Determining the optimal radiation dose for locally advanced esophageal cancer: A pooled analysis of reconstructed individual patient data from randomized clinical trials.

Background: The optimal radiation dose of definitive concurrent chemoradiotherapy (dCCRT) for esophageal cancer (EC) has always been a concern in radiation oncology and has remained controversial for several decades, we performed a meta-analysis based on individual patient data (IPD) to explore the optimal dose.

Methods: Randomized clinical trials (RCTs) comparing high-dose radiotherapy (HD-RT,≥59.4 Gy) with standard-dose radiotherapy (SD-RT, 50 Gy/50.4 Gy) were identified. Graphical reconstructive algorithms were employed to extract time-to-event outcomes from Kaplan-Meier curves presented in the original RCTs. Using reconstructed individual patient data, summary overall survival (OS), progression-free survival (PFS) and locoregional progression-free survival (LRPFS) for HD-RT versus SD-RT were recalculated. Hazard Ratios (HRs) of OS, PFS and LRPFS reported were also pooled by the fixed or random effects model.

Results: Six RCTs, including 1722 patients, were included. IPD for OS, PFS, and LRPFS were from 1287, 462, and 722 patients, respectively. Overall, HD-RT had no significant benefits in 3-year OS (RR = 1.00, P = 0.990), 3-year progression-free survival (PFS) (RR = 0.96, P = 0.320) and 3-year locoregional progression-free survival (LRPFS) (RR = 0.88, P = 0.204), compared with SD-RT. Consistent with above results, the pooled HRs of OS, PFS and LRPFS for HD-RT versus SD-RT were 0.99 (P = 0.854), 0.94 (P = 0.628) and 0.91 (P = 0.410), respectively. However, HD-RT had higher grade ≥ 3 treatment-related adverse effects (TRAEs) (OR = 1.26, P = 0.025). Subgroup analyses were also performed based on the RT techniques, histology, size of the RT target, dose-escalation mode, and stage editions. We found that dose escalation, even in subgroups, did not benefit long-term survival but resulted in a higher incidence of grade ≥ 3 TRAEs.

Conclusion: The results provide robust evidence that corroborates current guidelines and supports the clinical practice of employing SD-RT. Additionally, it provides implications for the feasibility of further research into novel drug combinations (e.g., immunotherapy) rather than radiation dose escalation.