovorin) 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 PubMed NCT00433927

FOLFIRI & Cetuximab (L-Leucovorin)

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

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Van Cutsem et al. 2009 (CRYSTAL)	2004-2005 (C)	Phase 3 (E-RT-esc)	FOLFIRI	Superior OS¹ Median OS: 23.5 vs 19.5 mo (HR 0.81, 95% CI 0.69-0.94)
Heinemann et al. 2014 (FIRE-3)	2007-2012 (C)	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

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
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

FOLFOX4

FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study	Years 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 (C)	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

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

14-day cycles

References

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: 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 PubMed NCT01228734

FOLFOX4 & Cetuximab

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

Regimen

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

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

Folinic acid (Leucovorin) 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: 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 PubMed NCT01228734

FOLFOX4 & Panitumumab

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Douillard et al. 2010 (PRIME)	2006-2008 (C)	Phase 3 (E-RT-esc)	FOLFOX4	Seems to have superior OS¹ 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)
Folinic acid (Leucovorin) 200 mg/m² IV over 2 hours once per day on days 1 & 2
Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1

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, Fluorouracil, OXaliplatin, Bevacizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Venook et al. 2017 (CALGB 80405)	2005-2012	Phase 3 (E-switch-ic)	1. mFOLFOX6 & Panitumumab 2. FOLFIRI & Panitumumab	Did not meet primary endpoint of OS
Venook et al. 2017 (CALGB 80405)	2005-2012	Phase 3 (E-switch-ic)	3. mFOLFOX6, Bevacizumab, Cetuximab 4. FOLFIRI, Bevacizumab, Cetuximab	Not reported
Awaiting publication (PARADIGM_CRC)	2015-2022	Phase 3 (C)	mFOLFOX6 & Panitumumab	Seems to have inferior OS

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
Folinic acid (Leucovorin) 200 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV 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
PARADIGM_CRC: NCT02394795

mFOLFOX6 & Cetuximab

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Venook et al. 2017 (CALGB 80405)	2005-2012	Phase 3 (E-switch-ic)	1. mFOLFOX6 & Panitumumab 2. FOLFIRI & Panitumumab	Did not meet primary endpoint of OS
Venook et al. 2017 (CALGB 80405)	2005-2012	Phase 3 (E-switch-ic)	3. mFOLFOX6, Bevacizumab, Cetuximab 4. FOLFIRI, Bevacizumab, Cetuximab	Not reported
Aranda et al. 2018 (MACRO-2)	2010-NR	Non-randomized portion 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)
Folinic acid (Leucovorin) 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, Fluorouracil, OXaliplatin, Panitumumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rossini et al. 2022 (TRIPLETE)	2017-2021	Phase 3 (C)	mFOLFOXIRI & Panitumumab	Did not meet primary endpoint of ORR

Biomarker eligibility criteria

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)
Folinic acid (Leucovorin) 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

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

mFOLFOXIRI & Cetuximab (L-Leucovorin)

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

Regimen

Study	Evidence
Cremolini et al. 2018 (MACBETH)	Non-randomized portion 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, Fluorouracil, OXaliplatin, IRInotecan, Panitumumab

Regimen

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

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)
Folinic acid (Leucovorin) 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	Years 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Aranda et al. 2018 (MACRO-2)	2010-NR	Randomized Phase 2 (E-de-esc)	mFOLFOX6 & Cetuximab	Non-inferior PFS

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

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

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 & Panitumumab

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Peeters et al. 2010 (20050181)	2006-2008	Phase 3 (E-esc)	FOLFIRI	Seems to have superior PFS¹ 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

Folinic acid (Leucovorin) 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	Years 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Seymour et al. 2013 (PICCOLO)	2006-2008	Phase 3 (C)	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)

Note: In some trials, this starting dose was intended for patients who were at least 70 years old, had ECOG performance status 2 or more, or had prior pelvic radiation. Patients in N9841 had not previously received irinotecan or oxaliplatin.

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Seymour et al. 2013 (PICCOLO)	2006-2008	Phase 3 (C)	1. Irinotecan & Cyclosporine 2. 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)

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	Years 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) 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 (Erbitux)

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Saltz et al. 2004	2001	Phase 2 (RT)
Cunningham et al. 2004 (BOND)	2001-2002	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 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, then 250 mg/m² IV over 60 minutes once per day on days 8, 15, 22
- Cycle 2 onwards: 250 mg/m² IV over 60 minutes once per day on days 1, 8, 15, 22

Supportive therapy

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

28-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 (Erbitux)

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 (Erbitux)

21-day cycles

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

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cunningham et al. 2004 (BOND)	2001-2002	Phase 3 (E-RT-esc)	Cetuximab	Superior TTP

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 (Erbitux)

42-day cycles

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

Study	Years 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 (Erbitux)

14-day cycles

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

Study	Years of enrollment	Evidence
Van Cutsem et al. 2012 (EVEREST)	2004-2005	Non-randomized portion 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: Continue standard dose versus escalate dose of cetuximab to 500 mg/m²
EVEREST, grade 2 or worse skin reaction: Continue standard dose

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

Study	Years 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 (Erbitux)
Dexamethasone (Decadron) & Ondansetron (Zofran) prior to Irinotecan (Camptosar)

14-day cycles

Regimen variant #6, 350/250, q3wk irinotecan

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cunningham et al. 2004 (BOND)	2001-2002	Phase 3 (E-RT-esc)	Cetuximab	Superior TTP

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) 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 (Erbitux)

