Importance The optimal treatment strategy for locally advanced esophageal squamous cell carcinoma (ESCC) remains controversial. Neoadjuvant chemoradiotherapy (NCRT) followed by surgery and surgery with adjuvant therapy (AT) are commonly used approaches. Objectives To compare the long-term survival outcomes, safety, and pathological benefits of NCRT followed by surgery vs surgery with AT in patients with locally advanced ESCC, and to evaluate the survival impact of pathological complete response (pCR) in the NCRT subgroup. Design, Setting, and Participants This prospective, randomized, open-label phase 3 trial was conducted at Sichuan Cancer Hospital, China, between January 2018 and April 2020. Eligible patients were aged 18 to 75 years; had histologically confirmed, resectable, locally advanced thoracic ESCC, staged as cT1N+M0 or cT2-4aNxM0; were expected to survive more than 6 months; and had adequate organ function. Key exclusion included prior malignant neoplasms, distant or cervical lymph node metastasis, contraindications to surgery, and prior gastrectomy precluding reconstruction. Data were analyzed April to December 2024. Interventions Patients in the NCRT group received intensity-modulated radiotherapy (40 Gy in 20 fractions) with concurrent paclitaxel and carboplatin followed by surgery. Patients in the AT group received an adjuvant chemoradiotherapy regimen designed by a multidisciplinary team. Main Outcomes and Measures The primary end point was overall survival (OS). Secondary end points included disease-free survival (DFS), pathological outcomes, treatment-related toxic effects, and perioperative complications. Results A total of 254 patients were initially enrolled; after exclusions and randomization, 118 patients in the NCRT group (median IQR age, 62 54-66 years; 102 86.4% male) and 112 patients in the AT group (median IQR age, 63 55-66 years; 97 86.6% male) were included in the analysis. After a median (IQR) follow-up of 59.1 (54.4-65.9) months, there were no significant differences in OS or DFS between the groups. The 5-year OS rates were 59.2% (95% CI, 51.0%-68.8%) for the NCRT group and 59.6% (95% CI, 51.2%-69.5%) for the AT group (hazard ratio HR, 1.01; 95% CI, 0.67-1.51; P = .97). The 5-year DFS rates were 53.1% (95% CI, 44.7%-63.1%) and 56.5% (95% CI, 47.9%-66.7%), respectively (HR, 1.13; 95% CI, 0.77-1.68; P = .53). Subgroup analysis showed that patients achieving pCR in the NCRT group had significantly improved survival outcomes, with a 5-year OS rate of 76.5% (95% CI, 63.5%-92.1%) compared with 52.1% (95% CI, 42.4%-64.1%) for non-pCR patients (HR, 0.39; 95% CI, 0.18-0.82; P = .01). Conclusions and Relevance In this randomized clinical trial, there were no differences in OS or DFS for patients treated with NCRT followed by surgery or surgery with AT. However, for the patients who achieved pCR with NCRT, there were significant advantages, with markedly improved long-term outcomes. Nevertheless, neoadjuvant chemoradiotherapy did not benefit all patients; for those less likely to respond, the combination of surgery with postoperative AT remains a reasonable strategy. These findings show that it may not be appropriate to universally recommend neoadjuvant chemoradiotherapy for all patients. Trial Registration ClinicalTrials.gov Identifier: NCT06775652
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