Radiation dose escalation in locally advanced oesophageal cancer: a systematic review and hierarchical Bayesian meta-analysis.

Abstract

Background: The impact of radiation dose escalation in locally advanced oesophageal cancer remains controversial. While higher doses may improve locoregional control, their effect on overall survival (OS) and progression-free survival (PFS) remains uncertain. The aim of this study was to thoroughly evaluate the impact of dose escalation on survival.

Methods: A systematic search on Jan 4, 2025, identified studies evaluating definitive chemoradiotherapy (CRTx) for locally advanced oesophageal cancer stratified by radiation dose. Bayesian and frequentist meta-analyses assessed OS, PFS, and locoregional PFS (LRPFS). Meta-regression examined the influence of histology, tumour location, chemotherapy, and radiation techniques. Additional analyses included gene set enrichment analysis and immune infiltration estimation. This study is registered with PROSPERO, CRD42024538961.

Findings: A total of 42 studies involving 8379 patients were included. High-dose radiotherapy significantly improved LRPFS, with the largest benefit observed at 1-year (median difference: 18.6%; 95% credible interval [CrI]: 10.7-26.1%). A modest improvement in OS was noted at 3-year (7.0%; 95% CrI: 0.01-13.9%), particularly in squamous cell carcinoma (SqCC). Meta-regression identified SqCC and taxane-based chemotherapy as key moderators, with high-dose conferring greater benefits in Asian populations. Genomic analysis revealed higher radiosensitivity and significant immune activation in Asian SqCC. Taxane-based chemotherapy regimens were the strongest predictors of 1-/2-year OS and PFS but diminished at 5-year. Any-grade pneumonitis was more common in high-dose, but frequencies of grade 3 or higher pneumonitis were similar. Modern techniques like intensity-modulated or volumetric-modulated radiotherapy were associated with higher complete response rate and a trend toward reduced toxicity. The study heterogeneity was moderate to high across pooled estimates but addressed through hierarchical modeling and subgroup/sensitivity analyses. Most included studies were retrospective with moderate risk of bias, and the certainty of evidence for primary outcomes was rated as low to high.

Interpretation: Radiation dose escalation improves locoregional control and may enhance OS in SqCC, particularly in Asian populations, highlighting the need for histology- and region-specific therapeutic strategies. The choice of chemotherapy regimen may affect the interpretation of survival effects associated with high-dose. Furthermore, the genomic correlates of radiosensitivity and immune activation suggest potential for biologically guided dose personalization and combination with immunotherapy.

Funding: None.