Survival Benefits and Treatment-Related Toxicities of Definitive Concurrent Chemoradiotherapy: A Systematic Review of Randomized Controlled Trials

Background: Definitive concurrent chemoradiotherapy (CRT) is a standard-of-care treatment for multiple locally advanced solid malignancies, including head and neck, cervical, esophageal, and non-small cell lung cancers. While randomized controlled trials (RCTs) consistently demonstrate improved survival with CRT compared to radiotherapy alone, treatment-related toxicities remain a significant clinical concern. A consolidated synthesis of RCT-level evidence focusing on the balance between survival benefit and toxicity burden across tumor sites is clinically relevant. Methods This systematic review was conducted in accordance with the PRISMA 2020 statement. A comprehensive search of PubMed, Embase, and Cochrane Library was performed to identify Phase II and III RCTs evaluating definitive concurrent CRT in head and neck, cervical, esophageal, and non-small cell lung cancers. Only RCTs reporting Grade ≥3 treatment-related toxicities and survival outcomes were included. Risk of bias was assessed using the Cochrane Collaboration Risk of Bias 2 (RoB 2) tool. A qualitative evidence synthesis was performed. Results Across the included RCTs, concurrent CRT consistently demonstrated superior overall survival compared with radiotherapy alone in all four tumor sites. Increased rates of Grade ≥3 mucositis and hematologic toxicity were observed in head and neck cancer trials; significant hematologic and gastrointestinal toxicities in cervical cancer; esophagitis and pneumonitis in esophageal cancer; and hematologic and pulmonary toxicities in lung cancer trials. Treatment-related mortality remained low but non-negligible. Despite increased acute toxicity, survival benefits were sustained at long-term follow-up. Conclusions Definitive concurrent CRT improves survival across multiple solid tumor sites but at the cost of increased acute toxicity. Careful patient selection, modern radiation techniques, and optimized supportive care are essential to maximize therapeutic benefit while minimizing harm