KEY POINTS
- The model-based meta-analysis included 65 studies, 74 dose-stratified cohorts and 5,235 patients with esophageal squamous cell carcinoma receiving neoadjuvant chemoradiotherapy. 4,540 patients proceeded to surgery.
- Across the pooled cohorts, pathological complete response occurred in 1,593 of 4,540 patients (35.1%). Median radiotherapy dose was 40 Gy, corresponding to a median BED10 of 48.7 Gy.
- After adjustment for treatment and cohort characteristics, every 10-Gy increase in BED10 was associated with 39% higher odds of pathological complete response (OR 1.39, 95% CI 1.13–1.70, p = 0.002).
- Radiotherapy technique was independently associated with response. Compared with 2D radiotherapy, pathological complete response odds were higher with 3D-CRT: OR 1.82, p = 0.007, and IMRT/VMAT: OR 1.96, p = 0.012.
- No convincing threshold was identified between BED values of 45–55 Gy; a continuous dose-response model fit the available data better than a simple high-dose versus low-dose cutoff.
- Higher pathological response also tracked with survival at the cohort level. Weighted mean two-year overall survival increased from 50.2% in cohorts with pCR ≤29.5% to 70.2% when pCR was ≥41.7%, with weighted correlation r = 0.519.
- The estimated BED needed for a 50% predicted pathological response was 73.3 Gy, but this exceeded the observed dose range and represents extrapolation. The authors explicitly caution that these findings do not support routine dose escalation without prospective validation.
CLINICAL TAKEAWAY
There appears to be a genuine cohort-level dose-response relationship for pathological response in esophageal squamous cell carcinoma, but this should not be translated directly into higher neoadjuvant prescriptions. Treatment era, technique, patient selection and other unmeasured differences are tightly entangled with dose, and survival benefit from escalation remains unproven.