Adjuvant versus neoadjuvant radiochemotherapy for locally advanced rectal cancer - A progress report of a phase-III randomized trial (protocol CAO/ARO/AIO-94)

Aim: The standard treatment for patients with clinically resectable rectal cancer is surgery. Postoperative radiochemotherapy is recommended for patie nts with advanced disease (pT3/4 or pN+). In recent years, encouraging resu lts of preoperative radiotherapy have been reported. This prospective rando mized phase-III trial (CAO/ARO/AIO-94) compares the efficacy of neoadjuvant radiochemotherapy to standard postoperative radiochemotherapy. We report o n the design of the study and first results with regard to toxicity of radi ochemotherapy 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 postoper ative radiochemotherapy: A total dose of 50.4 Gy (single dose 1.8 Gy) was a pplied to the tumor and the pelvic Lymph nodes. 5-FU (1,000 mg/m(2)/d) was administered concomitantly in the first and fifth week of radiation as 120- h continuous infusion. Four additional cycles of 5-FU chemotherapy (500 mg/ m(2)/d, iv bolus) were applied. Radiochemotherapy was identical in both arm s except for a small-volume boost of 5.4 Gy in the postoperative setting. T ime interval between radiochemotherapy and surgery was 4-6 weeks in both ar ms. Techniques of surgery were standardized and included total mesorectal e xcision. In addition, stratification according to surgeons involved has bee n provided for. Primary endpoints of the study are 5-year overall-survival. Local and distant control, secondary endpoints include rate of curative (R O) resections and sphincter saving procedures, toxicity of radiochemotherap y, surgical complications and quality of life. Results: As of 15th November 2000, 628 patients were randomized from 26 par ticipating institutions: 310 patients were randomized to postoperative radi ochemotherapy, 318 patients to preoperative radiochemotherapy. Acute toxici ty (WHO) of radiochemotherapy was Low, with less than 15% of patients exper iencing Grade 3 or higher toxicity: The principal toxicity was diarrhea, wi th 12% in the postoperative radiochemotherapy arm and 10% in the preoperati ve radiochemotherapy 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% (postoperative radiochemotherapy) and 13% (preoperative rad iochemotherapy) of patients, respectively, suffering from anastomotic Leaka ge, 4% (postoperative radiochemotherapy) and 3% (preoperative radiochemothe rapy) from postoperative bleeding, and 6% (postoperative radiochemotherapy) and 5% (preoperative radiochemotherapy) from delayed wound healing. Conclusion: The patient accrual of our trial is satisfactory, neoadjuvant r adiochemotherapy is well tolerated and bears, no higher risk for postoperat ive morbidity.