PROTOCOL: Immunomodulatory Low-dose Radiotherapy Combined with Chemoimmunotherapy for Conversion Therapy of Locally Advanced Borderline/Potentially Resectable Esophageal Squamous Cell Carcinoma: A Single Arm, Single Center, Prospective Trial (ROICE Trial)

Abstract

Background Radiotherapy and immunotherapy can be synergistically combined, and studies on immunotherapy combined with neoadjuvant chemoradiotherapy (nCRT) have achieved pathologic complete response (pCR) rates that exceed those of conventional nCRT. However, no data have confirmed that a pCR increase leads to overall survival (OS) improvements. The low-dose radiotherapy (LDRT) immunomodulatory function has attracted much attention in recent years. The purpose of this study is to investigate the efficacy and safety of low-dose immunomodulatory radiotherapy (iRT) combined with chemoimmunotherapy to convert locally advanced borderline/potential resectable esophageal squamous cell carcinoma (ESCC).Methods Forty-three pathologically confirmed thoracic ESCC patients with stage cT3-4NxM0 whose clinical primary lesions were not completely (R0) resectable and/or stage cT2-4N+M0 with unresectable metastatic lymph nodes were enrolled. The participants will receive the following radiotherapy combined with chemoimmunotherapy. The iRT prescribed doses for cycles 1−2 will be 6 Gy (2 Gy/Fr × 3 Fr), days 1−3, 22−24, and 6 Gy (3 Gy/Fr × 2 Fr) on days 1−2, 22−23 once a day. An intravenous drip of tislelizumab at 200 mg will be used after radiotherapy on the last day of iRT (on days 3 and 24 (2 Gy/Fr × 3 Fr regimen) or days 2 and 23 (3 Gy/Fr × 2 Fr regimen) at cycles 1–2, and at the third cycle be used on the second day after chemotherapy (on day 44). Chemotherapy (nanoparticle albumin-bound (nab-) paclitaxel at 175−260 mg/m2 + carboplatin area under the curve (AUC) = five days will be used on the 1st, 22nd, and 43rd days at cycles 1−3). Patients feasible for R0 resection following the third treatment cycle will be identified as successful conversions and undergo radical surgery. Patients with non-pathological complete response (pCR) results after esophagectomy will receive adjuvant chemotherapy combined with immunotherapy (nab-paclitaxel plus carboplatin and tislelizumab) for two cycles. Patients with postoperative stage ypT3-4N0 or N+ or R1/R2 resection will be considered to receive supplemental postoperative adjuvant radiotherapy according to the Chinese radiotherapy ESCC guideline. Unsuccessful conversion patients may receive definitive chemoradiotherapy based on the guideline (radiotherapy dose: 50 Gy/25 Fr, once a day, five times a week; nab-paclitaxel plus carboplatin, three-weekly regimen × two cycles). It will be determined whether immunotherapy could be combined with postoperative adjuvant therapy after a full pneumonia risk assessment. The primary endpoint of this study is the R0 resection rate. The secondary endpoints include safety, the conversion rate, the objective response rate (ORR), the pCR rate, the major pathologic response (MPR) rate, the event-free survival (EFS), and the overall survival (OS).Discussion This protocol was reviewed and approved by the Ethics Committee of the Nanjing Drum Tower Hospital (No. 202416802). This prospective clinical trial will be used to investigate the safety and efficacy of iRT combined with chemoimmunotherapy for conversion therapy of locally advanced borderline/potential resectable ESCC. We hypothesize that iRT combined with chemoimmunotherapy for conversion therapy will be a promising therapeutic strategy that could provide the required R0 resection rate in patients with borderline/potential resectable ESCC.