Phase II Trial Using a Combination of Oxaliplatin, Capecitabine, and Celecoxib with Concurrent Radiation for Newly Diagnosed Resectable Rectal Cancer

Lessons Learned: Colorectal cancers exhibit a high level of cyclooxygenase-2 (COX-2) expression with strong preclinical rationale for improved clinical outcomes with COX-2 inhibition. Celecoxib is a COX-2 inhibitor and we have shown that it can be safely combined with capecitabine and oxaliplatin as part of neoadjuvant treatment with radiation therapy (RT) in rectal cancer. There was a significant improvement in skin toxicity with this combination as compared with historical data. Considering the field has moved on to single-agent capecitabine, we believe future trials with capecitabine and celecoxib hold potential. Background: Improved survival is seen among patients with rectal cancer who achieve pathologic complete response (pCR) after neoadjuvant therapy. Cyclooxygenase-2 (COX-2) expression is increased in gastrointestinal malignancies and it may serve as a target to enhance pathologic response. A trial combining chemoradiation and COX-2 inhibition was conducted to evaluate the pCR rate, surgical outcomes, survival, and treatment toxicity. Methods: Patients with resectable (T3-4, N1-2) rectal cancer within 12 cm of the anal verge were included in this phase II clinical trial. The neoadjuvant treatment consisted of capecitabine 850 mg/m² b.i.d. Monday through Friday for 5 weeks, weekly oxaliplatin 50 mg/m² intravenous (IV), celecoxib 200 mg b.i.d. daily, along with concurrent 45 gray radiation therapy in 25 fractions. Results: Thirty-two patients were included in the final analysis. The primary endpoint was pCR: 31% (95% confidence interval [CI]: 16%–50%). Secondary endpoints were surgical downstaging (SD): 75% (95% CI: 57%–89%) and sphincter-sparing surgery (SSS): 56% (95% CI: 38%–74%). Common grade >3 toxicities were diarrhea and abnormal liver function tests (9% each). Grade 0 and 1 toxicities included radiation dermatitis (59% and 34%, respectively) and proctitis (63% and 28%, respectively). At 3 years, disease-free survival and overall survival (OS) were 84% (95% CI: 65%–93%) and 94% (95% CI: 77%–98%), respectively. Conclusion: Chemoradiation with celecoxib in rectal cancer was well tolerated and demonstrated high rates of pCR, SD, and SSS. Improvement in skin toxicity (34% grade 1 and no grade 3/4) as compared with historical results (43%–78% grade 3/4) seems to be a significant improvement with addition of celecoxib to neoadjuvant chemotherapy.