Chemo-radiotherapy for advanced non-small cell lung cancer: concurrent or sequential? It's no longer the question: a systematic review

There has been conflicting evidence concerning the best sequence of radiotherapy (RT) and chemotherapy (CT) for advanced non-small-cell-lung-cancer (NSCLC). To investigate whether current clinical trials can clarify this schedule and offer further bases for clinical decision making, we performed a systematic review of 11 trials (2,043 patients; concurrent-1,019, sequential-1,024) that compared concurrent RT-CT with sequential arm in advanced NSCLC patients. Primary end point was overall survival (OS). Pooled median ratios (MRs) and progression-free-survival ratios (FRs) for median survival and progression-free survival (PFS) were calculated using the weighted sum of the log ratio of MR and FR of individual study. Pooled odds ratios (ORs) for the objective response rate, relapse control rate, and toxic events were calculated using the Mantel-Haenszel estimate. Results confirmed that concurrent RT-CT determined a statistically significant increase in median survival time (16.3 vs. 13.9 months; MR = 1.17,95%CI:1.09-1.26), response rate (64.0% vs. 56.3%; OR = 1.38,95%CI:1.10-1.72), and tumor-relapse control (OR = 0.82,95%CI:0.69-0.97), though at the expense of increased hematological toxicity (neutropenia and thrombocytopenia) and non-hematological toxicity (nausea/vomiting, stomatitis, and esophagitis). Similar results were obtained from the sensitivity analysis of all Phase-III/trials designed to evaluate the primary end point of OS. Subgroup analysis revealed that concurrent strategy was mainly associated with improved loco-regional control (OR = 0.68,95%CI:0.52-0.87). However, no difference in PFS is shown. While careful interpretation of our conclusions is required because of potential bias, the present study, to some extent, exhibits the superiority of the concurrent arm over the sequential in the treatment of advanced NSCLC. Further improvements will be obtained by optimizing the conditions for a concurrent regimen.