Results of the Accord 12/0405 Prodige2 Randomized Trial are in Favor of Benefit of Radiation Dose Intensification in the Neoadjuvant Treatment of T3–4 M0 Rectal Cancer

Following the results of randomized trials (FFCD 9203, RTOG 0012) showing in T3–4 M0 rectal a better local control with neoadjuvant chemoradiation (CT-RT), the ACCORD 12/0405 Prodige2 was launched to define an optimum regimen. Inclusion was rectal adenocarcinoma accessible to digital rectal examination T3 or resectable T4 Nx M0 below 80 years. Treatment A: concurrent RT 45 Gy/25f/5 weeks (w) + capecitabine (800 mg/m2/b.i.d.). Treatment B: concurrent RT 50 Gy/25f/5 weeks + capecitabine (800 mg/m2/b.i.d./5/7 days) + oxaliplatin 50 mg/m2/week. Resection with total mesorectum excision was scheduled 6 weeks after the end of CT-RT. Adjuvant chemotherapy was optional. A total of 590 patients were needed to show an increase in the pathologic complete response (Dworak) rate from 11% (arm A) to 20% (arm B). Circumferential positive rectal margin (CRM R1) was defined as the presence of residual cancer cells within 0–1 mm from the perirectal surface. Evaluation of sexual and bowel function was made with a specific questionnaire. This trial closed in July 2008 after randomization of 598 patients since November 2005. Patients' characteristics of 586 eligible patients were well balanced: male 66%, median age 61 years, 66% low rectum, 87% T3 stage. Database was locked in March 2009. The Grade 3/4 all toxicity was, respectively, 11% (32 patients) vs. 25% (73 patients) in arm A (Cape 45) and arm B (Capox 50; p = 0.01). Surgery was performed in arm A in 98% of patients (289) and 98.6% in arm B (287 patients). There was no difference in sphincter-saving surgery 75% in A and 78% in B. Postoperative death at 60 days was identical in both groups (0.3%). A CRM R1 (0–1 mm) was found in 11% in arm A vs. 6% in arm B (18 vs. 9 patients; p = 0.12), and when the distance for CRM was 0–2 mm the difference between A and B was, respectively, 18% (30 patients) vs. 8% (12 patients; p < 0.05). The ypCR (Dworak) was 13.8 (40 patients) in arm A and 18.8% (54 patients) in arm B, p = 0.11. Results of sexual and bowel functions at 1 year will be reported at the time of the meeting. These results, when compared with other recent Phase III trials, show that radiation dose intensification in the Capox 50 regimen does not increase surgical complication and seems to provide a trend toward an increase in negative CRM and ypCR. A dose of 50 Gy/25F/5 weeks (with shrinking field after 44 Gy) could be proposed in locally-advanced rectal cancer as an efficient schedule.