Induction Immunochemotherapy Followed by Concurrent Chemoradiotherapy for Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma (RICE): A Prospective, Single-Arm, Phase II Trial

Concurrent chemoradiotherapy (CCRT) is the standard treatment for unresectable locally advanced esophageal squamous cell carcinoma (LA-ESCC), yet its 5-year overall survival (OS) is below 30%. In the era of immunotherapy, neoadjuvant immunochemotherapy (ICT) has demonstrated promising outcomes in resectable LA-ESCC, thus we extended this strategy to unresectable LA-ESCC by incorporating induction ICT before definitive CCRT. It is hypothesized that induction ICT can reduce tumor burden and target volume in CCRT. Besides, early intervention of ICT may eliminate micro-metastases, enhancing overall treatment efficacy. In this study, we assessed the safety and effectiveness of induction ICT followed by CCRT in patients with unresectable LA-ESCC. Patients aged over 18 with untreated, inoperable LA-ESCC were recruited for this trial. Two cycles of ICT (nab-paclitaxel 200mg/m 2 d1 q3w + carboplatin AUC = 5 d1 q3w + PD-1 inhibitor 200mg d1 q3w) were administered before CCRT (50.4Gy/28Fx; paclitaxel liposome 50mg/m 2 d1 qw + carboplatin AUC = 2 d1 qw for 5-6 cycles). Subsequently, patients were given consolidation immunotherapy for up to one year. The primary endpoint was 1-year OS, and secondary endpoints included safety, progression-free survival (PFS) and objective response rate (ORR). Safety was evaluated by grade 3 or higher adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) 5.0. The Kaplan-Meier method was used to estimate OS and PFS. Between May 2021 and November 2023, 51 patients (median age 67, 88.2% male) in stage II-IVB were enrolled. 50 (98.0%) patients completed 2 cycles of ICT and 48 (94.1%) underwent CCRT. Among these patients, 44 (91.7%) completed the radiotherapy, but only 29 (60.4%) were able to complete 5 or more cycles of weekly concurrent chemotherapy. Evaluation after CCRT revealed an ORR of 91.7%. After a median follow-up of 12 months, the 1-year PFS was 76%, and 1-year OS was 92.9%. Median PFS and OS were not reached. 13 patients (25.5%) and 40 patients (83.3%) had grade 3 or above AEs during ICT and CCRT, respectively. Common grade 3 or above AEs included lymphopenia (78.4%), leukopenia (31.4%), neutropenia (17.6%), thrombocytopenia (11.8%), anemia (9.8%) and esophagitis (5.9%). One patient died from esophageal fistula. Preliminary findings from the trial indicated both favorable safety profiles and promising efficacy of integrating induction ICT prior to CCRT as the first-line treatment for unresectable LA-ESCC. Long-term survival benefits require further follow-up.