Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: A randomized trial

Steven Robert Alberts, Daniel J. Sargent, Suresh Nair, Michelle R. Mahoney, Margaret Mooney, Stephen N Thibodeau, Thomas Christopher Smyrk, Frank A Sinicrope, Emily Chan, Sharlene Gill, Morton S. Kahlenberg, Anthony F. Shields, James T. Quesenberry, Thomas A. Webb, Gist H. Farr, Barbara A Pockaj, Axel F Grothey, Richard M. Goldberg

Research output: Contribution to journalArticle

302 Citations (Scopus)

Abstract

Context: Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer. Objective: To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wildtype KRAS colon cancer. Design, Setting, and Participants: A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS. A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a hazard ratio (HR) of 1.33 (2-sided α=.05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses. Main Outcome Measures: Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity. Results: Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98- 1.49; P=.08) in patients with wild-type KRAS, and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86-1.46; P=.38) in patients with mutated KRAS, with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1-2.8; P<.001) and failure to complete 12 cycles (33% vs 23%; OR, 1.6; 95% CI, 1.4-1.9; P<.001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older. Conclusion: Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival. Trial Registration: clinicaltrials.gov Identifier: NCT00079274.

Original languageEnglish (US)
Pages (from-to)1383-1393
Number of pages11
JournalJAMA - Journal of the American Medical Association
Volume307
Issue number13
DOIs
StatePublished - Mar 28 2012

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oxaliplatin
Leucovorin
Fluorouracil
Colonic Neoplasms
Survival
Disease-Free Survival
Cetuximab
Odds Ratio

ASJC Scopus subject areas

  • Medicine(all)

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Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer : A randomized trial. / Alberts, Steven Robert; Sargent, Daniel J.; Nair, Suresh; Mahoney, Michelle R.; Mooney, Margaret; Thibodeau, Stephen N; Smyrk, Thomas Christopher; Sinicrope, Frank A; Chan, Emily; Gill, Sharlene; Kahlenberg, Morton S.; Shields, Anthony F.; Quesenberry, James T.; Webb, Thomas A.; Farr, Gist H.; Pockaj, Barbara A; Grothey, Axel F; Goldberg, Richard M.

In: JAMA - Journal of the American Medical Association, Vol. 307, No. 13, 28.03.2012, p. 1383-1393.

Research output: Contribution to journalArticle

Alberts, SR, Sargent, DJ, Nair, S, Mahoney, MR, Mooney, M, Thibodeau, SN, Smyrk, TC, Sinicrope, FA, Chan, E, Gill, S, Kahlenberg, MS, Shields, AF, Quesenberry, JT, Webb, TA, Farr, GH, Pockaj, BA, Grothey, AF & Goldberg, RM 2012, 'Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: A randomized trial', JAMA - Journal of the American Medical Association, vol. 307, no. 13, pp. 1383-1393. https://doi.org/10.1001/jama.2012.385
Alberts, Steven Robert ; Sargent, Daniel J. ; Nair, Suresh ; Mahoney, Michelle R. ; Mooney, Margaret ; Thibodeau, Stephen N ; Smyrk, Thomas Christopher ; Sinicrope, Frank A ; Chan, Emily ; Gill, Sharlene ; Kahlenberg, Morton S. ; Shields, Anthony F. ; Quesenberry, James T. ; Webb, Thomas A. ; Farr, Gist H. ; Pockaj, Barbara A ; Grothey, Axel F ; Goldberg, Richard M. / Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer : A randomized trial. In: JAMA - Journal of the American Medical Association. 2012 ; Vol. 307, No. 13. pp. 1383-1393.
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abstract = "Context: Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer. Objective: To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wildtype KRAS colon cancer. Design, Setting, and Participants: A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48{\%} of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS. A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90{\%} power to detect a hazard ratio (HR) of 1.33 (2-sided α=.05), with planned interim efficacy analyses after 25{\%}, 50{\%}, and 75{\%} of expected relapses. Main Outcome Measures: Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity. Results: Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6{\%} vs 71.5{\%} with the addition of cetuximab (HR, 1.21; 95{\%} CI, 0.98- 1.49; P=.08) in patients with wild-type KRAS, and 67.1{\%} vs 65.0{\%} (HR, 1.12; 95{\%} CI, 0.86-1.46; P=.38) in patients with mutated KRAS, with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5{\%} vs 52.3{\%}; odds ratio [OR], 2.4; 95{\%} CI, 2.1-2.8; P<.001) and failure to complete 12 cycles (33{\%} vs 23{\%}; OR, 1.6; 95{\%} CI, 1.4-1.9; P<.001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older. Conclusion: Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival. Trial Registration: clinicaltrials.gov Identifier: NCT00079274.",
author = "Alberts, {Steven Robert} and Sargent, {Daniel J.} and Suresh Nair and Mahoney, {Michelle R.} and Margaret Mooney and Thibodeau, {Stephen N} and Smyrk, {Thomas Christopher} and Sinicrope, {Frank A} and Emily Chan and Sharlene Gill and Kahlenberg, {Morton S.} and Shields, {Anthony F.} and Quesenberry, {James T.} and Webb, {Thomas A.} and Farr, {Gist H.} and Pockaj, {Barbara A} and Grothey, {Axel F} and Goldberg, {Richard M.}",
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TY - JOUR

T1 - Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer

T2 - A randomized trial

AU - Alberts, Steven Robert

AU - Sargent, Daniel J.

AU - Nair, Suresh

AU - Mahoney, Michelle R.

AU - Mooney, Margaret

AU - Thibodeau, Stephen N

AU - Smyrk, Thomas Christopher

AU - Sinicrope, Frank A

AU - Chan, Emily

AU - Gill, Sharlene

AU - Kahlenberg, Morton S.

AU - Shields, Anthony F.

AU - Quesenberry, James T.

AU - Webb, Thomas A.

AU - Farr, Gist H.

AU - Pockaj, Barbara A

AU - Grothey, Axel F

AU - Goldberg, Richard M.

PY - 2012/3/28

Y1 - 2012/3/28

N2 - Context: Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer. Objective: To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wildtype KRAS colon cancer. Design, Setting, and Participants: A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS. A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a hazard ratio (HR) of 1.33 (2-sided α=.05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses. Main Outcome Measures: Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity. Results: Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98- 1.49; P=.08) in patients with wild-type KRAS, and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86-1.46; P=.38) in patients with mutated KRAS, with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1-2.8; P<.001) and failure to complete 12 cycles (33% vs 23%; OR, 1.6; 95% CI, 1.4-1.9; P<.001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older. Conclusion: Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival. Trial Registration: clinicaltrials.gov Identifier: NCT00079274.

AB - Context: Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer. Objective: To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wildtype KRAS colon cancer. Design, Setting, and Participants: A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS. A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a hazard ratio (HR) of 1.33 (2-sided α=.05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses. Main Outcome Measures: Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity. Results: Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98- 1.49; P=.08) in patients with wild-type KRAS, and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86-1.46; P=.38) in patients with mutated KRAS, with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1-2.8; P<.001) and failure to complete 12 cycles (33% vs 23%; OR, 1.6; 95% CI, 1.4-1.9; P<.001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older. Conclusion: Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival. Trial Registration: clinicaltrials.gov Identifier: NCT00079274.

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