Different Radiation Dose of Neoadjuvant Chemoradiation for Resectable Thoracic Esophageal Squamous Carcinoma: A Randomized Phase II Clinical Trial

Abstract

Radiation dose used in the neoadjuvant chemoradiotherapy (nCRT) for patients with locally advanced esophageal squamous cell carcinoma (ESCC) varies in clinical practice, no prospective studies have been conducted on this issue. The hypothesis of this study is that higher radiation dose in nCRT was associated with improved progression free survival in resectable ESCC. A phase II prospective randomized controlled trial was conducted from February 22, 2018 to February 22, 2021 in Zhejiang Cancer Hospital (NCT03381651). Patient with locally resectable advanced thoracic ESCC (cT2-T4aNxM0, T1-3N+M0) were randomized 1:1 to receive nCRT with different radiation doses of 50.4 Gy/28F and 41.4 Gy/23F, weekly TC regimen (paclitaxel 50 mg/m2, d1, carboplatin AUC = 2, d1) was administered as concurrent chemotherapy. The primary endpoint was 2-year progression free survival (PFS), and the secondary endpoints included complete pathological response (pCR) rate, overall survival (OS), local recurrence free survival (LRFS), and distant metastasis free survival (DMFS). The last follow-up date was February 22, 2022 and data analysis was performed from May 1, 2022, to October 31, 2022. A total of 147 patients were enrolled in the prospective study, including 72 patients in 50.4 Gy/28F group and 75 patients in 41.4 Gy/23F group. Among all the patients, 101 patients finally underwent surgical resection, 23/46(50%) achieved pCR in the high-dose group, while 18/55(32.7%) achieved pCR in the low-dose group (P = 0.10). In intention-to-treat population analysis, 2-year PFS in the high-dose and low-dose groups were 53.5% (95% CI: 42.9-66.7%) and 45.5% (95% CI: 35.4%-58.5%), respectively, and hazard ratio (HR) was 0.72 (95% CI: 0.46-1.12, P = 0.14). Median PFS were 44.4 months (95% CI: 16-NA) versus 20.8 months (95% CI: 15-NA) in high and low dose groups. 2-year OS in the high and low-dose groups were 61.8% (95% CI: 51.2 -74.5%) and 60.5% (95% CI: 50.3 -72.8%), respectively, with a HR = 0.78(95% CI: 0.48-1.27, P = 0.32). Median OS were not arrived in both groups up to the last follow-up. In addition, 2-year LRFS were 87.9% (95% CI: 78.4-98.5%) and 74.8% (95% CI: 63.3-88.3%) in high and low-dose groups, while 2-year DMFS were 70.6% (95% CI: 58.3-85.5%) and 73.6% (95% CI: 61.7-87.8%), respectively. No significant statistical difference was observed between the two groups in terms of side effects during nCRT and postoperative complications. Our results showed that neoadjuvant high-dose radiotherapy failed to improve overall survival in ESCC. However, it was found that pCR and local tumor control rates tended to be increased at 50.4 Gy/28F, compared to 41.4 Gy/23F, although the trend was not statistically significant. There was no significant difference in treatment side effects between the two groups. Longer-term follow-up is required to verify our findings.