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Van Cutsem et al. 2007 (20020408)	2004-2005	Phase 3 (E-RT-esc)	Best supportive care	Superior PFS 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
Kim et al. 2016 (20100007)	2011-2013	Phase 3 (E-RT-esc)	Best supportive care	Superior OS¹ 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|gyn}}
+{{#lst:Section editor transclusions|gi}}
-''Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit [[Endometrial cancer - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''
+<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.
+*See the [[Colon cancer, RAS wild-type|'''RAS wild-type colon cancer page''']] for adjuvant colon cancer regimens.</big>
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
@@ Line 13: / Line 15: @@
 =Guidelines=
 ==[http://www.esmo.org/ ESMO]==
-*'''2022:''' Oaknin et al. [https://doi.org/10.1016/j.annonc.2022.05.009 Endometrial cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up]
+*'''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]
-===Older===
+*'''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]
-*'''2016:''' Colombo et al. [https://www.esmo.org/Guidelines/Gynaecological-Cancers/ESMO-ESGO-ESTRO-Consensus-Conference-on-Endometrial-Cancer ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: diagnosis, treatment and follow-up]
+==[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]==
-*[https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf NCCN Guidelines - Uterine Neoplasms]
+*[https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf NCCN Guidelines - Colon Cancer]
-=Adjuvant therapy=
+=Perioperative therapy for oligometastatic disease=
-==Carboplatin & Paclitaxel (CP) {{#subobject:b9c21f|Regimen=1}}==
+==FOLFIRI {{#subobject:a051ec|Regimen=1}}==
+FOLFIRI: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 5/175 x 4 {{#subobject:6bc3c0|Variant=1}}===
+===Regimen {{#subobject:49d215|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 29: / Line 33: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1016/S1470-2045(18)30079-2 de Boer et al. 2018 (PORTEC-3)]
+|[https://doi.org/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]
-|2006-2013
+|2008-2011 (NR)
-|style="background-color:#1a9851"|Phase 3 (E-esc)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[Complex_multipart_regimens#PORTEC-3|See link]]
+|[[#FOLFIRI_.26_Cetuximab|FOLFIRI & Cetuximab]]
-| style="background-color:#91cf60" |[[Complex_multipart_regimens#PORTEC-3|See link]]
+| style="background-color:#d73027" |Inferior OS
 |-
 |}
-<div class="toccolours" style="background-color:#cbd5e8">
+''Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.''
-====Preceding treatment====
-**[[Surgery#Endometrial_cancer_surgery|Surgery]], then [[#Cisplatin_.26_RT|Cisplatin & RT]]
-</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Carboplatin (Paraplatin)]] AUC 5 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>)
-*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
+*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycle for 4 cycles'''
+*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1
-</div></div><br>
+'''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] NCT01564810
+==FOLFIRI & Cetuximab {{#subobject:a051ec|Regimen=1}}==
+FOLFIRI & Cetuximab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Cetuximab
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 6/175 x 6 {{#subobject:6bc5c0|Variant=1}}===
+===Regimen variant #1, weekly cetuximab {{#subobject:8f47f9|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 55: / Line 61: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1056/NEJMoa1813181 Matei et al. 2019 (GOG 258)]
+|[https://doi.org/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]
-|2009-2014
+|2008-2011 (NR)
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[#Cisplatin_.26_RT|Cisplatin & RT]], then [[#Carboplatin_.26_Paclitaxel_.28CP.29|CP]] x 4
+|[[#FOLFIRI|FOLFIRI]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
+| style="background-color:#1a9850" |Superior OS<br>Median OS: 30.9 vs 21 mo<br>(HR 0.54, 95% CI 0.33-0.88)
 |-
 |}
-<div class="toccolours" style="background-color:#cbd5e8">
+''Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.''
-====Preceding treatment====
+<div class="toccolours" style="background-color:#fdcdac">
-*[[Surgery#Hysterectomy|Hysterectomy]] and [[Surgery#Bilateral_salpingo-oophorectomy|bilateral salpingo-oophorectomy]], within 8 weeks
+====Biomarker eligibility criteria====
+*Wild-type KRAS, Wild-type NRAS
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Carboplatin (Paraplatin)]] AUC 6 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>)
-*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
+*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycle for 6 cycles'''
+*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1
-</div></div>
+====Targeted therapy====
-===References===
+*[[Cetuximab (Erbitux)]] as follows, '''given first''':
-# '''PORTEC-3:''' de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, Ottevanger PB, Ledermann JA, Khaw P, Colombo A, Fyles A, Baron MH, Jürgenliemk-Schulz IM, Kitchener HC, Nijman HW, Wilson G, Brooks S, Carinelli S, Provencher D, Hanzen C, Lutgens LCHW, Smit VTHBM, Singh N, Do V, D'Amico R, Nout RA, Feeney A, Verhoeven-Adema KW, Putter H, Creutzberg CL; PORTEC study group. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Mar;19(3):295-309. Epub 2018 Feb 12. [https://doi.org/10.1016/S1470-2045(18)30079-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840256/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29449189 PubMed] NCT00411138
+**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
-## '''Update:''' de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, Ottevanger PB, Ledermann JA, Khaw P, D'Amico R, Fyles A, Baron MH, Jürgenliemk-Schulz IM, Kitchener HC, Nijman HW, Wilson G, Brooks S, Gribaudo S, Provencher D, Hanzen C, Kruitwagen RF, Smit VTHBM, Singh N, Do V, Lissoni A, Nout RA, Feeney A, Verhoeven-Adema KW, Putter H, Creutzberg CL; PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019 Sep;20(9):1273-1285. Epub 2019 Jul 22. Erratum in: Lancet Oncol. 2019 Sep;20(9):e468. [https://doi.org/10.1016/S1470-2045(19)30395-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31345626 PubMed]
+**Cycles 2 up to 12: 250 mg/m<sup>2</sup> IV once per day on days 1 & 8
-# '''GOG 258:''' Matei D, Filiaci V, Randall ME, Mutch D, Steinhoff MM, DiSilvestro PA, Moxley KM, Kim YM, Powell MA, O'Malley DM, Spirtos NM, Small W Jr, Tewari KS, Richards WE, Nakayama J, Matulonis UA, Huang HQ, Miller DS. Adjuvant chemotherapy plus radiation for locally advanced endometrial cancer. N Engl J Med. 2019 Jun 13;380(24):2317-2326. [https://doi.org/10.1056/NEJMoa1813181 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31189035 PubMed] NCT00942357
+'''14-day cycles until lesions deemed resectable or up to 12 cycles'''
-# '''JGOG2043:''' Nomura H, Aoki D, Michimae H, Mizuno M, Nakai H, Arai M, Sasagawa M, Ushijima K, Sugiyama T, Saito M, Tokunaga H, Matoda M, Nakanishi T, Watanabe Y, Takahashi F, Saito T, Yaegashi N; Japanese Gynecologic Oncology Group. Effect of Taxane Plus Platinum Regimens vs Doxorubicin Plus Cisplatin as Adjuvant Chemotherapy for Endometrial Cancer at a High Risk of Progression: A Randomized Clinical Trial. JAMA Oncol. 2019 Jun 1;5(6):833-840. Epub 2019 Mar 21.  [https://jamanetwork.com/journals/jamaoncology/fullarticle/2728809 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567838/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30896757 PubMed] UMIN000000522
+</div></div><br>
-# '''KEYNOTE-B21:''' NCT04634877
-==CIM {{#subobject:ac4dbb|Regimen=1}}==
-CIM: '''<u>C</u>'''isplatin, '''<u>I</u>'''fosfamide, '''<u>M</u>'''esna
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:f97ea4|Variant=1}}===
+===Regimen variant #2, bi-weekly cetuximab {{#subobject:49d215|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 89: / Line 93: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752331 Wolfson et al. 2007 (GOG 150)]
+|[https://doi.org/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]
-|1993-2005
+|2008-2011 (NR)
-|style="background-color:#1a9851"|Phase 3 (E-switch-ooc)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[#Whole_abdominal_radiation_.28WAI.29|Whole abdominal irradiation]]
+|[[#FOLFIRI|FOLFIRI]]
-|style="background-color:#d9ef8b"|Might have superior OS<sup>1</sup><br>Median OS: 48 vs 24 mo<br>(HR 0.71, 95% CI 0.48-1.05)
+| style="background-color:#1a9850" |Superior OS<br>Median OS: 30.9 vs 21 mo<br>(HR 0.54, 95% CI 0.33-0.88)
 |-
 |}
-''<sup>1</sup>Median OS is not reported in the paper and is estimated from the K-M curve.''
+''Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.''
-<div class="toccolours" style="background-color:#cbd5e8">
-====Preceding treatment====
-*[[Surgery#Endometrial_cancer_surgery|Surgery]]
-</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 4, '''given first, at an infusion rate of approximately 1 mg/min'''
+*[[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>)
-*[[Ifosfamide (Ifex)]] 1500 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 4, '''given second, with mesna'''
+*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
-====Supportive therapy====
+*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1
-*[[Mesna (Mesnex)]] 120 mg/m<sup>2</sup> IV over 15 minutes once on day 1, then 1500 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, '''given second, with [[Ifosfamide (Ifex)]]'''
+====Targeted therapy====
-*Suggested hydration: 1 liter of NS or 1/2 NS over several hours once per day on days 1 to 4, prior to chemotherapy
+*[[Cetuximab (Erbitux)]] 500 mg/m<sup>2</sup> IV once on day 1, '''given first'''
-'''21-day cycle for 3 cycles'''
+'''14-day cycles until lesions deemed resectable or up to 12 cycles'''
 </div></div>
 ===References===
-# '''GOG 150:''' Wolfson AH, Brady MF, Rocereto T, Mannel RS, Lee YC, Futoran RJ, Cohn DE, Ioffe OB. A Gynecologic Oncology Group randomized phase III trial of whole abdominal irradiation (WAI) vs cisplatin-ifosfamide and mesna (CIM) as post-surgical therapy in stage I-IV carcinosarcoma (CS) of the uterus. Gynecol Oncol. 2007 Nov;107(2):177-85. Epub 2007 Sep 5. [https://www.gynecologiconcology-online.net/article/S0090-8258(07)00567-7 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752331/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17822748 PubMed] NCT00002546
+#'''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] NCT01564810
-==Cisplatin & Doxorubicin {{#subobject:4d10f0|Regimen=1}}==
+==mFOLFOX6 {{#subobject:8fcd39|Regimen=1}}==
-CD: '''<u>C</u>'''isplatin & '''<u>D</u>'''oxorubicin
+mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
-<br>AP: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>P</u>'''latinol (Cisplatin)
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 50/45, capped BSA {{#subobject:ef532f|Variant=1}}===
+===Regimen variant #1, 400/2800/85, resectable or suboptimally resectable {{#subobject:17252e|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 124: / Line 123: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://www.gynecologiconcology-online.net/article/S0090-8258(08)00938-4 Homesley et al. 2008 (GOG 184)]
+|[https://doi.org/10.1016/S1470-2045(14)70105-6 Primrose et al. 2014 (New EPOC)]
-|2000-2004
+|2007-2012 (F)
-|style="background-color:#1a9851"|Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Cisplatin.2C_Doxorubicin.2C_Paclitaxel_99|CDP]]
+|[[#mFOLFOX6_.26_Cetuximab|mFOLFOX6 & Cetuximab]]
-|style="background-color:#ffffbf"|Did not meet primary endpoint of RFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<sup>1</sup><br>Median PFS: 22.2 vs 15.5 mo<br>(HR 0.85, 95% CI 0.64-1.15)
 |-
 |}
-''Note: Treatment was to start within 8 weeks of completion of RT.''
+''<sup>1</sup>Reported efficacy is based on the 2020 update.''<br>
-<div class="toccolours" style="background-color:#cbd5e8">
+''Note: this trial was only open to KRAS wild-type patients with resectable or suboptimally resectable colorectal liver metastases.''
-====Preceding treatment====
+<div class="toccolours" style="background-color:#fdcdac">
-*[[Surgery#Endometrial_cancer_surgery|Surgery]], then [[#Radiation_therapy|RT]]
+====Biomarker eligibility criteria====
+*KRAS wild-type
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> (maximum dose of 100 mg) IV once on day 1, '''given second'''
+*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
-*[[Doxorubicin (Adriamycin)]] 45 mg/m<sup>2</sup> (maximum dose of 90 mg) IV once on day 1, '''given first'''
+*[[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>)
-====Supportive therapy====
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
-*G-CSF, ONE of the following:
+'''14-day cycle for 6 cycles, then surgery, then 14-day cycle for 6 cycles'''
-**[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day on days 2 to 11, or until ANC increases to 10,000/uL
-**[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2
-*[[Dexamethasone (Decadron)]] 10 mg IV once on day 1, prior to chemotherapy
-*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonist]]
-'''21-day cycle for 6 cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 50/60 x 6 {{#subobject:5fef3b|Variant=1}}===
+===Regimen variant #2, 400/2800/85, unresectable {{#subobject:e190fa|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 157: / Line 152: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567838/ Nomura et al. 2019 (JGOG2043)]
+|[https://doi.org/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]
-|2006-2011
+|2008-2011 (NR)
-|style="background-color:#1a9851"|Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29|Carboplatin & Paclitaxel]]<br> 2. [[#Cisplatin_.26_Docetaxel_.28DC.29_99|Cisplatin & Docetaxel]]
+|[[#mFOLFOX6_.26_Cetuximab|mFOLFOX6 & Cetuximab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
+| style="background-color:#d73027" |Inferior OS
 |-
 |}
-<div class="toccolours" style="background-color:#cbd5e8">
+''Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.''
-====Preceding treatment====
-*[[Surgery#Endometrial_cancer_surgery|Surgery]]
-</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV once on day 1, '''given second'''
+*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
-*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1, '''given first'''
+*[[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>)
-'''21-day cycle for 6 cycles'''
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
-</div></div><br>
+'''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] 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
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #3, 50/60 x 8 {{#subobject:5bab3b|Variant=1}}===
+===Regimen variant #1, weekly cetuximab {{#subobject:dcf5ee|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 183: / Line 182: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2004.00.7617 Randall et al. 2006 (GOG 122)]
+|[https://doi.org/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]
-|1992-2000
+|2008-2011 (NR)
-|style="background-color:#1a9851"|Phase 3 (E-switch-ooc)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[#Whole_abdominal_radiation_.28WAI.29|Whole abdominal irradiation]]
+|[[#mFOLFOX6|mFOLFOX6]]
-|style="background-color:#1a9850"|Superior OS<br>OS60: 55% vs 42%<br>(aHR 0.68, 95% CI 0.52-0.89)
+| style="background-color:#1a9850" |Superior OS<br>Median OS: 30.9 vs 21 mo<br>(HR 0.54, 95% CI 0.33-0.88)
 |-
 |}
-<div class="toccolours" style="background-color:#cbd5e8">
+''Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.''
-====Preceding treatment====
+<div class="toccolours" style="background-color:#fdcdac">
-*[[Surgery#Endometrial_cancer_surgery|Surgery]], with optimal debulking
+====Biomarker eligibility criteria====
+*Wild-type KRAS, Wild-type NRAS
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 50 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>)
-*[[Doxorubicin (Adriamycin)]] as follows:
+*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
-**Cycles 1 to 7: 60 mg/m<sup>2</sup> IV once on day 1
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
-====Supportive therapy====
+====Targeted therapy====
-*Normal saline at 500 mL/H for 2 hours prior to and after [[Cisplatin (Platinol)]]
+*[[Cetuximab (Erbitux)]] as follows, '''given first''':
-'''21-day cycle for 8 cycles'''
+**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
-</div></div>
+**Cycles 2 up to 12: 250 mg/m<sup>2</sup> IV once per day on days 1 & 8
-===References===
+'''14-day cycles until lesions deemed resectable or up to 12 cycles'''
-# '''GOG 122:''' Randall ME, Filiaci VL, Muss H, Spirtos NM, Mannel RS, Fowler J, Thigpen JT, Benda JA; Gynecologic Oncology Group. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2006 Jan 1;24(1):36-44. Epub 2005 Dec 5. [https://doi.org/10.1200/jco.2004.00.7617 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16330675 PubMed]
+</div></div><br>
-# '''GOG 184:''' Homesley HD, Filiaci V, Gibbons SK, Long HJ, Cella D, Spirtos NM, Morris RT, DeGeest K, Lee R, Montag A. A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: A Gynecologic Oncology Group study. Gynecol Oncol. 2009 Mar;112(3):543-52. Epub 2008 Dec 23. [http://www.gynecologiconcology-online.net/article/S0090-8258(08)00938-4 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459781/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19108877 PubMed] NCT00006011
-## '''Update:''' Spirtos NM, Enserro D, Homesley HD, Gibbons SK, Cella D, Morris RT, DeGeest K, Lee RB, Miller DS. The addition of paclitaxel to doxorubicin and cisplatin and volume-directed radiation does not improve overall survival (OS) or long-term recurrence-free survival (RFS) in advanced endometrial cancer (EC): a randomized phase III NRG/Gynecologic Oncology Group (GOG) study. Gynecol Oncol. 2019 Jul;154(1):13-21. Epub 2019 Apr 30. [https://doi.org/10.1016/j.ygyno.2019.03.240 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852648/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31053405 PubMed]
