Geen overlevingsvoordeel bij stralingsdosis-escalatie naar 60 Gy bij oesofageaal squameus celcarcinoom

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.