Effect of Celecoxib vs Placebo Added to Standard Adjuvant Therapy on Disease-Free Survival Among Patients With Stage III Colon Cancer: The CALGB/SWOG 80702 (Alliance) Randomized Clinical Trial

Abstract

Importance: 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.

Objective: 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.

Interventions: 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.

Results: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT01150045.

Conflict of interest statement

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.

Figures

Figure 1.. Study Enrollment and Flow Through CALGB/SWOG 80702 (Alliance) Randomized Clinical Trial

aSites were not required to provide screening logs during the recruitment phase. Thus, the number of patients assessed for eligibility is not available.

Figure 2.. Patient Adherence With Celecoxib or Placebo

Sixty-six patients in the celecoxib and 63 patients in the placebo plus fluorouracil, leucovorin, and oxaliplatin (FOLFOX) groups dropped out of the study before they received either celecoxib or placebo.

Figure 3.. Disease-Free and Overall Survival by Celecoxib vs Placebo

A, Disease-free survival (cancer recurrence or death from any cause); 337 events were observed in the celecoxib group and 363 events in the placebo group. Median observation time for celecoxib was 4.1 years (interquartile range [IQR], 1.6-5.3 years) and for placebo was 4.0 years (IQR, 1.4-5.2 years). The 3-year disease-free survival rate was 76.3% (95% CI, 73.8%-78.8%) in the celecoxib group and 73.4% (95% CI, 70.8%-76.0%) in the placebo group. Median disease-free survival was not reached. B, Overall survival (death from any cause); 212 deaths occurred in the celecoxib group and 236 in the placebo group. Median observation time for celecoxib was 5.5 years (IQR, 4.0-6.1 years) and for placebo was 5.5 years (IQR, 3.8-6.0 years). The 5-year overall survival rate was 84.3% (95% CI, 82.2%-86.5%) in the celecoxib group and 81.6% (95% CI, 79.4%-83.9%) in the placebo group. Median overall survival was not reached.