-# '''JGOG2043:''' Nomura H, Aoki D, Michimae H, Mizuno M, Nakai H, Arai M, Sasagawa M, Ushijima K, Sugiyama T, Saito M, Tokunaga H, Matoda M, Nakanishi T, Watanabe Y, Takahashi F, Saito T, Yaegashi N; Japanese Gynecologic Oncology Group. Effect of Taxane Plus Platinum Regimens vs Doxorubicin Plus Cisplatin as Adjuvant Chemotherapy for Endometrial Cancer at a High Risk of Progression: A Randomized Clinical Trial. JAMA Oncol. 2019 Jun 1;5(6):833-840. Epub 2019 Mar 21.  [https://jamanetwork.com/journals/jamaoncology/fullarticle/2728809 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567838/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30896757 PubMed] UMIN000000522
-==Cisplatin & RT {{#subobject:4d8gh0|Regimen=1}}==
-Cisplatin & RT: Cisplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:4bfa1d|Variant=1}}===
+===Regimen variant #2, bi-weekly cetuximab {{#subobject:e190fa|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 219: / Line 214: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1016/S1470-2045(18)30079-2 de Boer et al. 2018 (PORTEC-3)]
+|[https://doi.org/10.1200/JCO.2012.44.8308 Ye et al. 2013 (Fudan 2012-03)]
-|2006-2013
+|2008-2011 (NR)
-|style="background-color:#1a9851"|Phase 3 (E-esc)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[Complex_multipart_regimens#PORTEC-3|See link]]
+|[[#mFOLFOX6|mFOLFOX6]]
-| style="background-color:#91cf60" |[[Complex_multipart_regimens#PORTEC-3|See link]]
+| style="background-color:#1a9850" |Superior OS<br>Median OS: 30.9 vs 21 mo<br>(HR 0.54, 95% CI 0.33-0.88)
 |-
 |}
-''Note: in PORTEC-3, radiation is to start within 4 to 6 weeks after surgery, and no later than 8 weeks; reported efficacy is based on the 2019 update.''
+''Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.''
-<div class="toccolours" style="background-color:#cbd5e8">
-====Preceding treatment====
-*[[Surgery#Endometrial_cancer_surgery|Surgery]]
-</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 50 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>)
-'''21-day cycle for 2 cycles'''
+*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
-====Radiotherapy====
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
-*[[External beam radiotherapy]] to the pelvis, 1.8 Gy x 27 fractions (total dose: 48.6 Gy)
+====Targeted therapy====
-'''5.5-week course'''
+*[[Cetuximab (Erbitux)]] 500 mg/m<sup>2</sup> IV once on day 1, '''given first'''
-</div>
+'''14-day cycles until lesions deemed resectable or up to 12 cycles'''
-<div class="toccolours" style="background-color:#cbd5e7">
-====Subsequent treatment====
-*[[#Carboplatin_.26_Paclitaxel_.28CP.29|Carboplatin & Paclitaxel]] x 4
 </div></div>
 ===References===
-# '''PORTEC-3:''' de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, Ottevanger PB, Ledermann JA, Khaw P, Colombo A, Fyles A, Baron MH, Jürgenliemk-Schulz IM, Kitchener HC, Nijman HW, Wilson G, Brooks S, Carinelli S, Provencher D, Hanzen C, Lutgens LCHW, Smit VTHBM, Singh N, Do V, D'Amico R, Nout RA, Feeney A, Verhoeven-Adema KW, Putter H, Creutzberg CL; PORTEC study group. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Mar;19(3):295-309. Epub 2018 Feb 12. [https://doi.org/10.1016/S1470-2045(18)30079-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840256/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29449189 PubMed] NCT00411138
+#'''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] NCT01564810
-## '''Update:''' de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, Ottevanger PB, Ledermann JA, Khaw P, D'Amico R, Fyles A, Baron MH, Jürgenliemk-Schulz IM, Kitchener HC, Nijman HW, Wilson G, Brooks S, Gribaudo S, Provencher D, Hanzen C, Kruitwagen RF, Smit VTHBM, Singh N, Do V, Lissoni A, Nout RA, Feeney A, Verhoeven-Adema KW, Putter H, Creutzberg CL; PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019 Sep;20(9):1273-1285. Epub 2019 Jul 22. Erratum in: Lancet Oncol. 2019 Sep;20(9):e468. [https://doi.org/10.1016/S1470-2045(19)30395-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31345626 PubMed]
+=Advanced or metastatic disease, first-line=
-==Radiation therapy {{#subobject:24a846|Regimen=1}}==
+==CapeOx & Panitumumab {{#subobject:22cf7b|Regimen=1}}==
-RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+CapeOx & Panitumumab: '''<u>Cape</u>'''citabine, '''<u>Ox</u>'''aliplatin, Panitumumab
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:4bfd6d|Variant=1}}===
+===Regimen {{#subobject:944ac6|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 20%"|Study
+! style="width: 25%" |Study
-!style="width: 20%"|Years of enrollment
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.gynecologiconcology-online.net/article/S0090-8258(03)00863-1 Keys et al. 2004 (GOG 99)]
+|[https://doi.org/10.1007/s12032-018-1160-1 Papaxoinis et al. 2018 (HE 6A/09)]
-|1987-1995
+| style="background-color:#91cf61" |Phase 2
-|style="background-color:#1a9851"|Phase 3 (E-esc)
-|[[Endometrial_cancer_-_null_regimens#Observation|Observation]]
-| style="background-color:#1a9850" |Superior RFS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360651/ Maggi et al. 2006]
-|1990-1997
-|style="background-color:#1a9851"|Phase 3 (C)
-|[[#CAP_99|CAP]]
-| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS
-|-
-|[https://www.gynecologiconcology-online.net/article/S0090-8258(07)00786-X Susumu et al. 2007 (JGOG 2033)]
-|1994-2000
-|style="background-color:#1a9851"|Phase 3 (C)
-|[[#CAP_99|CAP]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS60
-|-
-|[http://www.gynecologiconcology-online.net/article/S0090-8258(08)00938-4 Homesley et al. 2008 (GOG 184)]
-|2000-2004
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://doi.org/10.1016/S1470-2045(18)30079-2 de Boer et al. 2018 (PORTEC-3)]
-|2006-2013
-|style="background-color:#1a9851"|Phase 3 (C)
-|[[#Cisplatin_.26_RT|Cisplatin & RT]], then [[#Carboplatin_.26_Paclitaxel_.28CP.29|Carboplatin & Paclitaxel]]
-| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
 |-
 |}
-''<sup>1</sup>Reported efficacy for PORTEC-3 is based on the 2019 update.''<br>
+<div class="toccolours" style="background-color:#fdcdac">
-''Note: in PORTEC-3, radiation is to start within 4 to 6 weeks after surgery, and no later than 8 weeks.''
+====Biomarker eligibility criteria====
-<div class="toccolours" style="background-color:#cbd5e8">
+*Wild-type KRAS, Wild-type NRAS
-====Preceding treatment====
-*[[Surgery#Endometrial_cancer_surgery|Surgery]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Radiotherapy====
+====Chemotherapy====
-*[[External beam radiotherapy]] to the pelvis, 40 to 50 Gy
+*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
-**If cervical involvement, brachytherapy boost
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
-'''One course'''
+====Targeted therapy====
-</div>
+*[[Panitumumab (Vectibix)]] 9 mg/kg IV once on day 1
-<div class="toccolours" style="background-color:#cbd5e7">
+'''21-day cycles'''
-====Subsequent treatment====
-*GOG 184: [[#Cisplatin_.26_Doxorubicin|CD]] x 6 versus [[#CDP_99|CDP]] x 6
 </div></div>
 ===References===
-# '''GOG 99:''' Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD, Pearlman A, Maiman MA, Bell JG; Gynecologic Oncology Group. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2004 Mar;92(3):744-51. Erratum in: Gynecol Oncol. 2004 Jul;94(1):241-2. [https://www.gynecologiconcology-online.net/article/S0090-8258(03)00863-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14984936 PubMed]
+#'''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] NCT01215539
-# Maggi R, Lissoni A, Spina F, Melpignano M, Zola P, Favalli G, Colombo A, Fossati R. Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial. Br J Cancer. 2006 Aug 7;95(3):266-71. Epub 2006 Jul 25. [https://www.nature.com/articles/6603279 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360651/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/16868539 PubMed]
+==FOLFIRI & Bevacizumab {{#subobject:80d6b8|Regimen=1}}==
-# '''JGOG 2033:''' Susumu N, Sagae S, Udagawa Y, Niwa K, Kuramoto H, Satoh S, Kudo R; Japanese Gynecologic Oncology Group. Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: a Japanese Gynecologic Oncology Group study. Gynecol Oncol. 2008 Jan;108(1):226-33. Epub 2007 Nov 9. [https://www.gynecologiconcology-online.net/article/S0090-8258(07)00786-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/17996926 PubMed]
+FOLFIRI & Bevacizumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Bevacizumab
-# '''GOG 184:''' Homesley HD, Filiaci V, Gibbons SK, Long HJ, Cella D, Spirtos NM, Morris RT, DeGeest K, Lee R, Montag A. A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: A Gynecologic Oncology Group study. Gynecol Oncol. 2009 Mar;112(3):543-52. Epub 2008 Dec 23. [http://www.gynecologiconcology-online.net/article/S0090-8258(08)00938-4 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459781/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19108877 PubMed] NCT00006011
-## '''Update:''' Spirtos NM, Enserro D, Homesley HD, Gibbons SK, Cella D, Morris RT, DeGeest K, Lee RB, Miller DS. The addition of paclitaxel to doxorubicin and cisplatin and volume-directed radiation does not improve overall survival (OS) or long-term recurrence-free survival (RFS) in advanced endometrial cancer (EC): a randomized phase III NRG/Gynecologic Oncology Group (GOG) study. Gynecol Oncol. 2019 Jul;154(1):13-21. Epub 2019 Apr 30. [https://doi.org/10.1016/j.ygyno.2019.03.240 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852648/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31053405 PubMed]
-# '''PORTEC-3:''' de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, Ottevanger PB, Ledermann JA, Khaw P, Colombo A, Fyles A, Baron MH, Jürgenliemk-Schulz IM, Kitchener HC, Nijman HW, Wilson G, Brooks S, Carinelli S, Provencher D, Hanzen C, Lutgens LCHW, Smit VTHBM, Singh N, Do V, D'Amico R, Nout RA, Feeney A, Verhoeven-Adema KW, Putter H, Creutzberg CL; PORTEC study group. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Mar;19(3):295-309. Epub 2018 Feb 12. [https://doi.org/10.1016/S1470-2045(18)30079-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840256/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29449189 PubMed] NCT00411138
-## '''Update:''' de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, Ottevanger PB, Ledermann JA, Khaw P, D'Amico R, Fyles A, Baron MH, Jürgenliemk-Schulz IM, Kitchener HC, Nijman HW, Wilson G, Brooks S, Gribaudo S, Provencher D, Hanzen C, Kruitwagen RF, Smit VTHBM, Singh N, Do V, Lissoni A, Nout RA, Feeney A, Verhoeven-Adema KW, Putter H, Creutzberg CL; PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019 Sep;20(9):1273-1285. Epub 2019 Jul 22. Erratum in: Lancet Oncol. 2019 Sep;20(9):e468. [https://doi.org/10.1016/S1470-2045(19)30395-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/31345626 PubMed]
-==Whole abdominal radiation (WAI) {{#subobject:37c051|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:1ab715|Variant=1}}===
+===Regimen {{#subobject:28b67a|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 322: / Line 271: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2004.00.7617 Randall et al. 2006 (GOG 122)]
+|[https://doi.org/10.1016/S1470-2045(14)70330-4 Heinemann et al. 2014 (FIRE-3)]
-|1992-2000
+|2007-2012 (C)
-|style="background-color:#1a9851"|Phase 3 (E-switch-ooc)
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|[[#Cisplatin_.26_Doxorubicin|Cisplatin & Doxorubicin]]
+|[[#FOLFIRI_.26_Cetuximab_2|FOLFIRI & Cetuximab]]
-|style="background-color:#d73027"|Inferior OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752331 Wolfson et al. 2007 (GOG 150)]
-|1993-2005
-|style="background-color:#1a9851"|Phase 3 (C)
-|[[#CIM|CIM]]
-|style="background-color:#fee08b"|Might have inferior OS
-|-
-|}
-''Not commonly used but was a comparator arm; here for reference purposes only.''
-====Radiotherapy====
-*[[External beam radiotherapy]]
-</div></div>
-===References===
-# '''GOG 122:''' Randall ME, Filiaci VL, Muss H, Spirtos NM, Mannel RS, Fowler J, Thigpen JT, Benda JA; Gynecologic Oncology Group. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2006 Jan 1;24(1):36-44. Epub 2005 Dec 5. [https://doi.org/10.1200/jco.2004.00.7617 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16330675 PubMed]
-# '''GOG 150:''' Wolfson AH, Brady MF, Rocereto T, Mannel RS, Lee YC, Futoran RJ, Cohn DE, Ioffe OB. A Gynecologic Oncology Group randomized phase III trial of whole abdominal irradiation (WAI) vs cisplatin-ifosfamide and mesna (CIM) as post-surgical therapy in stage I-IV carcinosarcoma (CS) of the uterus. Gynecol Oncol. 2007 Nov;107(2):177-85. Epub 2007 Sep 5. [https://www.gynecologiconcology-online.net/article/S0090-8258(07)00567-7 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752331/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17822748 PubMed] NCT00002546
-=Non-endocrine therapy for advanced, recurrent, or metastatic disease=
-==Bevacizumab monotherapy {{#subobject:b29ce2|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:8159f4|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107744/ Aghajanian et al. 2011 (GOG-0229E)]
-|style="background-color:#91cf61"|Phase 2
 |-
 |}
 <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'''
+*[[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'''
 ====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
+*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1, '''given second'''
-'''21-day cycles'''
+**In FIRE-3, initial infusion is over 90 minutes, next over 60 minutes, and subsequently over 30 minutes
+'''14-day cycles'''
 </div></div>
 ===References===
-<!-- Presented in part at the 45th Annual Meeting of the American Society of Clinical Oncology, May 29-June 2, 2009, Orlando, FL. -->
+#'''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] NCT00433927
-# '''GOG-0229E:''' Aghajanian C, Sill MW, Darcy KM, Greer B, McMeekin DS, Rose PG, Rotmensch J, Barnes MN, Hanjani P, Leslie KK; Gynecologic Oncology Group. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011 Jun 1;29(16):2259-65. Epub 2011 May 2. [https://doi.org/10.1200/jco.2010.32.6397 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107744/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21537039 PubMed] NCT00301964
+==FOLFIRI & Cetuximab {{#subobject:11cf7b|Regimen=1}}==
-==Carboplatin monotherapy {{#subobject:f9b8ad|Regimen=1}}==
+FOLFIRI & Cetuximab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Cetuximab
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 300 mg/m<sup>2</sup> {{#subobject:6a2df1|Variant=1}}===
+===Regimen {{#subobject:921ac6|Variant=1}}===
-{| class="wikitable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="color:white; background-color:#404040"
-!style="width: 33%"|Study
+|<small>'''FDA-recommended dose'''</small>
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.ejcancer.com/article/S0959-8049(02)00504-X van Wijk et al. 2003]
+|}
-|style="background-color:#91cf61"|Phase 2
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-| style="background-color:#88419d; color:white |ORR: 13% (95% CI 6-25%)
+!style="width: 20%"|Study
+!style="width: 20%"|Years 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/10.1056/NEJMoa0805019 Van Cutsem et al. 2009 (CRYSTAL)]
-''This dosing is intended for patients previously treated with chemotherapy.''
+|2004-2005 (C)
-====Chemotherapy====
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-*[[Carboplatin (Paraplatin)]] 300 mg/m<sup>2</sup> IV over 30 minutes once on day 1
+|[[#FOLFIRI|FOLFIRI]]
-'''28-day cycles'''
+| 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)
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 400 mg/m<sup>2</sup> {{#subobject:2d401b|Variant=1}}===
-{| class="wikitable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.ejcancer.com/article/S0959-8049(02)00504-X van Wijk et al. 2003]
+|[https://doi.org/10.1016/S1470-2045(14)70330-4 Heinemann et al. 2014 (FIRE-3)]
-|style="background-color:#91cf61"|Phase 2
+|2007-2012 (C)
-| style="background-color:#88419d; color:white |ORR: 13% (95% CI 6-25%)
+| 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
 |-
 |}
+''<sup>1</sup>Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*CRYSTAL: none
+*FIRE-3: Wild-type KRAS, Wild-type NRAS
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Carboplatin (Paraplatin)]] 400 mg/m<sup>2</sup> IV over 30 minutes once on day 1
+*[[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'''
-'''28-day cycles'''
+*[[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'''
+====Targeted therapy====
+*[[Cetuximab (Erbitux)]] as follows, '''given first and completed at least 1 hour before FOLFIRI begins''':
+**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 on day 8
+**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8
+'''14-day cycles'''
 </div></div>
 ===References===
-# van Wijk FH, Lhommé C, Bolis G, Scotto di Palumbo V, Tumolo S, Nooij M, Freire de Oliveira C, Vermorken JB; [[Study_Groups#EORTC|EORTC]] Gynaecological Cancer Group. Phase II study of carboplatin in patients with advanced or recurrent endometrial carcinoma: a trial of the EORTC Gynaecological Cancer Group. Eur J Cancer. 2003 Jan;39(1):78-85. [https://www.ejcancer.com/article/S0959-8049(02)00504-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12504662 PubMed]
+#'''CRYSTAL:''' Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. [https://doi.org/10.1056/NEJMoa0805019 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19339720 PubMed] NCT00154102
-==Carboplatin & Paclitaxel (CP) {{#subobject:b0e21f|Regimen=1}}==
+<!-- ## '''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://www.ejcancer.com/article/S0959-8049(12)00209-2 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] NCT00433927
+==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
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 5/175, finite duration {{#subobject:7ab5c0|Variant=1}}===
+===Regimen {{#subobject:8ugac6|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
+{| class="wikitable" style="color:white; background-color:#404040"
-!style="width: 25%"|Study
+|<small>'''FDA-recommended dose'''</small>
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.gynecologiconcology-online.net/article/S0090-8258(08)00083-8 Pectasides et al. 2008]
-|style="background-color:#91cf61"|Phase 2
-|-
-|}
-<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
-*[[Carboplatin (Paraplatin)]] AUC 5 IV over 60 minutes once on day 1, '''given second'''
