Celecoxib added to adjuvant chemotherapy does not improve survival or recurrence versus placebo in stage III colon cancer

1. Adding celecoxib to adjuvant chemotherapy did not increase disease-free survival or overall survival compared to placebo in patients with stage III colon cancer.

2. Celecoxib treatment led to increased incidence of hypertension and elevated levels of creatinine versus placebo.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Aspirin and cyclooxygenase 2 (COX-2) inhibitors have been associated with a lower risk of colorectal cancer in previous randomized trials. This study investigated whether the use of celecoxib, a selective COX-2 inhibitor, increased survival and reduced the risk of recurrence of stage III colon cancer in patients receiving adjuvant chemotherapy. Adjuvant chemotherapy included fluorouracil, leucovorin, and oxaliplatin (FOLFOX). Patients were randomized into four groups to receive FOLFOX for either three or six months with celecoxib or placebo for three years. Celecoxib treatment demonstrated no significant difference in disease-free survival (cancer recurrence or death from any cause) and overall survival (death from any cause) compared to placebo at 3-year and 5-year follow-ups. The duration of adjuvant chemotherapy did not alter the effectiveness of celecoxib. Patients treated with celecoxib had a significantly higher risk of hypertension and grade 2 or greater creatinine increase. Overall, given the poor efficacy and elevated risk of adverse events, the current data does not support the use of celecoxib supplementation to adjuvant chemotherapy for patients with stage III colon cancer.  The large sample size from 654 different centers strengthens the results of this trial. However, adherence to treatment limited this study since 29.6% of patients discontinued treatment before reaching the study’s end goals (death, recurrence of disease, or major adverse effects).

Click to read the study in JAMA

Click to read an accompanying editorial in JAMA

Relevant Reading: Aspirin use and survival after diagnosis of colorectal cancer

In-Depth [randomized controlled trial]: This study enrolled 2526 patients (mean age 61.0 years) with stage III colon cancer from centers across the National Cancer Trials Network between June 2010 and November 2015. Patients were randomized into four groups (3-months FOLFOX with celecoxib, 6-months FOLFOX with celecoxib, 3-months FOLFOX with placebo, and 6-months FOLFOX with placebo) and followed-up through August 10, 2020. This study’s primary endpoint was disease-free survival; secondary outcomes included overall survival and adverse events from treatment. Celecoxib or placebo treatment began the first day after the second chemotherapy treatment and was intended to be taken daily for three years unless there was death, recurrence of disease, or intolerable adverse effects; adherence to celecoxib or placebo treatment was 70.8% and 69.9% (p= 0.69), respectively. The 3-year disease-free survival rate for patients treated with celecoxib was 76.3% compared to 73.4% for those treated with placebo; the hazard ratio for death or recurrence of disease was 0.89 (95% CI: 0.76-1.03; p = 0.12). Celecoxib-treated patients had significantly higher risk of development of any grade hypertension compared to placebo during treatment of FOLFOX (14.6% vs 10.9%, p = 0.01) and following FOLFOX treatment completion (13.0% vs 10.0%, p = 0.04). Additionally, patients treated with celecoxib had a significantly higher risk of grade 2 or greater creatinine increase following completion of FOLFOX treatment (1.7% vs 0.5%, p = 0.01).

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