Aim: The standard treatment for patients with clinically resectable rectal cancer is surgery. Postoperative radiochemotherapy (RCT) is recommended for advanced disease (pT3/4 or pN+). In recent years, encouraging results of pre-operative radiotherapy have been reported. This prospective randomized phase-III-trial (CAO/ARO/AIO-94) compares the efficacy of neoadjuvant RCT to standard postoperative RCT. We report on the design of the study and first results with regard to toxicity of RCT and postoperative morbidity.
Patients and methods: Patients with locally advanced operable rectal cancer (uT3/4 or uN+, Mason CS III/IV) were randomly assigned to pre or postoperative RCT: A total dose of 50.4 Gy (single dose 1.8 Gy) was applied to the tumour and the pelvic lymph nodes. 5-FU (1000 mg/m2/d) was administered concomitantly in the 1th and 5th week of radiation as 120 h-continuous infusion. Four additional cycles of 5-FU-chemotherapy (500 mg/m2/d, i.v.-bolus) were applied. RCT was identical in both arms except for a small-volume boost of 5.4 Gy postoperatively. The time interval between RCT and surgery was 4-6 weeks in both arms. Techniques of surgery were standardized and included total mesorectal excision. Primary endpoints of the study are 5-year survival and local and distant control. Secondary endpoints include the rate of curative (R0) resection and sphincter saving procedures, toxicity of RCT, surgical complications and quality of life.
Results: As of July 2002, 805 patients were randomized from 26 participating institutions. Acute toxicity (WHO) of RCT was low, with less than 15% of patients experiencing grade 3 or higher toxicity: The principal toxicity was diarrhea, with 12% in the postoperative RCT-arm and 11% in the pre-operative RCT-arm having grade 3-, and 1% in either arm having grade 4-diarrhea. Erythema, nausea and leukopenia were the next common toxicities, with less than 3% of patients in either arm suffering grade 3 or greater leukopenia or nausea. Postoperative complication rates were similar in both arms, with 12% (postop. RCT) and 12% (pre-op. RCT) of patients, respectively, suffering from anastomotic leakage, 3% (postop. RCT) and 3% (pre-op. RCT) from postoperative bleeding, and 6% (postop. RCT) and 4% (pre-op. RCT) from delayed wound healing.
Conclusion: The patient accrual to the trial is satisfactory. Neoadjuvant RCT is well tolerated and bears no higher risk for postoperative morbidity.