-*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
-'''21-day cycle for 6 to 9 cycles'''
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 5/175, indefinite {{#subobject:100919|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/jco.2001.19.20.4048 Hoskins et al. 2001]
-|style="background-color:#91cf61"|Phase 2
-|-
-|[https://ijgc.bmj.com/content/18/4/803.abstract Sorbe et al. 2007]
-|style="background-color:#91cf61"|Phase 2
-|-
-|}
-''Note: this is the lower limit of carboplatin dosing allowed in Hoskins et al. 2001.''
-<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
-*[[Carboplatin (Paraplatin)]] AUC 5 IV over 60 minutes once on day 1, '''given second'''
-*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
-'''21-day cycles'''
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #3, 6/175 x 7 {{#subobject:a3c4b2|Variant=1}}===
-{| class="wikitable" style="color:black; background-color:#42f584"
-|<small>'''ESMO-preferred (I-A, 2016)'''</small>
 |-
 |}
@@ Line 449: / Line 357: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676887/ Miller et al. 2020 (GOG0209)]
+|[https://doi.org/10.1056/NEJMoa0805019 Van Cutsem et al. 2009 (CRYSTAL)]
-|2003-2009
+|2004-2005 (C)
-| style="background-color:#1a9851" |Phase 3 (E-de-esc)
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|[[#Cisplatin.2C_Doxorubicin.2C_Paclitaxel|TAP]]
+|[[#FOLFIRI|FOLFIRI]]
-| style="background-color:#eeee01" |Non-inferior OS<br>Median OS: 37 vs 41 mo<br>(HR 1.002, 90% CI 0.9-1.12)
+| 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)
+|-
+|[https://doi.org/10.1016/S1470-2045(14)70330-4 Heinemann et al. 2014 (FIRE-3)]
+|2007-2012 (C)
+| 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
 |-
 |}
-''Note: ESMO recommends 6 cycles, whereas the cited RCT uses 7 cycles.''
+''<sup>1</sup>Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*CRYSTAL: none
+*FIRE-3: Wild-type KRAS, Wild-type NRAS
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1, '''given second'''
+*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, 1 hour after completion of cetuximab, with irinotecan'''
-*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
+*[[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>)
-'''21-day cycle for 7 cycles'''
+*[[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 L-leucovorin'''
-</div></div><br>
+====Targeted therapy====
+*[[Cetuximab (Erbitux)]] as follows, '''given first and completed at least 1 hour before FOLFIRI begins''':
+**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 on day 8
+**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8
+'''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] 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://www.ejcancer.com/article/S0959-8049(12)00209-2 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] NCT00433927
+==FOLFOX4 {{#subobject:7239a0|Regimen=1}}==
+FOLFOX4: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #4, 6/175 x 6-10 {{#subobject:a3jqb2|Variant=1}}===
+===Regimen {{#subobject:ab483a|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 472: / Line 405: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8937015/ Powell et al. 2022 (GOG-0261)]
+|[https://doi.org/10.1200/JCO.2008.20.8397 Bokemeyer et al. 2008 (OPUS)]
-|2009-2014
+|2005-2006
-| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
-|[[#Ifosfamide_.26_Paclitaxel|Ifosfamide & Paclitaxel]]
+|[[#FOLFOX4_.26_Cetuximab|FOLFOX4 & Cetuximab]]
-| style="background-color:#eeee01" |Non-inferior OS<br>Median OS: 37 vs 29 mo<br>(HR 0.87, 90% CI 0.70-1.075)
+| style="background-color:#d73027" |Inferior OS<sup>1</sup>
 |-
-|}
+|[https://doi.org/10.1200/jco.2009.27.4860 Douillard et al. 2010 (PRIME)]
-<div class="toccolours" style="background-color:#b3e2cd">
+|2006-2008 (C)
-====Chemotherapy====
+| style="background-color:#1a9851" |Phase 3 (C)
-*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1, '''given second'''
+|[[#FOLFOX4_.26_Panitumumab|FOLFOX4 & Panitumumab]]
-*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
+| style="background-color:#fc8d59" |Seems to have inferior PFS<sup>2</sup>
-'''21-day cycle for 6 to 10 cycles'''
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #5, 7/175 {{#subobject:3a58ce|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/jco.2001.19.20.4048 Hoskins et al. 2001]
+|[https://doi.org/10.1200/JCO.2018.78.3183 Qin et al. 2018 (TAILOR-CRC)]
-|style="background-color:#91cf61"|Phase 2
+|2010-NR
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#FOLFOX4_.26_Cetuximab|FOLFOX4 & Cetuximab]]
+| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
 |}
-''Note: this is the upper limit of carboplatin dosing allowed in Hoskins et al. 2001.''
+''<sup>1</sup>Reported efficacy for OPUS is based on the 2012 pooled update and is only for KRAS wild-type tumors.''<br>
+''<sup>2</sup>In PRIME, patients with KRAS wild-type tumors receiving this regimen seem to have inferior OS, based on the 2014 update. Conversely, in KRAS mutants, this regimen seems to have superior PFS.''<br>
+''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.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Carboplatin (Paraplatin)]] AUC 7 IV once on day 1, '''given second'''
+*[[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'''
-*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
+*[[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>)
-'''21-day cycles'''
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
+'''14-day cycles'''
 </div></div>
 ===References===
-# Hoskins PJ, Swenerton KD, Pike JA, Wong F, Lim P, Acquino-Parsons C, Lee N. Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a phase II study. J Clin Oncol. 2001 Oct 15;19(20):4048-53. [https://doi.org/10.1200/jco.2001.19.20.4048 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11600606 PubMed]
+#'''OPUS:''' Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29. [https://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] NCT00125034
-# Sorbe B, Andersson H, Boman K, Rosenberg P, Kalling M. Treatment of primary advanced and recurrent endometrial carcinoma with a combination of carboplatin and paclitaxel-long-term follow-up. Int J Gynecol Cancer. 2008 Jul-Aug;18(4):803-8. Epub 2007 Oct 18. [https://ijgc.bmj.com/content/18/4/803.abstract link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17944917 PubMed]
+##'''Update:''' Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011 Jul;22(7):1535-46. Epub 2011 Jan 12. [https://doi.org/10.1093/annonc/mdq632 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21228335 PubMed]
-# Pectasides D, Xiros N, Papaxoinis G, Pectasides E, Sykiotis C, Koumarianou A, Psyrri A, Gaglia A, Kassanos D, Gouveris P, Panayiotidis J, Fountzilas G, Economopoulos T. Carboplatin and paclitaxel in advanced or metastatic endometrial cancer. Gynecol Oncol. 2008 May;109(2):250-4. Epub 2008 Mar 4. [http://www.gynecologiconcology-online.net/article/S0090-8258(08)00083-8 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18299146 PubMed] content property of [http://hemonc.org HemOnc.org]
+##'''Pooled update:''' Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://www.ejcancer.com/article/S0959-8049(12)00209-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22446022 PubMed]
-# '''Retrospective:''' Shechter-Maor G, Bruchim I, Ben-Harim Z, Altaras M, Fishman A. Combined chemotherapy regimen of carboplatin and paclitaxel as adjuvant treatment for papillary serous and clear cell endometrial cancer. Int J Gynecol Cancer. 2009 May;19(4):662-4. [https://ijgc.bmj.com/content/19/4/662-664.abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/19509567 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] NCT00364013
-# '''GOG0209:''' Miller DS, Filiaci VL, Mannel RS, Cohn DE, Matsumoto T, Tewari KS, DiSilvestro P, Pearl ML, Argenta PA, Powell MA, Zweizig SL, Warshal DP, Hanjani P, Carney ME, Huang H, Cella D, Zaino R, Fleming GF. Carboplatin and Paclitaxel for Advanced Endometrial Cancer: Final Overall Survival and Adverse Event Analysis of a Phase III Trial (NRG Oncology/GOG0209). J Clin Oncol. 2020 Nov 20;38(33):3841-3850. Epub 2020 Sep 29. [https://doi.org/10.1200/jco.20.01076 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676887/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33078978/ PubMed] NCT00063999
+##'''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]
-# '''GOG-0261:''' Powell MA, Filiaci VL, Hensley ML, Huang HQ, Moore KN, Tewari KS, Copeland LJ, Secord AA, Mutch DG, Santin A, Warshal DP, Spirtos NM, DiSilvestro PA, Ioffe OB, Miller DS. Randomized Phase III Trial of Paclitaxel and Carboplatin Versus Paclitaxel and Ifosfamide in Patients With Carcinosarcoma of the Uterus or Ovary: An NRG Oncology Trial. J Clin Oncol. 2022 Mar 20;40(9):968-977. Epub 2022 Jan 10. [https://doi.org/10.1200/jco.21.02050 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8937015/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35007153/ PubMed] NCT00954174
+##'''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]
-# '''RUBY:''' NCT03981796
+#'''TAILOR:''' 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://pubmed.ncbi.nlm.nih.gov/30199311 PubMed] NCT01228734
-==Carboplatin & Paclitaxel (CP) & Trastuzumab {{#subobject:b0ejgf|Regimen=1}}==
+==FOLFOX4 & Cetuximab {{#subobject:5e5bf3|Regimen=1}}==
-CP+T: '''<u>C</u>'''arboplatin, '''<u>P</u>'''aclitaxel, '''<u>T</u>'''rastuzumab
+FOLFOX4 & Cetuximab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Cetuximab
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:7ab110|Variant=1}}===
+===Regimen {{#subobject:9ec84d|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 521: / Line 453: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2017.76.5966 Fader et al. 2018]
+|[https://doi.org/10.1200/JCO.2008.20.8397 Bokemeyer et al. 2008 (OPUS)]
-|2011-2017
+|2005-2006
 | style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
-|[[#Carboplatin_.26_Paclitaxel_.28CP.29|CP]]
+|[[#FOLFOX4|FOLFOX4]]
-| style="background-color:#1a9850" |Superior PFS<sup>1</sup><br>Median PFS: 12.9 vs 8 mo<br>(HR 0.46, 90% CI 0.28-0.76)
+| 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)
+|-
+|[https://doi.org/10.1200/JCO.2018.78.3183 Qin et al. 2018 (TAILOR-CRC)]
+|2010-NR
+| 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)
 |-
 |}
-''<sup>1</sup>Reported efficacy is based on the 2020 update.''
+''<sup>1</sup>Reported efficacy for OPUS is based on the 2012 pooled update and is only for KRAS wild-type tumors.''<br>
+''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.''
 <div class="toccolours" style="background-color:#fdcdac">
 ====Biomarker eligibility criteria====
-*HER2 overexpression
+*OPUS: none
+*TAILOR-CRC: Wild-type KRAS, Wild-type NRAS
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Carboplatin (Paraplatin)]] as follows:
+*[[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'''
-**Cycles 1 to 6: AUC 5 IV once 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>)
-*[[Paclitaxel (Taxol)]] as follows:
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
-**Cycles 1 to 6: 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
 ====Targeted therapy====
-*[[Trastuzumab (Herceptin)]] as follows:
+*[[Cetuximab (Erbitux)]] '''given first''', as follows:
-**Cycle 1: 8 mg/kg IV once on day 1
+**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 on day 8
-**Cycle 2 onwards: 6 mg/kg IV once on day 1
+**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8
-'''21-day cycles'''
+'''14-day cycles'''
 </div></div>
 ===References===
-#Fader AN, Roque DM, Siegel E, Buza N, Hui P, Abdelghany O, Chambers SK, Secord AA, Havrilesky L, O'Malley DM, Backes F, Nevadunsky N, Edraki B, Pikaart D, Lowery W, ElSahwi KS, Celano P, Bellone S, Azodi M, Litkouhi B, Ratner E, Silasi DA, Schwartz PE, Santin AD. Randomized Phase II Trial of Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab in Uterine Serous Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu. J Clin Oncol. 2018 Jul 10;36(20):2044-2051. Epub 2018 Mar 27. [https://doi.org/10.1200/jco.2017.76.5966 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29584549/ PubMed] NCT01367002
+#'''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] NCT00125034
-##'''Update:''' Fader AN, Roque DM, Siegel E, Buza N, Hui P, Abdelghany O, Chambers S, Secord AA, Havrilesky L, O'Malley DM, Backes FJ, Nevadunsky N, Edraki B, Pikaart D, Lowery W, ElSahwi K, Celano P, Bellone S, Azodi M, Litkouhi B, Ratner E, Silasi DA, Schwartz PE, Santin AD. Randomized Phase II Trial of Carboplatin-Paclitaxel Compared with Carboplatin-Paclitaxel-Trastuzumab in Advanced (Stage III-IV) or Recurrent Uterine Serous Carcinomas that Overexpress Her2/Neu (NCT01367002): Updated Overall Survival Analysis. Clin Cancer Res. 2020 Aug 1;26(15):3928-3935. Epub 2020 Jun 29. [https://doi.org/10.1158/1078-0432.ccr-20-0953 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8792803/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32601075/ PubMed]
+##'''Update:''' Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011 Jul;22(7):1535-46. Epub 2011 Jan 12. [https://doi.org/10.1093/annonc/mdq632 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21228335 PubMed]
-==Carboplatin & Pegylated liposomal doxorubicin {{#subobject:c8ff00|Regimen=1}}==
+##'''Pooled update:''' Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. [https://www.ejcancer.com/article/S0959-8049(12)00209-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22446022 PubMed]
+#'''TAILOR:''' 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://pubmed.ncbi.nlm.nih.gov/30199311 PubMed] NCT01228734
+==FOLFOX4 & Panitumumab {{#subobject:486271|Regimen=1}}==
+FOLFOX4 & Panitumumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Panitumumab
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:d48f39|Variant=1}}===
+===Regimen {{#subobject:d862a3|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359926/ Pignata et al. 2007 (END-1)]
-|style="background-color:#91cf61"|Phase 2
-|-
-|}
-''Note: All patients received 3 cycles of therapy. If there was no unacceptable toxicity, patients with stable or responsive disease received an additional 3 cycles.''
-<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
-*[[Carboplatin (Paraplatin)]] AUC 5 IV over 30 minutes once on day 1, '''given first'''
-*[[Pegylated liposomal doxorubicin (Doxil)]] 40 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given second'''
-====Supportive therapy====
-*[[:Category:Granulocyte colony-stimulating factors|G-CSF]] by the following criteria:
-**Prophylaxis: not recommended
-**Grade 4 neutropenia: therapeutic and prophylactic use was allowed
-'''28-day cycle for 3 to 6 cycles'''
-</div></div>
-===References===
-# '''END-1:''' Pignata S, Scambia G, Pisano C, Breda E, Di Maio M, Greggi S, Ferrandina G, Lorusso D, Zagonel V, Febbraro A, Riva N, De Rosa V, Gallo C, Perrone F; Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies Group. A multicentre phase II study of carboplatin plus pegylated liposomal doxorubicin as first-line chemotherapy for patients with advanced or recurrent endometrial carcinoma: the END-1 study of the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) group. Br J Cancer. 2007 Jun 4;96(11):1639-43. Epub 2007 May 8. [https://doi.org/10.1038/sj.bjc.6603787 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359926/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17486128 PubMed]
-==CIM {{#subobject:ac4ecc|Regimen=1}}==
-CIM: '''<u>C</u>'''isplatin, '''<u>I</u>'''fosfamide, '''<u>M</u>'''esna
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:a26ea4|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 583: / Line 500: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.gynecologiconcology-online.net/article/S0090-8258(00)96001-3/pdf Sutton et al. 2000 (GOG 108)]
+|[https://doi.org/10.1200/jco.2009.27.4860 Douillard et al. 2010 (PRIME)]
-|1989-1996
+|2006-2008 (C)
-|style="background-color:#1a9851"|Phase 3 (E-esc)
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|[[#Ifosfamide_monotherapy|Ifosfamide]]
+|[[#FOLFOX4|FOLFOX4]]
-| style="background-color:#91cf60" |Seems to have superior PFS
+| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br>Median OS: 23.8 vs 19.4 mo<br>(HR 0.83, 95% CI 0.70-0.98)
 |-
 |}
+''<sup>1</sup>In KRAS wild-type patients, this regimen seems to have superior OS, based on the exploratory analysis in the 2014 update.''
+<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====
-*[[Cisplatin (Platinol)]]
+*[[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>)
-*[[Ifosfamide (Ifex)]]
+*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 2
-====Supportive therapy====
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-*[[Mesna (Mesnex)]]
+====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'''
 </div></div>
 ===References===
-# '''GOG 108:''' Sutton G, Brunetto VL, Kilgore L, Soper JT, McGehee R, Olt G, Lentz SS, Sorosky J, Hsiu JG. A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group study. Gynecol Oncol. 2000 Nov;79(2):147-53. [https://www.gynecologiconcology-online.net/article/S0090-8258(00)96001-3/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/11063636 PubMed]
+<!-- 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. -->
-==Cisplatin & Doxorubicin {{#subobject:7f9e48|Regimen=1}}==
+#'''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] NCT00364013
-AP: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>P</u>'''latinol (Cisplatin)
+##'''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
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 50/45 {{#subobject:1748e2|Variant=1}}===
+===Regimen {{#subobject:8baf2c|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 610: / Line 538: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2004.07.184 Fleming et al. 2004a (GOG 177)]
+|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545896/ Venook et al. 2017 (CALGB 80405)]
-|1998-2000
+|rowspan=2|2005-2012
-|style="background-color:#1a9851"|Phase 3 (C)
+|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|[[#Cisplatin.2C_Doxorubicin.2C_Paclitaxel|Cisplatin, Doxorubicin, Paclitaxel]]
+|1. [[#mFOLFOX6_.26_Panitumumab|mFOLFOX6 & Panitumumab]]<br>2. [[#FOLFIRI_.26_Panitumumab_88|FOLFIRI & Panitumumab]]
