Nodal status–guided postoperative radiotherapy after neoadjuvant chemoimmunotherapy for locally advanced esophageal squamous cell carcinoma: A multicenter cohort study.

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Background: In locally advanced esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoimmunotherapy (Chemo-IO) followed by surgery, the role of postoperative radiotherapy (PORT) remains unclear. Tumor-draining lymph nodes (TDLNs) are critical sites for priming antitumor immunity; therefore, excessive elective nodal irradiation may compromise radiotherapy–immunotherapy synergy. This study evaluated the clinical benefit of PORT and examined whether radiation exposure to postoperative residual, clinically negative TDLN basins (rTDLNs) influences outcomes. We hypothesized that PORT confers benefit in selected patients and that sparing rTDLNs may preserve immune function and improve survival. Methods: We retrospectively analyzed 259 patients with locally advanced ESCC treated at six centers between January 2022 and December 2024. All patients underwent neoadjuvant Chemo-IO followed by curative esophagectomy (R0 resection) and had pathologically confirmed ypT3–4 and/or ypN+ disease. Endpoints were disease-free survival (DFS) and overall survival (OS). Multivariable Cox models evaluated the effects of PORT and adjuvant immunotherapy. Among PORT-treated patients (n=51), rTDLN basins were contoured and dose–volume histogram (DVH) metrics (V15/V30/V40; percent volume) were analyzed. Results: With a median follow-up of 26 months, 259 patients were included (115 ypN+, 164 ypT3–4). In the overall cohort, ypN+ independently predicted poorer DFS (HR=2.04, 95% CI 1.25–3.33; P=0.004) and OS (HR=2.38, 95% CI 1.23–4.76; P=0.010). Adjuvant immunotherapy was associated with improved OS (HR=0.48, 95% CI 0.25–0.91; P=0.024). In ypN+ patients (n=115), PORT was associated with improved OS compared with no PORT (median OS: 41.0 vs 32.4 months; HR=0.30, 95% CI 0.11–0.84; P=0.022), and adjuvant immunotherapy also conferred benefit (HR=0.32, 95% CI 0.14–0.75; P=0.009). No benefit of PORT was observed in ypN0 patients. In the PORT cohort (n=51), higher-dose irradiation to rTDLNs was associated with inferior survival. Cox regression showed that a greater proportion of rTDLN volume receiving higher radiation doses was a significant risk factor: V40 (HR=1.04, 95% CI 1.01–1.08; P=0.026) was associated with increased mortality, with similar trends for V30 (HR=1.03, P=0.052) and V15 (HR=1.03, P=0.093). Conclusions: In ESCC treated with neoadjuvant Chemo-IO and surgery, nodal status is the dominant prognostic factor and identifies patients most likely to benefit from PORT. However, higher dose exposure of postoperative residual, clinically negative rTDLN basins was associated with inferior survival, supporting a risk-adapted “TDLN-sparing” PORT strategy that targets high-risk regions while constraining rTDLN DVH exposure. Prospective validation is warranted.