Postoperative Radiotherapy Involving Tumor Bed with or without Elective Nodal Irradiation in Patients with Locally Advanced Esophageal Squamous Cell Carcinoma: A Multi-Center, Prospective Randomized Phase II Trial

Abstract

<h3>Purpose/Objective(s)</h3> Postoperative radiotherapy (PORT) is necessary in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC) who have not received neoadjuvant chemoradiotherapy (NCRT). However, the optimal clinical target volume has under hot debate for decades. This clinical trial aims to estimate the optimal radiation volume of PORT for patients with LA-ESCC. <h3>Materials/Methods</h3> Patients confirmed LA-ESCC (pT3-4N0-3M0) after esophagectomy without NCRT were randomly assigned to either large-field irradiation (LFI, primary lesion and lymph node tumor bed plus elective nodal irradiation) arm or small-field irradiation (SFI, primary lesion and lymph node tumor bed alone) arm with a ratio of 1:1, stratified by T stage and number of lymph node metastasis (LN<3 vs LN≥3). The primary endpoint was disease-free survival (DFS); secondary endpoints included overall survival (OS), adverse events and first failure patterns. The log-rank test was used to estimate the survival differences. The Chi-square test was used to compare adverse events and failure patterns between groups. <h3>Results</h3> In the intention-to-treat analysis, a total of 401 patients with LA-ESCC were randomly assigned to the LFI arm (n=210) and the SFI arm (n=191). With a median follow-up of 38.9 months, the DFS and OS rates of the whole population at 1-year and 3-year were 72.9% and 51.8%, 88.4% and 61.7%, respectively, which were close to patients who received NCRT. Patients in the two irradiation arms had similar DFS (LFI vs SFI, 46.6 vs 48.1 months; HR=0.92, 95% CI, 0.68-1.25; p=0.60). The difference of OS between the two arms did not reach significant (NR vs 73.5 months, HR=0.82, 95% CI, 0.59-1.14; p=0.26). The locoregional recurrence-free survival (HR=0.57, 95% CI 0.35-0.92; p=0.022) and the failure patterns (p=0.021) between two arms were significantly different. Locoregional failure occurred in 12.9% and 20.4% of patients in the LFI arm and SFI arm, respectively; The differences of distant diseases and distant metastasis-free survival of patients between the two arms had no significance. The most frequent toxicity was grade 2 esophagitis (LFI vs SFI, 22.9% vs 16.8%). Grade 3 acute adverse events occurred in 6.7% and 2.6% of patients in the LFI and SFI arms, respectively. No toxicity of grade 4 or 5 was recorded in this study. <h3>Conclusion</h3> Both postoperative irradiation fields are alternatives for LA-ESCC patients without NCRT with the promising survival outcomes comparable to CROSS study. Patients in the LFI arm achieved better locoregional control with a safety profile consistent with the SFI arm.