Why Intensify the Neo-Adjuvant Approach with Chemotherapy and Radiotherapy in Rectal Cancer? A Systematic Review and Meta-Analysis

Abstract Background & Aims: Despite optimal local control, chemoradiotherapy (CRT) data on overall and disease-free survival are still equivocal. This meta-analysis aimed to estimate the pathological complete response (pCR), regression rate, disease-free survival and overall survival probabilities of rectal cancer patients treated with intensified chemotherapy. Data sources: Computerised bibliographic searches of MEDLINE and Cochrane Central Register of Controlled Trials databases (1970-2023) were supplemented with hand searches of reference lists. Study selection: Studies were included if they were randomised controlled trials (RCTs) comparing intensified chemotherapy with CRT to preoperative CRT and if they had patients with resectable, histologically-proven, rectal adenocarcinoma without metastases. Eighteen RCTs (7695 patients) were analysed. Data extraction: Data on population, intervention, and outcomes were extracted from each RCT, following the intention-to-treat method, by three independent observers and combined using the DerSimonian and Laird methods. Results: Intensified chemotherapy and CRT, compared to preoperative CRT, significantly increases the rate of pathological complete response (OR 1.37 (95% CI, 1.16-1.63) p=0.0003) and the regression rate (OR 1.57 (95% CI, 1.16-2.14) p < 0.00001). Furthermore, it increases disease-free survival HR 0.87 (95% CI, 0.79 to 0.95) p=0.002 and overall survival HR 0.84 (95% CI, 0.74 to 0.95) p= 0.007. Finally, the risk of therapy to severe adverse events (≥G3) is increased OR 1.96 (95% CI 1.35–2.85), p =0.0005. Conclusions: In patients with resectable rectal cancer, intensified chemotherapy can reduce by 13% the hazard of disease progression and by 16% the hazard of death.