-|style="background-color:#fc8d59"|Seems to have inferior OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|}
+|3. [[#mFOLFOX6.2C_Bevacizumab.2C_Cetuximab_99|mFOLFOX6, Bevacizumab, Cetuximab]]<br>4. [[#FOLFIRI.2C_Bevacizumab.2C_Cetuximab_99|FOLFIRI, Bevacizumab, Cetuximab]]
-''Note: body surface area was capped at 2 m<sup>2</sup>. This dosage was for patients with previous pelvic radiation or who were greater than 65 years old.''
+| style="background-color:#d3d3d3" |Not reported
-<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
-*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> (maximum dose of 100 mg) IV over 60 minutes once on day 1, '''given second'''
-*[[Doxorubicin (Adriamycin)]] 45 mg/m<sup>2</sup> (maximum dose of 90 mg) IV once on day 1, '''given first'''
-'''21-day cycle for 7 cycles'''
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 50/60, capped BSA {{#subobject:3b1876|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years 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.2004.07.184 Fleming et al. 2004a (GOG 177)]
+|Awaiting publication (PARADIGM<sub>CRC</sub>)
-|1998-2000
+|2015-2022
-|style="background-color:#1a9851"|Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Cisplatin.2C_Doxorubicin.2C_Paclitaxel|Cisplatin, Doxorubicin, Paclitaxel]]
+|[[#mFOLFOX6_.26_Panitumumab|mFOLFOX6 & Panitumumab]]
-|style="background-color:#fc8d59"|Seems to have inferior OS
+| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
 |}
-''Note: body surface area was capped at 2 m<sup>2</sup>.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> (maximum dose of 100 mg) IV over 60 minutes once on day 1, '''given second'''
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> (maximum dose of 120 mg) IV once on day 1, '''given first'''
+*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycle for 7 cycles'''
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
-</div></div><br>
+====Targeted therapy====
+*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1
+'''14-day cycles'''
+</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] NCT00265850
+#'''PARADIGM<sub>CRC</sub>:''' 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
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #3, 50/60, no cap on BSA {{#subobject:5baa3b|Variant=1}}===
+===Regimen {{#subobject:8baf2c|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 656: / Line 577: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1093/annonc/mdh316 Fleming et al. 2004 (GOG 163)]
+|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545896/ Venook et al. 2017 (CALGB 80405)]
-|1996-1998
+|rowspan=2|2005-2012
-|style="background-color:#1a9851"|Phase 3 (C)
+|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|[[#Doxorubicin_.26_Paclitaxel_.28AT.29_99|Doxorubicin & Paclitaxel]]
+|1. [[#mFOLFOX6_.26_Panitumumab|mFOLFOX6 & Panitumumab]]<br>2. [[#FOLFIRI_.26_Panitumumab_88|FOLFIRI & Panitumumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://doi.org/10.1200/JCO.2004.02.088 Thigpen et al. 2004 (GOG 107)]
+|3. [[#mFOLFOX6.2C_Bevacizumab.2C_Cetuximab_99|mFOLFOX6, Bevacizumab, Cetuximab]]<br>4. [[#FOLFIRI.2C_Bevacizumab.2C_Cetuximab_99|FOLFIRI, Bevacizumab, Cetuximab]]
-|NR
+| style="background-color:#d3d3d3" |Not reported
-|style="background-color:#1a9851"|Phase 3 (E-esc)
-|[[#Doxorubicin_monotherapy|Doxorubicin]]
-| style="background-color:#91cf60" |Seems to have superior PFS
 |-
-|}
+|[https://www.ejcancer.com/article/S0959-8049(18)30938-9 Aranda et al. 2018 (MACRO-2)]
-<div class="toccolours" style="background-color:#b3e2cd">
+|2010-NR
-====Chemotherapy====
+| style="background-color:#91cf61" |Non-randomized portion of phase 2 RCT
-*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV once on day 1
+| style="background-color:#d3d3d3" |
-*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
+| style="background-color:#d3d3d3" |
-====Supportive therapy====
-*Normal saline at 500 mL/H for 2 hours prior to and after [[Cisplatin (Platinol)]]
-'''21-day cycle for up to 8 cycles'''
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #4, 60/60 {{#subobject:828296|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years 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.2003.10.083 Gallion et al. 2003 (GOG 139)]
-|1993-1996
-|style="background-color:#1a9851"|Phase 3 (C)
-|[[#Cisplatin_.26_Doxorubicin_2|Cisplatin & Doxorubicin]]; chronomodulated
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
 |}
+''Note: In CALGB 80405, the arm receiving bevacizumab and cetuximab was terminated early.''
+<div class="toccolours" style="background-color:#fdcdac">
+====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)
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 60 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>)
-*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
+*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycle for up to 8 cycles'''
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
+====Targeted therapy====
+*[[Cetuximab (Erbitux)]] as follows, '''given first''':
+**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 (see below)'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*MACRO-2, after 8 cycles: continued [[#mFOLFOX6_.26_Cetuximab_2|mFOLFOX6 & Cetuximab]] until progression versus [[#Cetuximab_monotherapy|cetuximab]] maintenance
 </div></div>
 ===References===
-# '''GOG 139:''' Gallion HH, Brunetto VL, Cibull M, Lentz SS, Reid G, Soper JT, Burger RA, Andersen W; Gynecologic Oncology Group. Randomized phase III trial of standard timed doxorubicin plus cisplatin versus circadian timed doxorubicin plus cisplatin in stage III and IV or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2003 Oct 15;21(20):3808-13. [https://doi.org/10.1200/JCO.2003.10.083 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/14551299 PubMed]
+#'''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] NCT00265850
-# '''GOG 177:''' Fleming GF, Brunetto VL, Cella D, Look KY, Reid GC, Munkarah AR, Kline R, Burger RA, Goodman A, Burks RT. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2004 Jun 1;22(11):2159-66. [https://doi.org/10.1200/jco.2004.07.184 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15169803 PubMed] NCT00003691
+#'''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://www.ejcancer.com/article/S0959-8049(18)30938-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30054049 PubMed] NCT01161316
-# '''GOG 163:''' Fleming GF, Filiaci VL, Bentley RC, Herzog T, Sorosky J, Vaccarello L, Gallion H. Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: a Gynecologic Oncology Group study. Ann Oncol. 2004 Aug;15(8):1173-8. [https://doi.org/10.1093/annonc/mdh316 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15277255 PubMed]
+==mFOLFOX6 & Panitumumab {{#subobject:avn786|Regimen=1}}==
-# '''GOG 107:''' Thigpen JT, Brady MF, Homesley HD, Malfetano J, DuBeshter B, Burger RA, Liao S. Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2004 Oct 1;22(19):3902-8. [https://doi.org/10.1200/JCO.2004.02.088 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15459211 PubMed]
+mFOLFOX6 & Panitumumab: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, Panitumumab
-==Cisplatin, Doxorubicin, Paclitaxel {{#subobject:b61c1e|Regimen=1}}==
-TAP: '''<u>T</u>'''axol (Paclitaxel), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''latinol (Cisplatin)
-<br>CDP: '''<u>C</u>'''isplatin, '''<u>D</u>'''oxorubicin, '''<u>P</u>'''aclitaxel
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:68777b|Variant=1}}===
+===Regimen {{#subobject:8bukqc|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 716: / Line 628: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2004.07.184 Fleming et al. 2004 (GOG 177)]
+|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc9426812/ Rossini et al. 2022 (TRIPLETE)]
-|1998-2000
+|2017-2021
-|style="background-color:#1a9851"|Phase 3 (E-esc)
-|[[#Cisplatin_.26_Doxorubicin_2|Cisplatin & Doxorubicin]]
-|style="background-color:#91cf60"|Seems to have superior OS<br>Median OS: 15.3 vs 12.3 mo<br>(HR 0.75, 95% CI 0.57-0.99)
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676887/ Miller et al. 2020 (GOG0209)]
-|2003-2009
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Carboplatin_.26_Paclitaxel_.28CP.29_2|TC]]
+|[[#mFOLFOXIRI_.26_Panitumumab_99|mFOLFOXIRI & Panitumumab]]
-| style="background-color:#eeee01" |Non-inferior OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
 |}
-''Note: in GOG 177, body surface area was capped at 2 m<sup>2</sup>.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*Wild-type KRAS (exons 2 to 4), wild-type NRAS (exons 2 to 4), wild-type BRAF codon 600
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cisplatin (Platinol)]] 50 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given second'''
+*[[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>)
-*[[Doxorubicin (Adriamycin)]] 45 mg/m<sup>2</sup> IV once on day 1, '''given first'''
+*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1, '''given second'''
-*[[Paclitaxel (Taxol)]] 160 mg/m<sup>2</sup> IV over 3 hours once on day 2
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
-====Supportive therapy====
+====Targeted therapy====
-*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day on days 3 to 12
+*[[Panitumumab (Vectibix)]] 6 mg/kg IV over 30 to 60 minutes once on day 1, '''given first'''
-'''21-day cycle for 7 cycles'''
+'''14-day cycles'''
 </div></div>
 ===References===
-# '''GOG 177:''' Fleming GF, Brunetto VL, Cella D, Look KY, Reid GC, Munkarah AR, Kline R, Burger RA, Goodman A, Burks RT. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2004 Jun 1;22(11):2159-66. [https://doi.org/10.1200/jco.2004.07.184 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15169803 PubMed] NCT00003691
+#'''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] NCT03231722
-# '''GOG0209:''' Miller DS, Filiaci VL, Mannel RS, Cohn DE, Matsumoto T, Tewari KS, DiSilvestro P, Pearl ML, Argenta PA, Powell MA, Zweizig SL, Warshal DP, Hanjani P, Carney ME, Huang H, Cella D, Zaino R, Fleming GF. Carboplatin and Paclitaxel for Advanced Endometrial Cancer: Final Overall Survival and Adverse Event Analysis of a Phase III Trial (NRG Oncology/GOG0209). J Clin Oncol. 2020 Nov 20;38(33):3841-3850. Epub 2020 Sep 29. [https://doi.org/10.1200/jco.20.01076 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676887/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33078978/ PubMed] NCT00063999
+==mFOLFOXIRI & Cetuximab (L-Leucovorin){{#subobject:9bf7|Regimen=1}}==
-==Cisplatin & Paclitaxel {{#subobject:89fd88|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
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:b3c8fd|Variant=1}}===
+===Regimen {{#subobject:19365|Variant=1}}===
 {| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 25%"|Study
+! style="width: 25%" |Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.gynecologiconcology-online.net/article/S0090-8258(00)95827-X Dimopoulos et al. 2000]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885260/ Cremolini et al. 2018 (MACBETH)]
-|style="background-color:#91cf61"|Phase 2
+| style="background-color:#91cf61" |Non-randomized portion of phase 2 RCT
 |-
 |}
+''Note: 5-FU instructions are unusual in that no bolus is given.''
+<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====
-*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
+*[[Fluorouracil (5-FU)]] 1200 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1, '''given fourth''' (total dose per cycle: 2400 mg/m<sup>2</sup>)
-*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
+*[[Levoleucovorin (Fusilev)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given third, with oxaliplatin'''
-====Supportive therapy====
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given third, with L-leucovorin'''
-*[[Dexamethasone (Decadron)]] 20 mg IV or PO for two doses on day 1; 12 and 6 hours prior to [[Paclitaxel (Taxol)]]
+*[[Irinotecan (Camptosar)]] 130 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given second'''
-*[[Diphenhydramine (Benadryl)]] 25 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]
+====Targeted therapy====
-*[[Ranitidine (Zantac)]] 50 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]
+*[[Cetuximab (Erbitux)]] 500 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given first'''
-*900 mL normal saline mixed with 100 mL mannitol given over 1 hour prior to [[Cisplatin (Platinol)]]
+'''14-day cycle for 8 cycles'''
-*2 liters NS with potassium & magnesium after [[Cisplatin (Platinol)]]
+</div>
-*"Appropriate antiemetics"
+<div class="toccolours" style="background-color:#cbd5e7">
-*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 5 and continuing until WBC greater than 10,000 x 10<sup>9</sup>/L
+====Subsequent treatment====
-'''21-day cycle for up to 6 cycles'''
+*MACBETH, if deemed resectable: [[Surgery#Colorectal_cancer_surgery|Surgery]]
+*MACBETH, if deemed unresectable: [[#Cetuximab_monotherapy|Cetuximab]] versus [[#Bevacizumab_monotherapy_99|bevacizumab]] maintenance
 </div></div>
 ===References===
-# Dimopoulos MA, Papadimitriou CA, Georgoulias V, Moulopoulos LA, Aravantinos G, Gika D, Karpathios S, Stamatelopoulos S. Paclitaxel and cisplatin in advanced or recurrent carcinoma of the endometrium: long-term results of a phase II multicenter study. Gynecol Oncol. 2000 Jul;78(1):52-7. [http://www.gynecologiconcology-online.net/article/S0090-8258(00)95827-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10873410 PubMed]
+#'''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] NCT02295930
-==Dactinomycin monotherapy {{#subobject:97a01a|Regimen=1}}==
+==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
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:2019ab|Variant=1}}===
+===Regimen {{#subobject:19365|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 20%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Years of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://www.gynecologiconcology-online.net/article/S0090-8258(99)95652-4 Moore et al. 1999]
+|[https://doi.org/10.1200/JCO.19.01340 Modest et al. 2019 (VOLFI)]
-|style="background-color:#91cf61"|Phase 2
+|2011-2016
+| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
+|[[#FOLFIRINOX|FOLFOXIRI]]
+| style="background-color:#1a9850" |Superior 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====
-*[[Dactinomycin (Cosmegen)]] 2 mg/m<sup>2</sup> IV over 15 minutes once on day 1
+*[[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>)
-'''28-day cycles'''
+*[[Folinic acid (Leucovorin)]] 200 mg/m<sup>2</sup> IV once on day 1
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
+*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> 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'''
 </div></div>
 ===References===
-# Moore DH, Blessing JA, Dunton C, Buller RE, Reid GC; Gynecologic Oncology Group. Dactinomycin in the treatment of recurrent or persistent endometrial carcinoma: A Phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 1999 Dec;75(3):473-5. [http://www.gynecologiconcology-online.net/article/S0090-8258(99)95652-4 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10600310 PubMed]
+#'''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] NCT01328171
-==Dostarlimab monotherapy {{#subobject:ejg8a3|Regimen=1}}==
+=Maintenance after first-line therapy=
+==Bevacizumab monotherapy {{#subobject:ahag4f|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:5dnfj9|Variant=1}}===
+===Regimen {{#subobject:a72hg6|Variant=1}}===
-{| class="wikitable sortable" style="color:white; background-color:#404040"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-|<small>'''FDA-recommended dose'''</small>
+!style="width: 20%"|Study
+!style="width: 20%"|Years 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/10.1093/annonc/mdv490 Hagman et al. 2015 (Nordic ACT2)]
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+|2010-2012
-!style="width: 33%"|Study
+| style="background-color:#1a9851" |Phase 3 (C)
-!style="width: 33%"|Years of enrollment
+|[[#Erlotinib_.26_Bevacizumab_99|Erlotinib & Bevacizumab]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7530821/ Oaknin et al. 2020 (GARNET)]
-|2017-2019
-| style="background-color:#91cf61" |Phase 1, >20 pts in this cohort (RT)
 |-
 |}
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*Wild-type KRAS
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Immunotherapy====
+====Targeted therapy====
-*[[Dostarlimab (Jemperli)]] as follows:
+*[[Bevacizumab (Avastin)]] 7.5 mg/kg IV once on day 1
-**Cycles 1 to 4: 500 mg IV over 30 minutes once on day 1
+'''21-day cycles'''
-**Cycle 5 onwards: 1000 mg IV over 30 minutes once on day 1
-'''21-day cycle for 4 cycles, then 42-day cycles'''
 </div></div>
 ===References===
-#'''GARNET:''' Oaknin A, Tinker AV, Gilbert L, Samouëlian V, Mathews C, Brown J, Barretina-Ginesta MP, Moreno V, Gravina A, Abdeddaim C, Banerjee S, Guo W, Danaee H, Im E, Sabatier R. Clinical Activity and Safety of the Anti-Programmed Death 1 Monoclonal Antibody Dostarlimab for Patients With Recurrent or Advanced Mismatch Repair-Deficient Endometrial Cancer: A Nonrandomized Phase 1 Clinical Trial. JAMA Oncol. 2020 Nov 1;6(11):1766-1772. Epub 2020 Oct 1. [https://doi.org/10.1001/jamaoncol.2020.4515 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7530821/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33001143/ PubMed] NCT02715284
+#'''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] NCT01229813
-##'''Update:''' Oaknin A, Gilbert L, Tinker AV, Brown J, Mathews C, Press J, Sabatier R, O'Malley DM, Samouelian V, Boni V, Duska L, Ghamande S, Ghatage P, Kristeleit R, Leath C III, Guo W, Im E, Zildjian S, Han X, Duan T, Veneris J, Pothuri B. Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study. J Immunother Cancer. 2022 Jan;10(1):e003777. [https://doi.org/10.1136/jitc-2021-003777 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8785197/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35064011/ PubMed]
+==Cetuximab monotherapy {{#subobject:afad4f|Regimen=1}}==
-==Doxorubicin monotherapy {{#subobject:e5b103|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 7 cycles {{#subobject:5dn1e9|Variant=1}}===
