Celecoxib-chemotherapy led to more hypertension, higher creatinine levels

Three years’ worth of add-on celecoxib to standard adjuvant chemotherapy did not enhance disease-free survival (DFS) in patients with stage III colorectal cancer, researchers reported.

In the placebo-controlled, phase III CALGB/SWOG 80702 trial, patients were randomized to adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) every 2 weeks for 3 months versus 6 months, with or without celecoxib at 400 mg orally daily, explained Jeffrey A. Meyerhardt, MD, MPH, of the Dana-Farber Cancer Institute in Boston, and co-authors.

At a median 6 years of follow-up, the 3-year DFS was 76.3% for celecoxib-treated patients versus 73.4% for placebo-treated patients for a hazard ratio of 0.89 for disease recurrence or death (95% CI 0.76 to 1.03, P=0.12), they reported in JAMA. The results were first presented at the 2020 American Society of Clinical Oncology virtual meeting.

In addition, the effect of celecoxib treatment on DFS did not vary significantly according to assigned duration of adjuvant chemotherapy (P=0.61 for interaction), and any-grade hypertension, along with increased creatinine levels, occurred in more patients in the celecoxib group versus the placebo group.

The study “contributes important data on the use of COX-2 inhibitors for patients after resection of stage III colon cancer,” stated David J. Kerr, MD, DSc, of JR Hospital at the University of Oxford in England, and co-authors, in an editorial accompanying the study.

Kerr and co-authors highlighted the study limitations, pointing out that less than three-fourths of patients receiving their assigned treatment stayed on it for >2.75 years, although given the total duration of the study, “this adherence level may be acceptable,” they acknowledged.

Also, the original statistical assumptions of the trial assumed more rapid enrollment and more events than were achieved,” according to Kerr’s group. While that’s not an uncommon occurrence in contemporary trials — as diseases, diagnoses, and treatments continue to evolve over time — it should serve as a wake-up call that “[t]he oncology research community needs to adapt and increase recruitment into adjuvant trials to allow adequate power when event rates are inevitably lower than projected,” they said.

Finally, the study did not included patients with stage II disease, “which may increase the risk of a false-negative outcome in earlier stage disease,” Kerr and co-authors noted, adding that subgroup analysis in the VICTOR trial, which was stopped early when rofecoxib (Vioxx) was pulled from global markets in 2004, showed a “signal of possible benefit with less advanced disease.”

The trial findings could be seen as another wrong move for the COX-2 inhibitor, which has a checkered history. In 1998, the drug received FDA approval for use in rheumatoid arthritis and osteoarthritis, while also warning that carried the risk of heart disease and blood vessel complications. A year later, celecoxib got an FDA green light for the treatment of familial adenomatous polyposis, a colon cancer precursor. In the early Aughts, the APC trial demonstrated that daily use of celecoxib over 3 years significantly reduced the recurrence of adenoma and advanced adenoma versus placebo, but that it was also linked with increased risk of serious cardiovascular side effects. In 2005, the FDA tagged the drug with a black-box warning.

Meyerhardt and co-authors randomized 2,526 patients were randomized (mean age 61.0; 44.9% women; majority white) to the treatment arms, and 2,524 were included in the primary analysis. “Eligible patients had margin-negative resected, histologically documented colon adenocarcinoma, entirely lying above the peritoneal reflection,” they explained, adding that an aspirin regiment that did not exceed 100 mg/day was allowed.

Patients were excluded if they had uncontrolled high blood pressure, unstable angina, history of documented myocardial infarction or cerebrovascular accident, or New York Heart Association class III or IV heart failure.

The authors noted that treatment adherence was 70.8% for patients on celecoxib and 69.9% for patients on placebo (P=0.69). A total of 337 patients randomized to celecoxib and 363 to placebo experienced disease recurrence or died.

They reported the following:

  • Any-grade hypertension: 14.6% of patients in the FOLFOX-celecoxib group vs 10.9% of patients in the FOLFOX-placebo group
  • Grade ≥2 increase in creatinine levels post-FOLFOX: 1.7% vs 0.5% of patients, respectively
  • 5-year overall survival: 84.3% for celecoxib versus 81.6% for placebo (HR 0.86 for death, 95% CI 0.72 to 1.04, P=0.13)

Meyerhardt’s group pointed out that previous studies — the Seattle Colon Cancer Family Registry trial, an NIH trial (Meyerhardt was a co-author) — have demonstrated that “patients with colorectal cancer who take these drugs had a lower risk of recurrent disease and death from cancer,” but “reasons for discordance between [those]observational studies and the results of this trial are unclear.” One reason could have been that the current trial did not use “biomarker-directed patient selection,” although Kerr’s group noted that “the state of knowledge in terms of biomarker selection for response was not yet sufficiently robust,” during the time of the trial (2010-2015).

The authors plan a retrospective analyses of the findings so that data, along with those from ongoing studies (ASCOLT, Add-Aspirin) may help define the role of COX-2 inhibitors and aspirin in patients with colorectal cancer, Kerr and co-authors stated.

In an ASCO Post Newsreel, Meyerhardt stated that “Ultimately, the trial did not reach its primary endpoint…it is a very rich database that was collected throughout the duration of the trial, where we collected tumor blots, blood, questionnaires, and we plan to have an extensive correlate program, including looking at [the] specific molecular markers that may predict the potential benefit of celecoxin in this population.”

  1. The addition of celecoxib for 3 years, versus placebo, to standard adjuvant FOLFOX chemotherapy did not significantly improve disease-free survival in patients with stage III colorectal cancer.

  2. Patients in the celecoxib-FOLFOX group saw higher rates of hypertension and a higher increase in creatinine levels.

Shalmali Pal, Contributing Writer, BreakingMED™

The study was supported by, and/or funded by, the Alliance for Clinical Trials in Oncology, the Canadian Cancer Trials Group, the Eastern Cooperative Oncology Group–Alliance for Clinical Trials in Oncology, the Southwest Oncology Group, the National Cancer Institute, and Pfizer.

Meyerhardt reported support from, and/or relationships with, the Douglas Gray Woodruff Chair fund, the Guo Shu Shi Fund, Anonymous Family Fund for Innovations in Colorectal Cancer, the George Stone Family Foundation, Taiho, COTA Healthcare, Ignyta Single, and Boston Biomedical. Co-authors multiple relationships with industry including Pfizer.

Kerr and co-authors reported no relationships relevant to the contents of this paper to disclose.

Cat ID: 23

Topic ID: 78,23,730,16,23,192,925