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Does the cyclooxygenase 2 inhibitor celecoxib, when added to standard adjuvant chemotherapy, improve disease-free survival among patients with stage III colon cancer?
In this randomized clinical trial that involved 2526 patients, the addition of celecoxib for 3 years, compared with placebo, to standard adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) did not significantly improve disease-free survival (76.3% vs 73.4% at 3 years; hazard ratio for disease recurrence or death, 0.89).
Among patients with stage III colon cancer, the addition of celecoxib, compared with placebo, to standard adjuvant chemotherapy did not significantly improve disease-free survival.
Aspirin and cyclooxygenase 2 (COX-2) inhibitors have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies. The effect of celecoxib, a COX-2 inhibitor, as treatment for nonmetastatic colon cancer is unknown.
To determine if the addition of celecoxib to adjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) improves disease-free survival in patients with stage III colon cancer.
Design, Setting, and Participants
Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group 80702 was a 2 × 2 factorial design, phase 3 trial conducted at 654 community and academic centers throughout the United States and Canada. A total of 2526 patients with stage III colon cancer were enrolled between June 2010 and November 2015 and were followed up through August 10, 2020.
Patients were randomized to receive adjuvant FOLFOX (every 2 weeks) for 3 vs 6 months with or without 3 years of celecoxib (400 mg orally daily; n = 1263) vs placebo (n = 1261). This report focuses on the results of the celecoxib randomization.
Main Outcomes and Measures
The primary end point was disease-free survival, measured from the time of randomization until documented recurrence or death from any cause. Secondary end points included overall survival, adverse events, and cardiovascular-specific events.
Of the 2526 patients who were randomized (mean [SD] age, 61.0 years [11 years]; 1134 women [44.9%]), 2524 were included in the primary analysis. Adherence with protocol treatment, defined as receiving celecoxib or placebo for more than 2.75 years or continuing treatment until recurrence, death, or unacceptable adverse events, was 70.8% for patients treated with celecoxib and 69.9% for patients treated with placebo. A total of 337 patients randomized to celecoxib and 363 to placebo experienced disease recurrence or died, and with 6 years’ median follow-up, the 3-year disease-free survival was 76.3% for celecoxib-treated patients vs 73.4% for placebo-treated patients (hazard ratio [HR] for disease recurrence or death, 0.89; 95% CI, 0.76-1.03; P = .12). The effect of celecoxib treatment on disease-free survival did not vary significantly according to assigned duration of adjuvant chemotherapy (P for interaction = .61). Five-year overall survival was 84.3% for celecoxib vs 81.6% for placebo (HR for death, 0.86; 95% CI, 0.72-1.04; P = .13). Hypertension (any grade) occurred while treated with FOLFOX in 14.6% of patients in the celecoxib group vs 10.9% of patients in the placebo group, and a grade 2 or higher increase in creatinine levels occurred after completion of FOLFOX in 1.7% vs 0.5% of patients, respectively.
Conclusions and Relevance
Among patients with stage III colon cancer, the addition of celecoxib for 3 years, compared with placebo, to standard adjuvant chemotherapy did not significantly improve disease-free survival.
ClinicalTrials.gov Identifier: NCT01150045
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Corresponding Author: Jeffrey A. Meyerhardt, MD, MPH, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215 (firstname.lastname@example.org).
Accepted for Publication: February 10, 2021.
Author Contributions: Drs Meyerhardt and Shi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Meyerhardt, Shi, Fuchs, Niedzwiecki, Kuebler, Bertagnolli, Grothey, Goldberg, Venook, Shields.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: All authors.
Statistical analysis: Shi, Meyers, Zemla, Guthrie.
Obtained funding: Fuchs, Bertagnolli, Blanke.
Administrative, technical, or material support: Meyerhardt, Fuchs, Kumthekar, Couture, Kuebler, Bendell, Kumar, Tan, Bertagnolli, Hochster, Goldberg, Blanke, O'Reilly, Shields.
Supervision: Meyerhardt, Fuchs, Niedzwiecki, Bertagnolli, Goldberg, Shields.