+===Regimen variant #1, 250 mg/m<sup>2</sup> weekly {{#subobject:a72650|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 824: / Line 757: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1093/annonc/mdg112 Aapro et al. 2003 (EORTC 55872)]
+|[https://www.ejcancer.com/article/S0959-8049(18)30938-9 Aranda et al. 2018 (MACRO-2)]
-|1988-1994
+|2010-NR
-|style="background-color:#1a9851"|Phase 3 (C)
+| style="background-color:#1a9851" |Randomized Phase 2 (E-de-esc)
-|[[#Cisplatin_.26_Doxorubicin_2|Cisplatin & Doxorubicin]]
+|[[#mFOLFOX6_.26_Cetuximab_2|mFOLFOX6 & Cetuximab]]
-| style="background-color:#fee08b" |Might have inferior OS
+| style="background-color:#eeee01" |Non-inferior PFS
 |-
 |}
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
+''Note: regimen details are from ClinicalTrials.gov; they were not present in the abstract or the manuscript.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*Wild-type KRAS, Wild-type NRAS
+<div class="toccolours" style="background-color:#cbd5e8">
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Preceding treatment====
+*[[#mFOLFOX6_.26_Cetuximab_2|mFOLFOX6 & Cetuximab]] x 8
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
+====Targeted therapy====
-*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
+*[[Cetuximab (Erbitux)]] 250 mg/m<sup>2</sup> IV once on day 1
-'''28-day cycle for up to 7 cycles'''
+'''7-day cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 8 cycles {{#subobject:5d91e9|Variant=1}}===
+===Regimen variant #2, 500 mg/m<sup>2</sup> q2wk {{#subobject:3d7e64|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 20%"|Study
+! style="width: 25%" |Study
-!style="width: 20%"|Years of enrollment
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://pubmed.ncbi.nlm.nih.gov/369691 Thigpen et al. 1979]
-|NR
-| style="background-color:#91cf61" |Phase 2
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://doi.org/10.1002/1097-0142(19830815)52:4%3C626::AID-CNCR2820520409%3E3.0.CO;2-E Omura et al. 1983 (GOG 21)]
-|1973-1979
-|style="background-color:#1a9851"|Randomized (C)
-|[[#Dacarbazine_.26_Doxorubicin_99|Dacarbazine & Doxorubicin]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
-|[https://doi.org/10.1002/1097-0142(19850415)55:8%3C1648::AID-CNCR2820550806%3E3.0.CO;2-7 Muss et al. 1985 (GOG 42)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885260/ Cremolini et al. 2018 (MACBETH)]
-|1979-1982
+| style="background-color:#91cf61" |Randomized Phase 2
-|style="background-color:#1a9851"|Phase 3 (C)
-|[[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_99|Cyclophosphamide & Doxorubicin (AC)]]
-| style="background-color:#ffffbf" |Did not meet efficacy endpoints
-|-
-|[https://doi.org/10.1200/JCO.1994.12.7.1408 Thigpen et al. 1994 (GOG 48)]
-|1979-1985
-|style="background-color:#1a9851"|Randomized (C)
-|[[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_99|Cyclophosphamide & Doxorubicin (AC)]]
-| style="background-color:#ffffbf" |Did not meet efficacy endpoints
-|-
-|[https://doi.org/10.1200/JCO.2004.02.088 Thigpen et al. 2004 (GOG 107)]
-|NR
-|style="background-color:#1a9851"|Phase 3 (C)
-|[[#Cisplatin_.26_Doxorubicin_2|Cisplatin & Doxorubicin]]
-|style="background-color:#fc8d59"|Seems to have inferior PFS
-|-
-|[https://doi.org/10.1056/nejmoa2108330 Makker et al. 2022 (KEYNOTE-775)]
-|2018-2020
-|style="background-color:#1a9851"|Phase 3 (C)
-|[[#Lenvatinib_.26_Pembrolizumab|Lenvatinib & Pembrolizumab]]
-| style="background-color:#d73027" |Inferior OS
 |-
 |}
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
+''Note: this was a non-comparative study.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*Wild-type KRAS, Wild-type NRAS
+<div class="toccolours" style="background-color:#cbd5e8">
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Preceding treatment====
+*[[#mFOLFOXIRI_.26_Cetuximab_.28L-Leucovorin.29|mFOLFOXIRI & Cetuximab]] x 8
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
+====Targeted therapy====
-*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV over 60 minutes once on day 1
+*[[Cetuximab (Erbitux)]] 500 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycle for up to 8 cycles'''
+'''14-day cycles'''
 </div></div>
 ===References===
-# Thigpen JT, Buchsbaum HJ, Mangan C, Blessing JA; Gynecologic Oncology Group. Phase II trial of adriamycin in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Cancer Treat Rep. 1979 Jan;63(1):21-7. [https://pubmed.ncbi.nlm.nih.gov/369691 PubMed]
+#'''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] NCT02295930
-# '''GOG 21:''' Omura GA, Major FJ, Blessing JA, Sedlacek TV, Thigpen JT, Creasman WT, Zaino RJ. A randomized study of adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcomas. Cancer. 1983 Aug 15;52(4):626-32. [https://doi.org/10.1002/1097-0142(19830815)52:4%3C626::AID-CNCR2820520409%3E3.0.CO;2-E link to original article] [https://pubmed.ncbi.nlm.nih.gov/6344983 PubMed]
+#'''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://www.ejcancer.com/article/S0959-8049(18)30938-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30054049 PubMed] NCT01161316
-# '''GOG 42:''' Muss HB, Bundy B, DiSaia PJ, Homesley HD, Fowler WC Jr, Creasman W, Yordan E. Treatment of recurrent or advanced uterine sarcoma: a randomized trial of doxorubicin versus doxorubicin and cyclophosphamide (a phase III trial of the Gynecologic Oncology Group). Cancer. 1985 Apr 15;55(8):1648-53. [https://doi.org/10.1002/1097-0142(19850415)55:8%3C1648::AID-CNCR2820550806%3E3.0.CO;2-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3884128 PubMed]
+=Advanced or metastatic disease, second-line=
-# '''GOG 48:''' Thigpen JT, Blessing JA, DiSaia PJ, Yordan E, Carson LF, Evers C. A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 1994 Jul;12(7):1408-14. [https://doi.org/10.1200/JCO.1994.12.7.1408 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8021731 PubMed]
+==FOLFIRI & Panitumumab {{#subobject:8c0093|Regimen=1}}==
-# '''EORTC 55872:''' Aapro MS, van Wijk FH, Bolis G, Chevallier B, van der Burg ME, Poveda A, Freire de Oliveira C, Tumolo S, Scotto di Palumbo V, Piccart M, Franchi M, Zanaboni F, Lacave AJ, Fontanelli R, Favalli G, Zola P, Guastalla JP, Rosso R, Marth C, Nooij M, Presti M, Scarabelli C, Splinter TA, Ploch E, Beex LV, ten Bokkel Huinink W, Forni M, Melpignano M, Blake P, Kerbrat P, Mendiola C, Cervantes A, Goupil A, Harper PG, Madronal C, Namer M, Scarfone G, Stoot JE, Teodorovic I, Coens C, Vergote I, Vermorken JB; [[Study_Groups#EORTC|EORTC]] Gynaecological Cancer Group. Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group. Ann Oncol. 2003 Mar;14(3):441-8. Erratum in: Ann Oncol. 2003 May;14(5):811. [https://doi.org/10.1093/annonc/mdg112 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12598351 PubMed]
+FOLFIRI & Panitumumab: '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Panitumumab
-# '''GOG 107:''' Thigpen JT, Brady MF, Homesley HD, Malfetano J, DuBeshter B, Burger RA, Liao S. Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2004 Oct 1;22(19):3902-8. [https://doi.org/10.1200/JCO.2004.02.088 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15459211 PubMed]
-# '''KEYNOTE-775:''' Makker V, Colombo N, Casado Herráez A, Santin AD, Colomba E, Miller DS, Fujiwara K, Pignata S, Baron-Hay S, Ray-Coquard I, Shapira-Frommer R, Ushijima K, Sakata J, Yonemori K, Kim YM, Guerra EM, Sanli UA, McCormack MM, Smith AD, Keefe S, Bird S, Dutta L, Orlowski RJ, Lorusso D; Study 309–KEYNOTE-775 Investigators. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022 Feb 3;386(5):437-448. Epub 2022 Jan 19. [https://doi.org/10.1056/nejmoa2108330 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35045221/ PubMed] NCT03517449
-==Ifosfamide monotherapy {{#subobject:b078a0|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 1200 mg/m<sup>2</sup> (3 days/cycle) {{#subobject:fc7107|Variant=1}}===
+===Regimen {{#subobject:ebf6e5|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 907: / Line 819: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2006.06.4907 Homesley et al. 2007 (GOG 161)]
+|[https://doi.org/10.1200/jco.2009.27.6055 Peeters et al. 2010 (20050181)]
-|1997-2004
+|2006-2008
-|style="background-color:#1a9851"|Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[#Ifosfamide_.26_Paclitaxel|Ifosfamide & Paclitaxel]]
+|[[#FOLFIRI|FOLFIRI]]
-|style="background-color:#fc8d59"|Seems to have inferior OS
+| 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)
 |-
 |}
-''Note: GOG 161 specifies that PO [[Mesna (Mesnex)]] is to be taken in 3 divided doses, but only lists 2 time points for its use. The timing of the middle dose is estimated based on other references. This dosage is intended for patients with previous radiation.''
+''<sup>1</sup>Reported efficacy is for wild-type KRAS, only, and is based on the 2014 update.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*None
+<div class="toccolours" style="background-color:#fdcdac">
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Prior treatment criteria====
+*First-line fluoropyrimidine-based chemotherapy, with progression
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Ifosfamide (Ifex)]] 1200 mg/m<sup>2</sup> IV once per day on days 1 to 3
+*[[Folinic acid (Leucovorin)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second, with irinotecan'''
-====Supportive therapy====
+*[[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>)
-*[[Mesna (Mesnex)]] 2000 mg IV over 12 hours once per day on days 1 to 3, starting 15 minutes before [[Ifosfamide (Ifex)]] (total dose per cycle: 6000 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'''
-**Alternate PO dosing: 1330 mg PO three times per day on days 1 to 3, taken 1 hour before, 4 hours after, and 8 hours after [[Ifosfamide (Ifex)]] (total dose per cycle: 11,970 mg)
+====Targeted therapy====
-*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 4, to continue until ANC is greater than or equal to 2000/uL
+*[[Panitumumab (Vectibix)]] 6 mg/kg IV over 60 minutes once on day 1, '''given first'''
-'''21-day cycle for 8 cycles'''
+'''14-day cycles'''
-</div></div><br>
+</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] 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]
+==Irinotecan monotherapy {{#subobject:d4d4f9|Regimen=1}}==
+===Example orders===
+*[[Example orders for Irinotecan (Camptosar) in colon cancer]]
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 1500 mg/m<sup>2</sup> (5 days/cycle) {{#subobject:450cd5|Variant=1}}===
+===Regimen variant #1, 180 mg/m<sup>2</sup> q2wk {{#subobject:175e25|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 933: / Line 860: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.gynecologiconcology-online.net/article/S0090-8258(00)96001-3/pdf Sutton et al. 2000 (GOG 108)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534840/ Shi et al. 2019 (CRC009)]
-|1989-1996
+|2009-2011
-|style="background-color:#1a9851"|Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#CIM_2|CIM]]
+|[[#Irinotecan_.26_CMAB009_77|Irinotecan & CMAB009]]
-|style="background-color:#fc8d59"|Seems to have inferior PFS
+| style="background-color:#d73027" |Inferior PFS50%
 |-
 |}
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*Exposure to FOLFOX, with progression or discontinuation due to toxicity
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Ifosfamide (Ifex)]] 1500 mg/m<sup>2</sup> IV once per day on days 1 to 5
+*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-====Supportive therapy====
+'''14-day cycles'''
-*[[Mesna (Mesnex)]] 1500 mg/m<sup>2</sup> IV once per day on days 1 to 5
-'''21-day cycle for 8 cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #3, 1600 mg/m<sup>2</sup> (3 days/cycle) {{#subobject:5e6305|Variant=1}}===
+===Regimen variant #2, 300 mg/m<sup>2</sup> q3wk {{#subobject:190e25|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 956: / Line 885: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2006.06.4907 Homesley et al. 2007 (GOG 161)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699713/ Seymour et al. 2013 (PICCOLO)]
-|1997-2004
+|2006-2008
-|style="background-color:#1a9851"|Phase 3 (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Ifosfamide_.26_Paclitaxel|Ifosfamide & Paclitaxel]]
+|[[#Irinotecan_.26_Panitumumab_99|Irinotecan & Panitumumab]]
-|style="background-color:#fc8d59"|Seems to have inferior OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br>Median OS: 10.9 vs 10.4 mo<br>(HR 0.99, 95% CI 0.81-1.20)
 |-
 |}
-''Note: GOG 161 specifies that PO [[Mesna (Mesnex)]] is to be taken in 3 divided doses, but only lists 2 time points for its use. The timing of the middle dose is estimated based on other references.''
+''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.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*First-line fluoropyrimidine-based chemotherapy, with progression
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Ifosfamide (Ifex)]] 1600 mg/m<sup>2</sup> IV once per day on days 1 to 3
+*[[Irinotecan (Camptosar)]] 300 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-**Dosage for patients with previous radiation: 1200 mg/m<sup>2</sup> IV once per day on days 1 to 3
+'''21-day cycles'''
-====Supportive therapy====
+</div></div><br>
-*[[Mesna (Mesnex)]] 2000 mg IV over 12 hours once per day on days 1 to 3, starting 15 minutes before [[Ifosfamide (Ifex)]] (total dose per cycle: 6000 mg/m<sup>2</sup>)
-**Alternate PO dosing: 1330 mg PO three times per day on days 1 to 3, taken 1 hour before, 4 hours after, and 8 hours after [[Ifosfamide (Ifex)]] (total dose per cycle: 11,970 mg)
-*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 4, to continue until ANC is greater than or equal to 2000/uL
-'''21-day cycle for 8 cycles'''
-</div></div>
-===References===
-# '''GOG 108:''' Sutton G, Brunetto VL, Kilgore L, Soper JT, McGehee R, Olt G, Lentz SS, Sorosky J, Hsiu JG. A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group study. Gynecol Oncol. 2000 Nov;79(2):147-53. [https://www.gynecologiconcology-online.net/article/S0090-8258(00)96001-3/pdf link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11063636 PubMed]
-# '''GOG 161:''' Homesley HD, Filiaci V, Markman M, Bitterman P, Eaton L, Kilgore LC, Monk BJ, Ueland FR; Gynecologic Oncology Group. Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group study. J Clin Oncol. 2007 Feb 10;25(5):526-31. [https://doi.org/10.1200/jco.2006.06.4907 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17290061 PubMed] NCT00003128
-==Ifosfamide & Paclitaxel {{#subobject:824258|Regimen=1}}==
-PI: '''<u>P</u>'''aclitaxel & '''<u>I</u>'''fosfamide
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:d519c4|Variant=1}}===
+===Regimen variant #3, 350 mg/m<sup>2</sup> q3wk {{#subobject:627110|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 988: / Line 911: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2006.06.4907 Homesley et al. 2007 (GOG 161)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699713/ Seymour et al. 2013 (PICCOLO)]
-|1997-2004
+|2006-2008
-|style="background-color:#1a9851"|Phase 3 (E-esc)
-|[[#Ifosfamide_monotherapy|Ifosfamide]]
-|style="background-color:#91cf60"|Seems to have superior OS<br>Median OS: 13.5 vs 8.4 mo<br>(HR 0.69, 95% CI 0.49-0.97)
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8937015/ Powell et al. 2022 (GOG-0261)]
-|2009-2014
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Carboplatin_.26_Paclitaxel_.28CP.29_2|Carboplatin & Paclitaxel]]
+|1. [[#Irinotecan_.26_Cyclosporine_99|Irinotecan & Cyclosporine]]<br> 2. [[#Irinotecan_.26_Panitumumab_99|Irinotecan & Panitumumab]]
-| style="background-color:#eeee01" |Non-inferior OS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br>Median OS: 10.9 vs 10.4 mo<br>(HR 0.99, 95% CI 0.81-1.20)
 |-
 |}
-''Note: GOG 161 specifies that PO [[Mesna (Mesnex)]] is to be taken in 3 divided doses, but only lists 2 time points for its use. The timing of the middle dose is estimated based on other references. Treatment was given for 8 cycles in GOG 161.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*First-line fluoropyrimidine-based chemotherapy, with progression
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Ifosfamide (Ifex)]] by the following criteria:
+*[[Irinotecan (Camptosar)]] 350 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-**No previous radiation: 1600 mg/m<sup>2</sup> IV once per day on days 1 to 3
-**Previous radiation: 1200 mg/m<sup>2</sup> IV once per day on days 1 to 3
-*[[Paclitaxel (Taxol)]] 135 mg/m<sup>2</sup> IV over 3 hours once on day 1
 ====Supportive therapy====
-Per GOG 161:
+*(varied depending on reference):
-*[[Mesna (Mesnex)]] 2000 mg IV over 12 hours once per day on days 1 to 3, starting 15 minutes before [[Ifosfamide (Ifex)]] (total dose per cycle: 6000 mg/m<sup>2</sup>)
+*"Standard regimens of [[:Category:Emesis_prevention|antiemetics]], [[Atropine (Atropen)]], and intensive [[Loperamide (Imodium)]]," but no prophylactic [[Atropine (Atropen)]] allowed on cycle 1 day 1
-**Alternate PO dosing: 1330 mg PO three times per day on days 1 to 3, taken 1 hour before, 4 hours after, and 8 hours after [[Ifosfamide (Ifex)]] (total dose per cycle: 11,970 mg)
+'''21-day cycles'''
-*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 4, to continue until ANC is greater than or equal to 2000/uL
-*[[Dexamethasone (Decadron)]] 20 mg IV or PO for two doses on day 1; 12 and 6 hours prior to [[Paclitaxel (Taxol)]]
-*[[Diphenhydramine (Benadryl)]] 50 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]
-*One of the following H2 blockers:
-**[[Cimetidine (Tagamet)]] 300 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]
-**[[Ranitidine (Zantac)]] 50 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]
-'''21-day cycle for 6 to 10 cycles'''
 </div></div>
 ===References===
-# '''GOG 161:''' Homesley HD, Filiaci V, Markman M, Bitterman P, Eaton L, Kilgore LC, Monk BJ, Ueland FR; Gynecologic Oncology Group. Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group study. J Clin Oncol. 2007 Feb 10;25(5):526-31. [https://doi.org/10.1200/jco.2006.06.4907 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17290061 PubMed] NCT00003128
+#'''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] NCT00389870
