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Can a COX-2 Inhibitor Boost Disease-free Survival in CRC?

— Large trial tested addition of the agent to standard FOLFOX

MedpageToday
A box of Celebrex (celecoxib) capsules over a computer rendering of colon cancer

In patients with stage III colon cancer, 3 years of add-on celecoxib (Celebrex) during standard adjuvant chemotherapy did not significantly improve disease-free survival (DFS) or overall survival (OS) versus placebo, a large 2×2 factorial randomized trial showed.

With a median 6 years of follow-up, the 3-year DFS rate was 76.3% in patients treated with the selective cyclooxygenase-2 (COX-2) inhibitor versus 73.4% in placebo-treated patients, translating to an HR for disease recurrence or death of 0.89 (95% CI 0.76-1.03, P=0.12), reported Jeffrey A. Meyerhardt, MD, MPH, of Dana-Farber Cancer Institute in Boston, and colleagues.

As shown in their study online in , celecoxib treatment also did not have a significant effect on DFS according to the assigned duration of 3 or 6 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX), with P for interaction of 0.6.

The 2,526-patient Phase III found a similar 5-year OS rate in both arms: 84.3% for celecoxib versus 81.6% for placebo, with an HR for death of 0.86 (95% CI 0.72-1.04, P=0.13).

The use of celecoxib did, however, significantly increase the risk of hypertension of any grade during FOLFOX treatment, affecting 14.6% of the celecoxib group versus 10.9% of the placebo group. Celecoxib also increased the risk of a grade 2 or higher elevation in creatinine levels after completion of FOLFOX, in 1.7% and 0.5% of the two arms patients, respectively.

Patients were enrolled at 654 centers in the U.S. and Canada from June 2010 to November 2015 and followed through August 2020. The mean age of participants was 61 (standard deviation 11 years), and 44.9% were women. Participants were assigned to receive adjuvant FOLFOX every 2 weeks for either 3 or 6 months with or without 3 years of celecoxib 400 mg orally daily (1,263 patients) versus placebo (1,261 patients).

Of the 2,524 patients available for the primary analysis, 337 and 363 in the celecoxib and placebo arms, respectively, had recurrent disease or died, the researchers reported.

They noted that the results were at odds with findings from previous observational studies suggesting that colorectal cancer (CRC) patients who take aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) have a of recurrent disease and cancer death. In the Seattle Colon Cancer Family Registry, for example, NSAID usage before diagnosis was associated with a of CRC mortality following diagnosis compared with never use.

Similarly, another found that regular usage of aspirin after diagnosis was associated with a 35% lower risk in CRC-specific mortality in the Nurses' Health Study. And in an adjuvant therapy trial, researchers found that consistent users of aspirin had significant improvement in recurrence-free survival: 83.1% at 5 years versus 74.9% for nonusers, with an HR for recurrence of 0.5 (95% CI 0.28-0.95).

The reasons for the discordance between previous observational studies and the results of the current trial are unclear, Meyerhardt and co-authors stated: "In this trial, a selective COX-2 inhibitor was used. Although COX-2–dependent pathways are associated with antineoplastic effects of NSAIDs, it is plausible that COX-2–independent pathways are critical and affected by aspirin more effectively than by celecoxib."

The team noted that several adjuvant CRC trials using aspirin in this setting are ongoing.

Limitations of their study, the investigators said, included that 29.6% of patients discontinued celecoxib or placebo before recurrence, an adverse event, or completion of 3 years of therapy; that the trial design did not incorporate biomarker-directed patient selection; that the original statistical assumptions of the trial presupposed faster enrollment and more events than occurred, which required an adjustment to power that could increase the potential for a false-negative result; and that the population was limited to stage III patients already receiving adjuvant chemotherapy, and it is unknown if any benefit at an earlier stage of disease, including disease not treated with chemotherapy, would have emerged.

Writing in an , David J. Kerr, MD, DSc, of the University of Oxford, and colleagues said the trial contributes important data on survival with the use of COX-2 inhibitors for patients after resection of stage III colon cancer. "The authors planned retrospective analyses and the analyses performed using samples gleaned from the ongoing aspirin studies may be helpful to define and may refine any potential role of aspirin, other COX-2 inhibitors, and other potential novel agents in patients with colorectal cancer," the editorialists explained.

They noted that in the prematurely terminated which likewise found no recurrence or survival advantage from adding the COX-2 inhibitor rofecoxib (Vioxx), a subgroup analysis suggested a signal of possible benefit with less advanced disease. "Although the difference between the subgroups was not statistically significant (possibly due to the low numbers) and the results need to be interpreted with caution, it is feasible that the earlier stage the tumor, the more biologically similar it is to precancerous polyps that seem more susceptible to anti-COX effects," Kerr and co-authors said.

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    Diana Swift is a freelance medical journalist based in Toronto.

Disclosures

The study was supported by National Cancer Institute grants to the Alliance for Clinical Trials in Oncology, the Canadian Cancer Trials Group, the Eastern Cooperative Oncology Group–Alliance for Clinical Trials in Oncology, and the Southwest Oncology Group; funding was also provided by Pfizer.

Meyerhardt is supported by the Douglas Gray Woodruff Chair fund, the Guo Shu Shi Fund, the Anonymous Family Fund for Innovations in Colorectal Cancer, and the George Stone Family Foundation. He reported relationships with Taiho, COTA Healthcare, Ignyta Single, and Boston Biomedical. Co-authors reported financial relationships with Celgene–Bristol Myers Squibb, Yiviva Inc., Boehringer Ingelheim, Johnson & Johnson, Merck, Amgen, Genentech, Agios, Amylin Pharma, Bain Capital, CytomX Therapeutics, Daiichi-Sankyo, Eli Lilly, Entrinsic Health, and EvolveImmune Therapeutics

Kerr and co-authors noted no competing interests.

Primary Source

JAMA

Meyerhardt JA, et al "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" JAMA 2021; 325: 1277-1285.

Secondary Source

JAMA

Kerr DJ, et al "Celecoxib for stage III colon cancer" JAMA 2021; 325: 1257-1258.