Cetuximab in Combination With Capecitabine, Irinotecan, and Radiotherapy for Patients With Locally Advanced Rectal Cancer: Results of a Phase II MARGIT Trial

Purpose To evaluate the safety and efficacy of preoperative radiotherapy (RT) in combination with cetuximab, capecitabine, and irinotecan in patients with locally advanced rectal cancer. Methods and Materials Patients with rectal cancer (clinical stage T3/4 or N+) were scheduled to receive cetuximab (400 mg/m 2 Day 1, 250 mg/m 2 Days 8, 15, 22, 29) in combination with weekly irinotecan 40 mg/m 2 and capecitabine 500 mg/m 2 twice daily (Days 1–38). RT was given to a dose of 50.4 Gy (45 + 5.4 Gy). Primary endpoint was toxicity, and antitumor activity as assessed by the pathologic complete remission (pCR) rate was a secondary endpoint. Results Fifty patients were enrolled; 88% showed T3 or T4 and 76% nodal-positive tumors with a median distance from the anal verge of 7.5 cm. The actual dose intensity was as follows (median/mean, %): cetuximab 100/92, irinotecan 100/91, capecitabine 100/89). Main adverse events Grades 2/3/4 were (National Cancer Institute common toxicity criteria version 3.0, %): leukocytopenia 6/2/2, nausea/vomiting 4/2/0, diarrhea 34/30/0, proctitis 26/2/0, elevation of liver transaminases 8/10/0, and acnelike skin rash 46/6/0. All patients underwent surgery, and no postoperative deaths occurred. Eighty-four percent underwent low-anterior resection, and 68% of the specimen exhibited moderate or good tumor regression, but only 4 patients had a pCR. Conclusion Preoperative chemoradiation with cetuximab-CapIri-RT has manageable toxicity, with diarrhea being the most commonly observed adverse event. Nevertheless, the efficacy of this regimen with a pCR rate of only 8% was significantly lower than that observed in a previous Phase I trial.