-# '''GOG-0261:''' Powell MA, Filiaci VL, Hensley ML, Huang HQ, Moore KN, Tewari KS, Copeland LJ, Secord AA, Mutch DG, Santin A, Warshal DP, Spirtos NM, DiSilvestro PA, Ioffe OB, Miller DS. Randomized Phase III Trial of Paclitaxel and Carboplatin Versus Paclitaxel and Ifosfamide in Patients With Carcinosarcoma of the Uterus or Ovary: An NRG Oncology Trial. J Clin Oncol. 2022 Mar 20;40(9):968-977. Epub 2022 Jan 10. [https://doi.org/10.1200/jco.21.02050 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8937015/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35007153/ PubMed] NCT00954174
+#'''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] NCT01550055
-==Lenvatinib & Pembrolizumab {{#subobject:cffdf6|Regimen=1}}==
+==Irinotecan & Cetuximab {{#subobject:c912ee|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:a27gua|Variant=1}}===
+===Regimen {{#subobject:b7315f|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 1,033: / Line 943: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1016/S1470-2045(19)30020-8 Makker et al. 2019 (KEYNOTE-146)]
+|[https://doi.org/10.1200/jco.2007.13.1193 Sobrero et al. 2008 (EPIC)]
-|2015-2017
+|2003-2006
-|style="background-color:#91cf61"|Phase 2 (RT)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-| style="background-color:#d3d3d3" |
+|[[Colon_cancer#Irinotecan_monotherapy_2|Irinotecan]]
-| style="background-color:#d3d3d3" |
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://doi.org/10.1056/nejmoa2108330 Makker et al. 2022 (KEYNOTE-775)]
-|2018-2020
-|style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc)
-|1. [[#Doxorubicin_monotherapy|Doxorubicin]]<br>2. [[#Paclitaxel_monotherapy|Paclitaxel]]
-| style="background-color:#1a9850" |Superior OS<sup>1</sup><br>Median OS: 18.3 vs 11.4 mo<br>(HR 0.62, 95% CI 0.51-0.75)
 |-
 |}
-''<sup>1</sup>Reported efficacy is for the overall population.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*First-line fluoropyrimidine and oxaliplatin treatment, with progression or discontinuation due to toxicity
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Irinotecan (Camptosar)]] 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====
-*[[Lenvatinib (Lenvima)]] 20 mg PO once per day
+*[[Cetuximab (Erbitux)]] as follows:
-====Immunotherapy====
+**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
-*[[Pembrolizumab (Keytruda)]] as follows:
+**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15
-**Cycle 1 up to 35: 200 mg IV over 30 minutes once on day 1
+====Supportive therapy====
+*[[:Category:Antihistamines|Antihistamine]] prior to at least the first infusion of [[Cetuximab (Erbitux)]]
 '''21-day cycles'''
 </div></div>
 ===References===
-# '''KEYNOTE-146:''' Makker V, Rasco D, Vogelzang NJ, Brose MS, Cohn AL, Mier J, Di Simone C, Hyman DM, Stepan DE, Dutcus CE, Schmidt EV, Guo M, Sachdev P, Shumaker R, Aghajanian C, Taylor M. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019 May;20(5):711-718. Epub 2019 Mar 25. [https://doi.org/10.1016/S1470-2045(19)30020-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30922731 PubMed] NCT02501096
+<!-- 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. -->
-##'''Update:''' Makker V, Taylor MH, Aghajanian C, Oaknin A, Mier J, Cohn AL, Romeo M, Bratos R, Brose MS, DiSimone C, Messing M, Stepan DE, Dutcus CE, Wu J, Schmidt EV, Orlowski R, Sachdev P, Shumaker R, Casado Herraez A. Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer. J Clin Oncol. 2020 Sep 10;38(26):2981-2992. Epub 2020 Mar 13. [https://doi.org/10.1200/jco.19.02627 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7479759/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32167863/ PubMed]
+#'''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] NCT00063141
-# '''KEYNOTE-775:''' Makker V, Colombo N, Casado Herráez A, Santin AD, Colomba E, Miller DS, Fujiwara K, Pignata S, Baron-Hay S, Ray-Coquard I, Shapira-Frommer R, Ushijima K, Sakata J, Yonemori K, Kim YM, Guerra EM, Sanli UA, McCormack MM, Smith AD, Keefe S, Bird S, Dutta L, Orlowski RJ, Lorusso D; Study 309–KEYNOTE-775 Investigators. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022 Feb 3;386(5):437-448. Epub 2022 Jan 19. [https://doi.org/10.1056/nejmoa2108330 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35045221/ PubMed] NCT03517449
+=Advanced or metastatic disease, subsequent lines of therapy=
-==Paclitaxel monotherapy {{#subobject:ceedf6|Regimen=1}}==
+==Cetuximab monotherapy {{#subobject:a41ec2|Regimen=1}}==
+===Example orders===
+*[[Example orders for Cetuximab (Erbitux) in colon cancer]]
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 80 mg/m<sup>2</sup> {{#subobject:f1676a|Variant=1}}===
+===Regimen variant #1, weekly {{#subobject:e4f241|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+{| class="wikitable" style="color:white; background-color:#404040"
-!style="width: 20%"|Study
+|<small>'''FDA-recommended dose'''</small>
-!style="width: 20%"|Years 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/10.1056/nejmoa2108330 Makker et al. 2022 (KEYNOTE-775)]
-|2018-2020
-|style="background-color:#1a9851"|Phase 3 (C)
-|[[#Lenvatinib_.26_Pembrolizumab|Lenvatinib & Pembrolizumab]]
-| style="background-color:#d73027" |Inferior OS
 |-
 |}
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
-<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
-*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15
-'''28-day cycles'''
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 175 mg/m<sup>2</sup> {{#subobject:f1656b|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 1,091: / Line 986: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1093/oxfordjournals.annonc.a010768 Lissoni et al. 1996]
+|[https://doi.org/10.1200/JCO.2004.10.182 Saltz et al. 2004]
-|1993-1995
+|2001
-|style="background-color:#91cf61"|Phase 2
+| style="background-color:#91cf61" |Phase 2 (RT)
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
-|[http://www.gynecologiconcology-online.net/article/S0090-8258(02)00068-9 Lincoln et al. 2003]
+|[https://doi.org/10.1056/NEJMoa033025 Cunningham et al. 2004 (BOND)]
-|1994-1996
+|2001-2002
-|style="background-color:#91cf61"|Phase 2
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Irinotecan_.26_Cetuximab_2|Irinotecan & Cetuximab]]
+| style="background-color:#d73027" |Inferior TTP
+|-
+|[https://doi.org/10.1200/jco.2006.06.7595 Lenz et al. 2006 (SALVAGE)]
+|NR
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
-|[https://www.gynecologiconcology-online.net/article/S0090-8258(15)00855-0 McMeekin et al. 2015 (IXAMPLE2)]
+|[https://doi.org/10.1056/NEJMoa071834 Jonker et al. 2007 (NCIC-CTG CO.17)]
-|2009-2012
+|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)
+|-
+|[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_77|Brivanib & Cetuximab]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|[https://doi.org/10.1016/S1470-2045(14)70118-4 Price et al. 2014 (ASPECCT)]
+|2010-2012
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Ixabepilone_monotherapy_99|Ixabepilone]]
+|[[#Panitumumab_monotherapy|Panitumumab]]
-| style="background-color:#91cf60" |Seems to have superior OS
+| style="background-color:#eeee01" |Non-inferior OS
 |-
 |}
-''Note: in Lincoln et al. 2003, this was the dosage for patients with previous pelvic radiation.''
+<div class="toccolours" style="background-color:#fdcdac">
+====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
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
+====Targeted therapy====
-*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
+*[[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 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22
 ====Supportive therapy====
-*[[Hydrocortisone (Cortef)]] 250 mg IV once on day 1; 60 minutes prior to [[Paclitaxel (Taxol)]]
+*Varies depending on reference
-*[[Chlorpheniramine (Chlor-Trimeton)]] 10 mg IM once on day 1; 60 minutes prior to [[Paclitaxel (Taxol)]]
+*[[:Category:Antihistamines|Antihistamine]] (such as [[Diphenhydramine (Benadryl)]] 50 mg IV) prior to at least the first infusion of [[Cetuximab (Erbitux)]]
-*[[Cimetidine (Tagamet)]] 300 mg IV once on day 1; 60 minutes prior to [[Paclitaxel (Taxol)]]
+'''28-day cycles'''
-'''21-day cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:a2c4fa|Variant=1}}===
+===Regimen variant #2, bi-weekly {{#subobject:315dde|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
+! style="width: 25%" |Study
-!style="width: 33%"|Years of enrollment
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.gynecologiconcology-online.net/article/S0090-8258(96)90227-9 Ball et al. 1996]
+|[https://doi.org/10.1093/annonc/mdp549 Tabernero et al. 2009]
-|NR in abstract
+| style="background-color:#ffffbe" |Phase 1
-|style="background-color:#91cf61"|Phase 2
 |-
-|[http://www.gynecologiconcology-online.net/article/S0090-8258(02)00068-9 Lincoln et al. 2003]
+|}
-|1994-1996
+''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".''
-|style="background-color:#91cf61"|Phase 2
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Cetuximab (Erbitux)]] 500 mg/m<sup>2</sup> IV over 2 hours once on day 1
+**If tolerated, subsequent doses can be given over 1 hour
+====Supportive therapy====
+*[[:Category:Antihistamines|Antihistamine]] prior to [[Cetuximab (Erbitux)]]
+'''14-day cycles'''
+</div></div>
+===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. [https://doi.org/10.1200/JCO.2004.10.182 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14993230 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. [https://doi.org/10.1056/NEJMoa033025 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15269313 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. [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] 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] 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] 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]
+==Irinotecan & Cetuximab {{#subobject:5d7e80|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 125/250, irinotecan 2 weeks on, 1 week off {{#subobject:e734bb|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
 |-
 |}
-''Note: in Ball et al. 1996, this was the dosage for patients with previous pelvic radiation.''
+''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.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1
+*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 8
-**Ball et al. 1996 gave as a 24 hour continuous infusion
+====Targeted therapy====
-**Dose can be changed to 135 or 110 mg/m<sup>2</sup> depending on toxicity
+*[[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
+**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15
 ====Supportive therapy====
-*[[Dexamethasone (Decadron)]] 20 mg IV or PO for 2 doses on day 1; 12 and 6 hours prior to [[Paclitaxel (Taxol)]]
+*[[:Category:Antihistamines|Antihistamine]] prior to at least the first infusion of [[Cetuximab (Erbitux)]]
-*[[Diphenhydramine (Benadryl)]] 50 mg IV or PO once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]
-*[[Cimetidine (Tagamet)]] 300 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]
 '''21-day cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #4, 250 mg/m<sup>2</sup> {{#subobject:68d2e|Variant=1}}===
+===Regimen variant #2, 125/250, irinotecan 4 weeks on, 2 weeks off {{#subobject:a4d073|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
+{| class="wikitable" style="color:white; background-color:#404040"
-!style="width: 25%"|Study
+|<small>'''FDA-recommended dose'''</small>
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|}
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Years of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://www.gynecologiconcology-online.net/article/S0090-8258(96)90227-9 Ball et al. 1996]
+|[https://doi.org/10.1056/NEJMoa033025 Cunningham et al. 2004 (BOND)]
-|style="background-color:#91cf61"|Phase 2
+|2001-2002
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[#Cetuximab_monotherapy_2|Cetuximab]]
+| style="background-color:#1a9850" |Superior TTP
 |-
 |}
+''Note that the FDA-recommended dosing is for the cetuximab component; no comment is made about irinotecan dosing.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*BOND: Exposure to irinotecan-containing therapy, with progression
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Paclitaxel (Taxol)]] 250 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
+*[[Irinotecan (Camptosar)]] 125 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 8, 15, 22
-**Dosage for patients with previous pelvic radiation: 200 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
+====Targeted therapy====
-**Dose can be changed to 200, 170, 135, 110 mg/m<sup>2</sup> depending on toxicity
+*[[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, 29, 36
+**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36
 ====Supportive therapy====
-*[[Dexamethasone (Decadron)]] 20 mg IV or PO for 2 doses on day 1; 12 and 6 hours prior to [[Paclitaxel (Taxol)]]
+*[[:Category:Antihistamines|Antihistamine]] prior to at least the first infusion of [[Cetuximab (Erbitux)]]
-*[[Diphenhydramine (Benadryl)]] 50 mg IV or PO once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]
+'''42-day cycles'''
-*[[Cimetidine (Tagamet)]] 300 mg IV once on day 1; 30 minutes prior to [[Paclitaxel (Taxol)]]
+</div></div><br>
-*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 3, 24 hours after [[Paclitaxel (Taxol)]], continued for at least 12 days or until two successive total leukocyte counts are 10,000 or greater, whichever comes last
-'''21-day cycles'''
-</div></div>
-===References===
-# Ball HG, Blessing JA, Lentz SS, Mutch DG; Gynecologic Oncology Group. A phase II trial of paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol. 1996 Aug;62(2):278-81. [http://www.gynecologiconcology-online.net/article/S0090-8258(96)90227-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8751561 PubMed]
-# Lissoni A, Zanetta G, Losa G, Gabriele A, Parma G, Mangioni C. Phase II study of paclitaxel as salvage treatment in advanced endometrial cancer. Ann Oncol. 1996 Oct;7(8):861-3. [https://doi.org/10.1093/oxfordjournals.annonc.a010768 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8922203 PubMed]
-# Lincoln S, Blessing JA, Lee RB, Rocereto TF; Gynecologic Oncology Group. Activity of paclitaxel as second-line chemotherapy in endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2003 Mar;88(3):277-81. [http://www.gynecologiconcology-online.net/article/S0090-8258(02)00068-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12648575 PubMed]
-# '''IXAMPLE2:''' McMeekin S, Dizon D, Barter J, Scambia G, Manzyuk L, Lisyanskaya A, Oaknin A, Ringuette S, Mukhopadhyay P, Rosenberg J, Vergote I. Phase III randomized trial of second-line ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer. Gynecol Oncol. 2015 Jul;138(1):18-23. Epub 2015 Apr 26. [https://www.gynecologiconcology-online.net/article/S0090-8258(15)00855-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25925990 PubMed] NCT00883116
-# '''KEYNOTE-775:''' Makker V, Colombo N, Casado Herráez A, Santin AD, Colomba E, Miller DS, Fujiwara K, Pignata S, Baron-Hay S, Ray-Coquard I, Shapira-Frommer R, Ushijima K, Sakata J, Yonemori K, Kim YM, Guerra EM, Sanli UA, McCormack MM, Smith AD, Keefe S, Bird S, Dutta L, Orlowski RJ, Lorusso D; Study 309–KEYNOTE-775 Investigators. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022 Feb 3;386(5):437-448. Epub 2022 Jan 19. [https://doi.org/10.1056/nejmoa2108330 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35045221/ PubMed] NCT03517449
-==Pembrolizumab monotherapy {{#subobject:e0d17a|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, bi-weekly {{#subobject:87f9c7|Variant=1}}===
+===Regimen variant #3, 150/500, bi-weekly {{#subobject:c0c538|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
@@ Line 1,184: / Line 1,134: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481136/ Le et al. 2015 (KEYNOTE-016)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113428/ Osumi et al. 2018]
-|2013-2016
+|2011-2014
-| style="background-color:#ffffbe" |Phase 2, <20 pts of this subtype
+| style="background-color:#91cf61" |Phase 2
-|-
-|[https://doi.org/10.1200/JCO.2017.72.5952 Ott et al. 2017b (KEYNOTE-028)]
-|NR
-|style="background-color:#91cf61"|Phase 1b
 |-
 |}
-''Note: KEYNOTE-016 was an expansion to a CRC-specific trial.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*Exposure to fluoropyrimidine‐ and oxaliplatin‐based chemotherapy, with treatment failure
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Immunotherapy====
+====Chemotherapy====
-*[[Pembrolizumab (Keytruda)]] 10 mg/kg IV once on day 1
+*[[Irinotecan (Camptosar)]] 150 mg/m<sup>2</sup> IV once on day 1
-'''14-day cycle for up to 52 cycles (2 years)'''
+====Targeted therapy====
+*[[Cetuximab (Erbitux)]] 500 mg/m<sup>2</sup> IV over 2 hours once on day 1
+**Subsequent doses are given over 60 minutes
+====Supportive therapy====
+*[[:Category:Antihistamines|Antihistamine]] prior to [[Cetuximab (Erbitux)]]
+'''14-day cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, q3wk {{#subobject:87fj18|Variant=1}}===
+===Regimen variant #4, 180/250, bi-weekly, with response adaptation {{#subobject:7c9e16|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
@@ Line 1,206: / Line 1,160: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8887941/ O'Malley et al. 2022 (KEYNOTE-158)]
+|[https://doi.org/10.1200/JCO.2011.40.9243 Van Cutsem et al. 2012 (EVEREST)]
-|2016-2020
+|2004-2005
-|style="background-color:#91cf61"|Phase 2 (RT)
+| style="background-color:#91cf61" |Non-randomized portion of phase 1/2 RCT
 |-
 |}
 <div class="toccolours" style="background-color:#fdcdac">
-====Biomarker eligibility criteria====
+====Prior treatment criteria====
-*Cohort K: MSI-H/dMMR endometrial cancer
+*Exposure to irinotecan-containing chemotherapy
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Immunotherapy====
+====Chemotherapy====
-*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
+*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15
-'''21-day cycle for up to 35 cycles (2 years)'''
-</div></div>
-===References===
-# '''KEYNOTE-028:''' Ott PA, Bang YJ, Berton-Rigaud D, Elez E, Pishvaian MJ, Rugo HS, Puzanov I, Mehnert JM, Aung KL, Lopez J, Carrigan M, Saraf S, Chen M, Soria JC. Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer: results from the KEYNOTE-028 study. J Clin Oncol. 2017 Aug 1;35(22):2535-2541. Epub 2017 May 10. [https://doi.org/10.1200/JCO.2017.72.5952 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28489510 PubMed] NCT02054806
