Fraction dose escalation of split-course concurrent chemoradiotherapy following induction chemo-immunotherapy in unresectable locally advanced oesophageal squamous carcinoma in China (GASTO-10102): a single-centre phase 1 study

Background: The optimal fractionation patterns and safety of hypofractionated radiotherapy remain poorly defined in locally advanced oesophageal squamous cell carcinoma (LA-ESCC). We aimed to determine the maximum tolerated fraction dose (MTFD) of split-course concurrent chemoradiotherapy (CCRT) following induction chemo-immunotherapy in patients with LA-ESCC. Methods: , twice daily on days 1-14 of each radiotherapy course). Radiotherapy was delivered in two courses separated by a 4-week break using volumetric modulated arc therapy. Three dose levels were evaluated sequentially in cohorts of six patients: level 1 (30 Gy in 10 fractions + 20 Gy in 10 fractions), level 2 (28 Gy in 7 fractions + 22 Gy in 10 fractions), and level 3 (25 Gy in 5 fractions + 25 Gy in 10 fractions). The primary endpoint was MTFD within 12 months after completion of CCRT. The primary endpoint and safety analysis were assessed in all patients who received any study treatment. The trial is registered with ClinicalTrials.gov, NCT06020885. Findings: Between Aug 31, 2023, and July 23, 2024, 18 patients were enrolled (n = 6 per dose), and all completed split-course CCRT per protocol. The MTFD was not reached, and dose level 3 was tolerable. The most common grade 3 toxicity was lymphopenia (72.2%), followed by esophagitis (11.1%). No grade 4 or 5 toxicities occurred. The objective response rate after induction therapy was 100%. After CCRT, the clinical complete response rate was 83.3%. With a median follow-up of 20.5 months, median progression-free and overall survival were not reached; 1-year rates were 88.9% and 94.4%, respectively. Interpretation: Fraction dose-escalated split-course CCRT following induction chemo-immunotherapy was feasible, well tolerated, and showed encouraging preliminary efficacy. Larger prospective studies are warranted. Funding: The National Key Research and Development Program of China and the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center.