Continuation of first-line therapy with radiotherapy for oligoprogression versus early switch to second-line therapy in oligoprogressive hepatocellular carcinoma (CROSS): study protocol of a multicentre, randomised, controlled, open-label, phase III trial.

introductionTreatment options remain limited for patients with advanced hepatocellular carcinoma (HCC) who experience oligoprogression during first-line systemic therapy (FLST), especially given the modest efficacy and restricted availability of second-line systemic therapy (SLST). This trial aims to evaluate whether continuing FLST combined with radiotherapy (RT) to oligoprogressive lesions can improve progression-free survival (PFS) compared with an early switch to SLST in patients with oligoprogressive HCC while maintaining an acceptable safety profile. METHODS AND ANALYSIS: The continuation of first-line therapy with radiotherapy for oligoprogression versus early switch to second-line therapy in oligoprogressive hepatocellular carcinoma trial is a prospective, multicentre, randomised phase III study that will enrol 132 patients with advanced HCC who experience their first oligoprogression during FLST. Oligoprogression is defined as one to five progressive lesions involving no more than one to three organs. Participants will be randomised (1:1) to either continuation of FLST combined with RT to all oligoprogressive lesions or discontinuation of FLST followed by initiation of SLST. RT will be delivered with a biologically effective dose (linear-quadratic model, α/β=10) of at least 60 Gy whenever feasible. The primary endpoint is PFS. Secondary endpoints include overall survival, objective response rate, disease control rate, duration of response and quality of life. Predefined exploratory analyses include circulating tumour DNA profiling, optional paired tumour biopsies, functional imaging with fibroblast activation protein inhibitor positron emission tomography-CT and longitudinal immune profiling. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of the Affiliated Cancer Hospital of Shandong First Medical University (number: SDZLEC2025-025-02) and has been registered in ClinicalTrials. gov (NCT06841172). Final study results will be disseminated through peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT06841172.