Long-term outcomes and exploratory analysis from a randomized phase 3 trial of radiation dose escalation in definitive chemoradiotherapy for locally advanced esophageal squamous cell carcinoma
In brief
Increasing radiation to 60 Gy does not improve 5-year control versus standard 50 Gy in esophageal
In a phase 3 trial of 319 patients with locally advanced ESCC, 5-year locoregional progression-free survival was 41.8% with 60 Gy versus 43.3% with 50 Gy, and overall survival and other outcomes were indistinguishable. The data confirm 50 Gy as the appropriate dose for unselected patients, while spatial profiling suggests immune-active tumors may drive long-term survival.
- Journal
- Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy (Q1)
- Published
- 9 July 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- Qi Cheng, Baiqiang Dong, Weiguo Zhu, Jiancheng Li, Rong Huang, Xiao Lin, et al.
- PMID
- 42442129
- DOI
- 10.1016/j.drup.2026.101446
Why clinicians should know about it
- Picked for Transplantation (top studies of the week, 19 July 2026).
Abstract
The optimal radiation dose for definitive chemoradiotherapy in locally advanced unresectable esophageal squamous cell carcinoma (ESCC) remains controversial, particularly whether dose escalation can overcome treatment resistance. We previously reported that escalation to 60 Gy increased radiation-related toxicity without improving short-term locoregional control versus 50 Gy. Here, we present the long-term outcomes and exploratory analyses of this randomized phase 3 trial. Between 2013 and 2017, 324 patients with stage IIA-IVA ESCC were randomly assigned 1:1 to receive 60 Gy or 50 Gy of conventionally fractionated radiotherapy with concurrent chemotherapy. Pretreatment biopsy specimens were analyzed using NanoString GeoMx digital spatial profiling for spatial transcriptomic and proteomic characterization. The full analysis set included 319 patients (60 Gy, n = 160; 50 Gy, n = 159). After a median follow-up of 99.5 months, no significant differences were observed in locoregional progression-free survival between the 60 Gy and 50 Gy groups, with 5- and 8-year rates of 41.8% and 32.7% versus 43.3% and 36.3%, respectively (HR 1.06, 95% CI 0.80-1.39, p = 0.70). Overall survival, progression-free survival, distant metastasis-free survival, and failure patterns were also comparable between groups. Spatial multi-omics analyses identified distinct baseline tumor microenvironment states associated with outcome. Long survivors showed an immune-activated profile with higher interferon and HLA signaling, and increased CD8+ T cell infiltration, whereas early progressors showed an immunosuppressive stromal profile suggestive of intrinsic resistance to definitive chemoradiotherapy. These findings support 50 Gy as an appropriate standard radiation dose for unselected patients with locally advanced ESCC treated with definitive chemoradiotherapy and do not support routine escalation to 60 Gy. Baseline spatial tumor microenvironment features may help identify resistance-associated states and provide biological context for divergent clinical outcomes.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.