Conflict of Interest Disclosures: Dr Meyerhardt reported receiving personal fees from Taiho for grant review for the National Comprehensive Cancer Network, fees for serving on the advisory boards of COTA Healthcare and Ignyta Single, and institutional support from Boston Biomedical for a clinical trial outside the submitted work. Dr Shi reported receiving institutional grant support from Celgen–Bristol Myers Squibb and Roche/Genetech; serving as a consultant to Yiviva Inc and Boehringer Ingelheim Pharmaceuticals; and owning stock in Johnson & Johnson, Merck, and Amgen. Dr Fuchs reported receiving personal fees from Agios, Amylin Pharma, Bain Capital, CytomX Therapeutics, Daiichi-Sankyo, Eli Lilly, Entrinsic Health, Evolveimmune Therapeutics, Genentech, Merck, Taiho, Unum Therapeutics, and Astra-Zeneca; serving as a director for CytomX Therapeutics; owning unexercised stock options for CytomX and Entrinsic Health; being a cofounder of Evolveimmune Therapeutics; and serving as an expert witness for Amylin Pharmaceuticals and Eli Lilly. Dr Kumthekar reported receiving grants from Genentech and Novocure; serving as a consultant for Biocept and Angiochem, being on the advisory board of Orbus Therapeutics; and became an employee of Genetech after the trial’s conclusion. Dr Guthrie reported receiving grants from the National Cancer Institute. Dr Kuebler reported receiving grants from the Columbus National Community Oncology Research Program and the National Institutes of Cancer. Dr Bendell reported receiving institutional grants from Gilead, Genentech/Roche, Bristol Myers Squibb, Five Prime, Lilly Payment, Merck, MedImmune, Celgene, EMD Serono, Taiho, MacroGenics, GlaxoSmithKline, Novartis, OncoMed, LEAP, TG Therapeutics, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Bayer, Incyte, Apexigen, Koltan, SynDevRx, Forty Seven, AbbVie, Array, Onyx, Sanofi, Takeda, Eisai, Celldex, Agios, CytomX, Nektar, ARMO BioSciences, Boston Biomedical, Ipsen, Merrimack, Tarveda Therapeutics, Tyrogenex, OncoGenex, MEI Pharma, Pieris, Mersana, Cailthera Biosciences, Blueprint, Evelo, Forma Therapeutics, Merus, Jacobio, eFFECTOR, NovoCare, Arrys, Tracon, Sierra, Innate, ArchOncology, Prelude Theapeutics, Unum Therapeutics, Vyriad, Harpoon, ADC Therapeutics, Amgen, Pfizer, Millennium, Imclome, Acerta Pharma, Rgenix, Bellicum, Gossamer Bio, Arcus Bio, Seattle Genetics, Tempest Tx, Shattuck Labs, Synthorx Inc, Revolution Medicines, Bicycle Therapeutics, Zymeworks, Relay Therapeutics, AtlasMedx, Scholar Rock, NGM Biopharmaceuticals, Treadwell Therapeutics, IGM Biosciences, MabSpace, Repare Therapeutics, and NeolmmuneTech and other institutional support from Gilead, Genentech/Roche, Bristol Myers Squibb, Five Prime, Lilly, Merck, MedImmune, Celgene, Taiho, MacroGenics, GlaxoSmithKline, Novartis, OncoMed, LEAP, TG Therapeutics, AstraZenca, Boehringer Ingelheim, Daiichi Sankyo, Bayer, Incyte, Apexigen, Array, Sanofi, Agios, ARMO BioSciences, Ispen, OncoGenex, Merrimack, Evelo, Forma Therapeutics, Innate, ArchOncology, Prelude Therapeutics, Amgen, Pfizer, Seattle Genentics, Bicycle Therapeutics, Relay Therapeutics, Phoenix Bio, Cyteir, Molecular Partners, Torque, Tizona, Janssen, Translational Drug Development, Moderna Therapeutics, Tanabe Research Laboratories, Beigene, Continuum Clinical, Piper Biotech, Samsung Bioepios, and Fusion Therapeutics. Dr Bertagnolli reported receiving institutional funding from Pfizer. Dr Goldberg reported receiving grants from the National Cancer Institute to Alliance for the National Clinical Trials Network; travel fees from Amgen; and consulting fees from Taiho, Astra Zeneca, Merck, Novartis, and Genentech. Dr Venook reported receiving grants from the National Institutes of Health. Dr Blanke reported receiving grants from the National Cancer Institute during the conduct of the study. Dr O'Reilly reported receiving institutional grants from Genentech/Roche, Celgene/Bristol Myers Squibb, BioNTech, AstraZeneca, and Arcus; receiving personal fees from CytomX Therapeutics, Rafael Therapeutics, Sobi Consulting, and Synthorx Inc; nonfinancial support from Silenseed Consulting, consulting fees from Boehringer Ingelheim, BioNTech, Ipsen, and Merck; and his spouse receives consulting fees from Bayer, Genentech/Roche, Celgene/Bristol Myers Squibb, Eisai, and Polaris; and personal fees from Molecular Templates Consulting. Dr Shields reported receiving grants from National Cancer Institute. No other disclosures were reported.
Funding/Support: This study was supported by grants U10CA180821 and U10CA180882 to the Alliance for Clinical Trials in Oncology; U10CA180794, UG1CA233163, UG1CA233253,UG1CA233290, UG1CA233320, UG1CA233337, UG1CA233339, UG1CA189954, and U10CA180863 to the Canadian Cancer Trials Group; UG1CA233196, U10CA180820 to the Eastern Cooperative Oncology Group–Alliance for Clinical Trials in Oncology; U10CA180868 to NRG Oncology); and U10CA180888 to the Southwest Oncology Group from the National Cancer Institute of the National Institutes of Health. Also supported in part by funds from Pfizer; Dr Meyerhardt is supported by the Douglas Gray Woodruff Chair fund, the Guo Shu Shi Fund, Anonymous Family Fund for Innovations in Colorectal Cancer, and the George Stone Family Foundation.
Role of the Funder/Sponsor: The National Cancer Institute was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; review and approval of the manuscript; and decision to submit the manuscript for publication. Pfizer only participated in initial protocol development and review and approval of the final manuscript. Pfizer provided celecoxib and placebo tablets. Pfizer did not have involvement in collection, management, analysis, and interpretation of the data. Neither Pfizer nor the National Cancer Institute had neither the right to veto publication nor control the decision to which journal the article was submitted.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. https://acknowledgments.alliancefound.org.
Meeting Presentation: The initial results of this study were presented at the American Society of Clinical Oncology annual meeting; June 5-9, 2020, which was conducted virtually.
Data Sharing Statement: See Supplement 3.
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