-# '''KEYNOTE-016:''' Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20. Epub 2015 May 30. [https://doi.org/10.1056/NEJMoa1500596 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481136/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26028255 PubMed] NCT01876511
-## '''Update:''' Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413. Epub 2017 Jun 8. [http://science.sciencemag.org/content/357/6349/409.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576142/ link to PMC article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/28596308 PubMed]
-# '''KEYNOTE-158:''' O'Malley DM, Bariani GM, Cassier PA, Marabelle A, Hansen AR, De Jesus Acosta A, Miller WH Jr, Safra T, Italiano A, Mileshkin L, Xu L, Jin F, Norwood K, Maio M. Pembrolizumab in Patients With Microsatellite Instability-High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study. J Clin Oncol. 2022 Mar 1;40(7):752-761. Epub 2022 Jan 6. [https://doi.org/10.1200/jco.21.01874 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8887941/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34990208/ PubMed] NCT02628067
-==Temsirolimus monotherapy {{#subobject:c19c6|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:53c722|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158598/ Oza et al. 2011 (NCIC IND.160)]
-|style="background-color:#91cf61"|Phase 2
-|-
-|}
-<div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
-*[[Temsirolimus (Torisel)]] 25 mg IV over 30 minutes once per day on days 1, 8, 15, 22
+*[[Cetuximab (Erbitux)]] 400 mg/m<sup>2</sup> IV once on day 1, then 250 mg/m<sup>2</sup> IV once per day on days 8 & 15
-'''28-day cycles'''
+'''21-day course'''
-</div></div>
+</div>
-===References===
+<div class="toccolours" style="background-color:#cbd5e7">
-# '''NCIC IND.160:''' Oza AM, Elit L, Tsao MS, Kamel-Reid S, Biagi J, Provencher DM, Gotlieb WH, Hoskins PJ, Ghatage P, Tonkin KS, Mackay HJ, Mazurka J, Sederias J, Ivy P, Dancey JE, Eisenhauer EA; NCIC Clinical Trials Group. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011 Aug 20;29(24):3278-85. Epub 2011 Jul 25. [https://doi.org/10.1200/jco.2010.34.1578 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158598/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21788564 PubMed] NCT00072176
+====Subsequent treatment====
-==Topotecan monotherapy {{#subobject:9a02a0|Regimen=1}}==
+*EVEREST, grade 0 or 1 skin reaction: Continue standard dose versus escalate dose of cetuximab to 500 mg/m<sup>2</sup>
+*EVEREST, grade 2 or worse skin reaction: Continue standard dose
+</div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:1c2f98|Variant=1}}===
+===Regimen variant #5, 180/500, bi-weekly {{#subobject:3062ba|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 33%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|Years of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/jco.2003.12.093 Wadler et al. 2003 (ECOG E3E93)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2527794/ Martín-Martorell et al. 2008]
-|style="background-color:#91cf61"|Phase 2
+|2005-2007
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*One previous line of chemotherapy
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Topotecan (Hycamtin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1 to 5
+*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 minutes once on day 1
-**Dosage for patients with previous pelvic radiation: 1.2 mg/m<sup>2</sup>, which can be increased to the 1.5 mg/m<sup>2</sup> dose in later cycles if there are no toxicities higher than grade 1
+====Targeted therapy====
-'''21-day cycles'''
+*[[Cetuximab (Erbitux)]] 500 mg/m<sup>2</sup> IV over 2 hours once on day 1
-</div></div>
+**If tolerated, subsequent doses can be given over 1 hour
-===References===
+====Supportive therapy====
-# '''ECOG E3E93:''' Wadler S, Levy DE, Lincoln ST, Soori GS, Schink JC, Goldberg G. Topotecan is an active agent in the first-line treatment of metastatic or recurrent endometrial carcinoma: Eastern Cooperative Oncology Group Study E3E93. J Clin Oncol. 2003 Jun 1;21(11):2110-4. [https://doi.org/10.1200/jco.2003.12.093 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12775736 PubMed]
+*[[:Category:Antihistamines|Antihistamine]] prior to [[Cetuximab (Erbitux)]]
-=Endocrine therapy for advanced, recurrent, or metastatic disease=
+*[[Dexamethasone (Decadron)]] & [[Ondansetron (Zofran)]] prior to [[Irinotecan (Camptosar)]]
-==Anastrozole monotherapy {{#subobject:534a|Regimen=1}}==
+'''14-day cycles'''
+</div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:8c4e67|Variant=1}}===
+===Regimen variant #6, 350/250, q3wk irinotecan {{#subobject:ada904|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
+{| class="wikitable" style="color:white; background-color:#404040"
-!style="width: 25%"|Study
+|<small>'''FDA-recommended dose'''</small>
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.gynecologiconcology-online.net/article/S0090-8258(00)95865-7 Rose et al. 2000]
-|style="background-color:#91cf61"|Phase 2
 |-
 |}
-<div class="toccolours" style="background-color:#b3e2cd">
-====Endocrine therapy====
-*[[Anastrozole (Arimidex)]] 1 mg PO once per day
-'''Continued indefinitely'''
-</div></div>
-===References===
-# Rose PG, Brunetto VL, VanLe L, Bell J, Walker JL, Lee RB; Gynecologic Oncology Group. A phase II trial of anastrozole in advanced recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2000 Aug;78(2):212-6. [http://www.gynecologiconcology-online.net/article/S0090-8258(00)95865-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10926805 PubMed]
-==Medroxyprogesterone monotherapy {{#subobject:6c7bb9|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:8b5e67|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 1,291: / Line 1,221: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1056/NEJM196102022640503 Kelley & Baker 1961]
+|[https://doi.org/10.1056/NEJMoa033025 Cunningham et al. 2004 (BOND)]
-|1950-1959
+|2001-2002
-| style="background-color:#91cf61" |Non-randomized
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-| style="background-color:#d3d3d3" |
+|[[#Cetuximab_monotherapy_2|Cetuximab]]
-| style="background-color:#d3d3d3" |
+| style="background-color:#1a9850" |Superior TTP
-|-
-|[https://doi.org/10.1200/jco.1999.17.6.1736 Thigpen et al. 1999]
-|1985-1989
-|style="background-color:#1a9851"|Phase 3 (C)
-|[[#Medroxyprogesterone_monotherapy|Medroxyprogesterone]]; high-dose
-|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR
 |-
 |}
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. Kelley & Baker 1961 examined a variety of progestins and is included for historic interest.''
+''Note that the FDA-recommended dosing is for the cetuximab component; no comment is made about irinotecan dosing.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*BOND: Exposure to irinotecan-containing therapy, with progression
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Endocrine therapy====
+====Chemotherapy====
-*[[Medroxyprogesterone (MPA)]] 200 mg PO once per day
+*[[Irinotecan (Camptosar)]] 350 mg/m<sup>2</sup> IV over 90 minutes once on day 1
-'''Continued indefinitely'''
+**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
-</div></div>
+====Targeted therapy====
-===References===
+*[[Cetuximab (Erbitux)]] as follows:
-# Kelley RM, Baker WH. Progestational agents in the treatment of carcinoma of the endometrium. N Engl J Med. 1961 Feb 2;264:216-22. [https://doi.org/10.1056/NEJM196102022640503 link to original article] [https://pubmed.ncbi.nlm.nih.gov/13752346 PubMed]
+**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
-# Thigpen JT, Brady MF, Alvarez RD, Adelson MD, Homesley HD, Manetta A, Soper JT, Given FT; Gynecologic Oncology Group. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group. J Clin Oncol. 1999 Jun;17(6):1736-44. [https://doi.org/10.1200/jco.1999.17.6.1736 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10561210 PubMed]
+**Cycle 2 onwards: 250 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15
-==Medroxyprogesterone & Tamoxifen {{#subobject:60584d|Regimen=1}}==
+====Supportive therapy====
-<div class="toccolours" style="background-color:#eeeeee">
+*[[:Category:Antihistamines|Antihistamine]] prior to at least the first infusion of [[Cetuximab (Erbitux)]]
-===Regimen {{#subobject:334b8c|Variant=1}}===
+'''21-day cycles'''
-{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.gynecologiconcology-online.net/article/S0090-8258(03)00651-6 Whitney et al. 2004]
-|style="background-color:#91cf61"|Phase 2
-|-
-|}
-<div class="toccolours" style="background-color:#b3e2cd">
-====Endocrine therapy====
-*[[Medroxyprogesterone (MPA)]] 100 mg PO twice per day on even-numbered weeks (for example, week 2, 4, 6, etc.)
-*[[Tamoxifen (Nolvadex)]] 20 mg PO twice per day
-'''Continued indefinitely'''
-</div></div>
-===References===
-# Whitney CW, Brunetto VL, Zaino RJ, Lentz SS, Sorosky J, Armstrong DK, Lee RB; Gynecologic Oncology Group. Phase II study of medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2004 Jan;92(1):4-9. [http://www.gynecologiconcology-online.net/article/S0090-8258(03)00651-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14751130 PubMed]
-==Megestrol monotherapy {{#subobject:4b50ea|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:52dc53|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years 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/10.1056/NEJM196102022640503 Kelley & Baker 1961]
-|1950-1959
-| style="background-color:#91cf61" |Non-randomized
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[http://journals.lww.com/amjclinicaloncology/Fulltext/2001/02000/Megestrol_and_Tamoxifen_in_Patients_With_Advanced.7.aspx Pandya et al. 2001 (ECOG E4882)]
-|1982-1984
-|style="background-color:#1a9851"|Randomized Phase 2 (C)
-|[[#Megestrol_.26_Tamoxifen|Megestrol & Tamoxifen]]
-|style="background-color:#ffffbf"|Did not meet efficacy endpoints
-|-
-|}
-''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. Kelley & Baker 1961 examined a variety of progestins and is included for historic interest.''
-<div class="toccolours" style="background-color:#b3e2cd">
-====Endocrine therapy====
-*[[Megestrol (Megace)]] 80 mg PO twice per day
-'''Continued indefinitely'''
 </div></div>
 ===References===
-# Kelley RM, Baker WH. Progestational agents in the treatment of carcinoma of the endometrium. N Engl J Med. 1961 Feb 2;264:216-22. [https://doi.org/10.1056/NEJM196102022640503 link to original article] [https://pubmed.ncbi.nlm.nih.gov/13752346 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. [https://doi.org/10.1056/NEJMoa033025 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15269313 PubMed]
-# '''ECOG E4882:''' Pandya KJ, Yeap BY, Weiner LM, Krook JE, Erban JK, Schinella RA, Davis TE. Megestrol and tamoxifen in patients with advanced endometrial cancer: an Eastern Cooperative Oncology Group Study (E4882). Am J Clin Oncol. 2001 Feb;24(1):43-6. [http://journals.lww.com/amjclinicaloncology/Fulltext/2001/02000/Megestrol_and_Tamoxifen_in_Patients_With_Advanced.7.aspx link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11232948 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. [https://doi.org/10.1038/sj.bjc.6604530 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2527794/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18665167 PubMed]
-==Megestrol & Tamoxifen {{#subobject:f03c30|Regimen=1}}==
+#'''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. [https://doi.org/10.1200/JCO.2011.40.9243 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22753904 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. [https://doi.org/full/10.1111/cas.13698 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113428/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29908105 PubMed] UMIN000019893
+==Panitumumab monotherapy {{#subobject:5a3eb5|Regimen=1}}==
+===Example orders===
+*[[Example orders for Panitumumab (Vectibix) in colon cancer]]
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:4e79f7|Variant=1}}===
+===Regimen {{#subobject:fa978e|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 1,374: / Line 1,262: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://journals.lww.com/amjclinicaloncology/Fulltext/2001/02000/Megestrol_and_Tamoxifen_in_Patients_With_Advanced.7.aspx Pandya et al. 2001 (ECOG E4882)]
+|[https://doi.org/10.1200/jco.2006.08.1620 Van Cutsem et al. 2007 (20020408)]
-|1982-1984
+|2004-2005
-|style="background-color:#1a9851"|Randomized Phase 2 (E-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|[[#Megestrol_monotherapy|Megestrol]]
+|[[Colon_cancer_-_null_regimens#Best_supportive_care_2|Best supportive care]]
-|style="background-color:#ffffbf"|Did not meet primary efficacy endpoints
+| style="background-color:#1a9850" |Superior PFS<br>Median PFS: 8 vs 7.3 wks<br>(HR 0.54, 95% CI 0.44-0.66)
 |-
-|[http://www.gynecologiconcology-online.net/article/S0090-8258(03)00787-X Fiorica et al. 2004]
+|[https://doi.org/10.1016/S1470-2045(14)70118-4 Price et al. 2014 (ASPECCT)]
-|1994-1995
+|2010-2012
-| style="background-color:#91cf61" |Phase 2
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
-| style="background-color:#d3d3d3" |
+|[[#Cetuximab_monotherapy_2|Cetuximab]]
-| style="background-color:#d3d3d3" |
+| style="background-color:#eeee01" |Non-inferior OS
 |-
-|}
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104888/ Kim et al. 2016 (20100007)]
-<div class="toccolours" style="background-color:#b3e2cd">
+|2011-2013
-====Endocrine therapy, part 1====
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-*[[Megestrol (Megace)]] 80 mg PO twice per day
+|[[Colon_cancer_-_null_regimens#Best_supportive_care_2|Best supportive care]]
-'''21-day cycles, alternating with tamoxifen'''
+| 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)
-====Endocrine therapy, part 2====
-*[[Tamoxifen (Nolvadex)]] 20 mg PO twice per day
-'''21-day cycles, alternating with megestrol'''
-</div></div>
-===References===
-# '''ECOG E4882:''' Pandya KJ, Yeap BY, Weiner LM, Krook JE, Erban JK, Schinella RA, Davis TE. Megestrol and tamoxifen in patients with advanced endometrial cancer: an Eastern Cooperative Oncology Group Study (E4882). Am J Clin Oncol. 2001 Feb;24(1):43-6. [http://journals.lww.com/amjclinicaloncology/Fulltext/2001/02000/Megestrol_and_Tamoxifen_in_Patients_With_Advanced.7.aspx link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11232948 PubMed]
-# Fiorica JV, Brunetto VL, Hanjani P, Lentz SS, Mannel R, Andersen W; Gynecologic Oncology Group. Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2004 Jan;92(1):10-4. [http://www.gynecologiconcology-online.net/article/S0090-8258(03)00787-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14751131 PubMed]
-==Tamoxifen monotherapy {{#subobject:ab84a1|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:af71e3|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.gynecologiconcology-online.net/article/0090-8258(89)90839-1/pdf Quinn et al. 1989]
-|style="background-color:#91cf61"|Phase 2
-|-
-|[https://doi.org/10.1200/jco.2001.19.2.364 Thigpen et al. 2001 (GOG-81F)]
-|style="background-color:#91cf61"|Phase 2
 |-
 |}
+''<sup>1</sup>Reported efficacy for 20100007 is based on the 2018 update.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*20020408 & 20100007: Exposure to irinotecan, oxaliplatin, and a fluoropyrimidine
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Endocrine therapy====
+====Targeted therapy====
-*[[Tamoxifen (Nolvadex)]] 20 mg PO twice per day
+*[[Panitumumab (Vectibix)]] 6 mg/kg IV over 60 minutes once on day 1
-'''Continued indefinitely'''
+'''14-day cycles'''
 </div></div>
 ===References===
-# Quinn MA, Campbell JJ. Tamoxifen therapy in advanced/recurrent endometrial carcinoma. Gynecol Oncol. 1989 Jan;32(1):1-3. [http://www.gynecologiconcology-online.net/article/0090-8258(89)90839-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/2909443 PubMed]
+<!-- Presented at the 97th Annual Meeting of the American Association for Cancer Research, April 1-5, 2006, Washington, DC; 2nd Annual Conference of the Hematology/Oncology Pharmacy Association, June 15-18, 2006, Orlando, FL; 8th Annual Conference of the World Congress on Gastrointestinal Cancer, June 28-July 1, 2006, Barcelona, Spain; and at the 31st European Society of Medical Oncology Congress, September 29-October 3, 2006, Istanbul, Turkey. -->
-# '''GOG-81F:''' Thigpen T, Brady MF, Homesley HD, Soper JT, Bell J. Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2001 Jan 15;19(2):364-7. [https://doi.org/10.1200/jco.2001.19.2.364 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11208827 PubMed]
+#'''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] NCT00113763
-[[Category:Endometrial cancer regimens]]
+#'''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] NCT01001377
-[[Category:Disease-specific pages]]
+##'''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]
-[[Category:Gynecologic cancers]]
+#'''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] 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://www.clinical-colorectal-cancer.com/article/S1533-0028(17)30529-7 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 "Endometrial cancer"

Revision as of 01:06, 14 October 2022

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 & Bevacizumab

Regimen

Chemotherapy

Targeted therapy

References

FOLFIRI & Cetuximab

Regimen

Biomarker eligibility criteria

Chemotherapy

Targeted therapy

References

FOLFIRI & Cetuximab (L-Leucovorin)

Regimen

Biomarker eligibility criteria

Chemotherapy

Targeted therapy

References

FOLFOX4

Regimen

Chemotherapy

References

FOLFOX4 & Cetuximab

Regimen

Biomarker eligibility criteria

Chemotherapy

Targeted therapy

References

FOLFOX4 & Panitumumab

Regimen

Biomarker eligibility criteria

Chemotherapy

Targeted therapy

References

mFOLFOX6-B

Regimen

Chemotherapy

Targeted therapy

Regimen variant #1, 250 mg/m² weekly

Regimen variant #2, 500 mg/m² q2wk

Regimen variant #1, 180 mg/m² q2wk

Regimen variant #2, 300 mg/m² q3wk

Regimen variant #3, 350 mg/m² q3wk