RTOG 0247: A randomized phase II study of neoadjuvant capecitabine and irinotecan versus capecitabine and oxaliplatin with concurrent radiation therapy for locally advanced rectal cancer

4021 Background: Preoperative chemoradiation for distal rectal cancer is an effective treatment strategy in which achievement of pathologic complete response (pCR) may be associated with a favorable prognosis. Methods: A randomized phase II trial evaluated preoperative RT (50.4 Gy in 1.8 Gy fractions) with (1) concurrent capecitabine (1,200 mg/m2/d orally M-F during RT) and irinotecan (50 mg/m2 IV weekly x 4 doses) (Arm 1), and with (2) concurrent capecitabine (1,650 mg/m2/d orally M-F during RT) and oxaliplatin (50 mg/m2 IV weekly x 5 doses) (Arm 2) in patients with clinical stage T3 or T4 rectal cancer < 12 cm from the anal verge. Surgery was performed 4–8 weeks following completion of chemoradiation. Four to 6 weeks after surgery, adjuvant chemotherapy (oxaliplatin 85 mg/m2; leucovorin 400 mg/m2 IV over 2 hours; 5-FU 400 mg/m2 IV bolus; 5- FU 2,400 mg/m2/46 hr infusion) was administered every 2 weeks x 9 cycles. The primary endpoint was pCR rate. Forty eight evaluable patients were required for each arm. Either treatment arm would be considered for further study if there were at least 9 pCRs out of 48 evaluable patients. Results: Of 146 accrued patients, 101 were analyzable after initial temporary closure and amendment (final regimens noted above) for excessive GI toxicity. Patient characteristics were similar for both arms. Median age was 57 years; 68% male (69/101); 88% T3 (89/101). Following chemoRT, tumor downstaging was 56% (27/48) and 58% (28/48), and nodal downstaging was 36% (12/33) and 33% (9/27), for Arms 1 and 2, respectively. The pCR rate for Arm 1 was 10% (5/48) and for Arm 2 was 21% (10/48). Preop chemoRT grade 3/4 hematologic toxicity was 8% (6/49) and 4% (2/52), and preop chemoRT grade 3/4 non-hematologic toxicity was 24% (12/49) and 29% (15/52) for Arms 1 and 2, respectively (CTCAE v3.0). The predominant non-hematologic toxicity was GI. Conclusions: Preoperative radiation with concurrent capecitabine plus oxaliplatin for distal rectal cancer has manageable toxicity and with 10/48 pCRs, this regimen warrants further study. This combination will become the backbone for the next RTOG rectal cancer study examining the potential benefit of intensity modulated radiation in reducing GI morbidity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen, Genentech, ImClone, Pfizer, sanofi-aventis Pfizer, Roche, sanofi-aventis Roche, sanofi-aventis