Results of RTOG-0012 randomized phase II study of neoadjuvant combined modality chemoradiation for distal rectal cancer

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To evaluate in a randomized phase II study the rate of pathological complete response and toxicity of neoadjuvant chemoradiation for advanced T3/T4 distal rectal cancers. 106 patients with clinical T3/T4 distal rectal cancers, 0–9cm from the dentate line, were randomized in a phase II study to receive combined neoadjuvant preoperative chemoradiation followed by surgical resection of disease. Patients were stratified by clinical stage and were randomized to receive either CVI 5-FU, 225 mg/m2 per day, 7 days per week plus pelvic Hyperfractionated radiation (HRT) 45.6 Gy at 1.2 Gy bid, >6 hour interval plus a boost to the tumor of 9.6 Gy for T3 and 14.4 Gy for fixed T4 cancers (Arm 1) or CVI 5-FU 225 mg/m2 per day Monday to Friday, 120 hours per week plus Irinotecan (CPT-11) 50 mg/m2 once weekly × 4 plus pelvic RT 45 Gy at 1.8 Gy per day and boost to the tumor of 5.4 Gy for T3 and 9 Gy for fixed T4 cancers (Arm 2). Surgery was performed 4 to 10 weeks following completion of neo-adjuvant therapy. The primary end point of this study was assessment of pathological complete response (CR). Secondary end points included acute and late normal tissue morbidity. 96 of the 106 patients were evaluable for response. 3 patients were ineligible and 7 patients did not undergo surgery (4 in Arm 1 and 3 in Arm 2) for either disease progression or patient/physician refusal for an overall respectability rate of 93%. The median time to surgery was 7 weeks. Patient characteristics were similar in both arms except for a higher percent of male patients (78% vs. 55%) and also a slightly higher incidence of T4 (32% vs. 25%) cancers in Arm 1. Overall tumor downstaging was observed in 78% of patients in both arms of the study. For all eligible patients who started treatment. The pathological complete response (pCR) rate was 26% (13/50) in Arm 1 and 26% (14/53) in Arm 2. For patients who had surgery the pCR rate was also the same in Arm 1, 28% (13/46) and 28% (14/50) in Arm 2. Acute and late toxicity in the two arms of the study was also similar. Grade 3s4 acute hematological and non-hematological toxicity occurred in 13% and 38% respectively in Arm 1 and 12% and 45% in Arm 2. Although the overall complete response rate and toxicity appears similar in both arm, this is the first multi institutional study to establish a 28% pathological complete response rate following neo-adjuvant therapy for T3/T4 rectal cancer and should be the standard for future trials in this disease.