Effect of Adjuvant Radiation Dose on Survival in Patients with Esophageal Squamous Cell Carcinoma

SIMPLE SUMMARY: For patients with esophageal cancer, postoperative radiotherapy (PORT) improved LRFS. However, concerns about treatment-related toxicity issues limited its application. The authors found that for patients receiving upfront surgical resection, with adjuvant radiation dose (aRTD) escalation, the hazard ratio (HR) of LRFS declined until aRTD exceeded 50 Gy, then remained steady. However, HR of treatment-related mortality was stable until aRTD exceeded 50 Gy, then it increased. There is an adequate aRTD that can afford balanced PORT-related LRFS enhancement and related toxicity. The authors highlighted that clinicians should be aware that PORT has the potential to improve unfavorable LRFS and survival outcomes in ESCC patients treated with upfront surgery. The findings of the current study could serve as evidence for delivering appropriate aRTD and designing additional prospective stratified randomized controlled trials. ABSTRACT: Background: For patients with esophageal squamous cell carcinoma (ESCC) treated with surgery alone, the incidence of local-regional recurrence remains unfavorable. Postoperative radiotherapy (PORT) has been associated with increased local-regional recurrence-free survival (LRFS), although its application is limited by concerns of PORT-related toxicities. Methods: Among 3591 patients with ESCC analyzed in this study, 2765 patients with T3-4N0 and T1-4N1-3 lesions and specific local-regional status information were analyzed in a subsequent analysis of adjuvant radiation dose (aRTD) effect. Application of the restricted cubic spline regression model revealed a non-linear relationship between aRTD and survival/radiotoxicity. Linear regression analysis (LRA) was performed to evaluate correlations between LRFS and overall survival (OS)/ disease-free survival (DFS). Results: For patients staged T1–2N0, T1–2N1–3, T3–4N0, and T3–4N1–3, 5-year OS in PORT and non-PORT groups were 77.38% vs. 72.91%, p = 0.919, 52.35% vs. 46.60%, p = 0.032, 73.41% vs. 61.19%, p = 0.005 and 38.30% vs. 25.97%, p < 0.001. With aRTD escalation, hazard ratios (HRs) of OS/DFS declined until aRTD exceeded 50Gy, then increased, whereas that of LRFS declined until aRTD exceeded 50 Gy, then remained steady. HR of treatment-related mortality was stable until aRTD exceeded 50 Gy, then increased. LRA revealed strong correlations between LRFS and OS/DFS (r = 0.984 and r = 0.952, respectively). An absolute 1% advancement in LRFS resulted in 0.32% and 0.34% improvements in OS and DFS. Conclusions: An aRTD of 50Gy was well-tolerated, with favorable survival resulting from PORT-related LRFS improvement in patients staged T3–4N0 or T1-4N1–3. Further stratification analyses based on tumor burden would help determine potential PORT-beneficiaries.