Phase Ii Randomized Trial of 41.4 Gy Vs. 50.4 Gy in Neoadjuvant Chemoradiotherapy for Resectable Esophageal Cancer Publisher



Esmati E ; Nazari R ; Aqamolaei A ; Maddah Safaei A ; Miri R ; Shirkhoda M ; Jalaeefar A ; Salarvand S ; Aghili M ; Farhan F ; Mousavi Darzikolaee N ; Kolahdouzan K ; Abyaneh R ; Ghalehtaki R
Source: Clinical and Translational Radiation Oncology Published:2026

Abstract

AbstractBackgroundThe optimal total dose of radiotherapy for non-metastatic resectable esophageal cancer remains unclear. We compared standard (41.4 Gy) versus intensified (50.4 Gy) chemoradiotherapy (CRT) regimen.MethodsIn a prospective, phase II, randomized controlled trial (Iran Cancer Institute, March 2021-March 2023), non-metastatic resectable esophageal cancer patients were randomly assigned 1:1 to 41.4 Gy or 50.4 Gy plus weekly carboplatin-paclitaxel followed by surgery, unless a clinical complete response (cCR) was confirmed or the patient refused. The primary outcome of the study was the composite major response rate, defined as pathological complete response (pCR)/pathological near complete response (pnCR) for surgical patients and cCR for non-surgical patients. Survival outcomes and toxicity were secondary outcomes.ResultsSeventy-eight patients were randomized; 70 cases received the allocated CRT in the standard group (34) and intensified group (36). Subsequently, 23 and 21 patients underwent surgery, respectively. The composite major response rate was 54.8% versus 65.6% in the standard and intensified arms, respectively (p = 0.382). The cCR rates were 35.48%vs 45.16%, respectively(p = 0.437). Among resected patients, pCR rates were 45.45% vs 52.38% (p = 0.650), and R0 resection rates were 95.2% vs 100%, respectively. No significant differences were observed between treatment groups in overall and disease-free survival. Grade 2 or higher pneumonitis was significantly more frequent with 50.4 Gy (25% vs 5.9%, p = 0.028). Additionally, cCR predicted pCR with high specificity (90.5%) but modest sensitivity (60%).ConclusionsEscalating the total dose of neoadjuvant radiotherapy from 41.4 Gy to 50.4 Gy did not improve response rates or survival but significantly increased pneumonitis. Radiotherapy with a 41.4 Gy dose and concurrent carboplatin-paclitaxel, also known as the CROSS regimen, remains an optimal standard. Our findings also highlight a key clinical dilemma: while a cCR can identify candidates for organ preservation, but does not reliably exclude residual disease.Trial registration: IRCT20250118064427N1 (Registration date: 2025–07-28). © 2026 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. This is an open access article under the CC BY-NC-ND license. http://creativecommons.org/licenses/by-nc-nd/4.0/