Can chemotherapy concomitantly delivered with radiotherapy improve survival of patients with resectable rectal cancer? A meta-analysis of literature data

BACKGROUND: There is clear evidence from two systematic reviews that radiotherapy (RT) reduces the risk of local recurrence in patients with resectable rectal cancer, though the data on survival are still equivocal. OBJECTIVE: To assess the effects of chemotherapy combined concomitantly with radiotherapy (CRT) on the increase of overall survival, and on the prevention of local recurrence and distant metastases. DATA SOURCES: Computerized bibliographic searches of MEDLINE and CANCERLIT (1970-2008) were supplemented with hand searches of reference lists. STUDY SELECTION: Studies were included if they were randomized controlled trials (RCTs) comparing preoperative or postoperative CRT to preoperative or postoperative RT alone, and if they included patients with resectable, histologically-proven, rectal adenocarcinoma without metastases. Thirteen RCTs, seven of preoperative CRT vs. preoperative RT (2787 patients), four of postoperative CRT vs. postoperative RT (726 patients) and two of postoperative CRT vs. preoperative RT (1400 patients), were analyzed. DATA EXTRACTION: Data on population, intervention, and outcomes were extracted from each RCT, in accordance with the intention-to-treat method, by three independent observers, and combined using the DerSimonian method and Laird method. RESULTS:Preoperative CRT compared to preoperative RT alone significantly reduces the 5-year local recurrence rate (RR 1.05; 95%CI 1.01-1.10). No increase was observed in 5-year overall survival rate (RR 0.94; 95%CI 0.94-1.09), and in the occurrence of distant metastases (RR 0.97; 95%CI 0.93-1.02). Instead, postoperative CRT did not reduce local recurrence (RR 0.96; 95%CI 0.80-1.16), distant metastases (RR 1.11; 95%CI 0.94-1.31) and overall mortality (RR 1.09; 95%CI 0.83-1.41). By pooling data on postoperative CRT vs. preoperative RT a significant reduction of local recurrence was found for the preoperative approach (RR 0.93; 95%CI 0.90-0.96), though no difference was found in distant metastases rates and overall survival. Finally, the risk of mortality related to toxic events was significantly higher when adding chemotherapy to radiotherapy (RR 2.86; 95%CI 0.99-8.26). CONCLUSIONS: In patients with resectable rectal cancer, CRT does not increase overall survival, despite the fact that preoperative CRT significantly reduces the risk of the local recurrence. No reduction in the distant metastases rate was found. Toxicity-related mortality is significantly increased by the concomitant approach, emphasizing the need for safer treatment combinations.