Approximately 70% of hepatocellular carcinoma (HCC) patients are diagnosed at an advanced stage, with no opportunity for curative treatments. For these patients, systemic therapies are the main treatment modalities. However, the objective response rates of first-line systemic treatments are currently only 20-35%, and most patients inevitably develop drug resistance and disease progression during treatment, thus taking second-line therapies. Second-line treatment options include regorafenib, pembrolizumab, and others, but clinical studies have shown a median progression-free survival of only 2.6-3.1 months, indicating an urgent need to improve efficacy.
Stereotactic body radiotherapy (SBRT) has been widely used in recent years for curative treatment of early-stage liver cancer or as neoadjuvant and adjuvant therapy for patients with portal vein tumor thrombus. It is one of the important approaches in the multidisciplinary management of HCC. Researches have shown that SBRT has a synergistic effect with systemic drug therapy, potentially enhancing the efficacy of targeted and immunotherapies. Therefore, this study aims to conduct a prospective, randomized, controlled phase II clinical trial in patients with oligoprogressive HCC after standard first-line systemic treatment to evaluate whether adding SBRT to second-line systemic therapy can improve the efficacy of second-line treatment. The primary endpoint of the study is progression-free survival (PFS), while secondary endpoints include overall survival (OS), objective response rate (ORR), and treatment-related adverse events. We aim to comprehensively assess the effectiveness and safety of combining SBRT with second-line systemic therapy in treating oligoprogressive HCC patients.
KPS (Karnofsky Performance Status) score ≥ 80;
Pathologically, or clinically diagnosed hepatocellular carcinoma (HCC) based on the " Chinese Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma (2024 Edition) ";
Patients with oligoprogression after first-line standard systemic therapy (bevacizumab combined with atezolizumab/sintilimab or lenvatinib with or without PD-1 antibody).
All oligoprogressive lesions are deemed suitable for radiotherapy, with a maximum diameter of any single oligoprogressive lesion not exceeding 5 cm, and at least one measurable lesion (according to RECIST v1.1 criteria); bone metastases without soft tissue formation are eligible but considered non-measurable lesions; if bone metastases have soft tissue formation and meet measurable criteria, they are considered measurable lesions;
Received first-line treatment other than bevacizumab combined with atezolizumab/sintilimab or lenvatinib with or without PD-1 antibody;
Tumor progression within 3 months after first-line standard systemic therapy;
Experienced ≥ Grade 3 severe adverse reactions after first-line standard therapy;
Brain metastasis with hemorrhage at baseline or after first-line systemic therapy;
Parallel
SBRT and second-line systemic therapy
RadiationPatients in the SBRT arm will receive second-line systemic therapy combined with SBRT. The choice and stipulations for second-line systemic therapy drugs are the same as those for the control arm.SBRT will be administered to all oligoprogressive lesions and must begin within 2 weeks after the start of second-line therapy. Systemic therapy will not be paused during SBRT. Patients who do not withdraw from the study will not receive crossover treatment; however, if a patient in the control group withdraws from the study due to tumor progression and is assessed as suitable for SBRT, salvage SBRT will be administered promptly.
Second-line systemic therapy
DrugPatients in the control arm will receive second-line systemic therapy. The following stipulations apply to the second-line treatment drugs: for patients who received bevacizumab combined with atezolizumab/sintilimab as the first-line treatment, lenvatinib or regorafenib will be used for second-line treatment; for patients who received lenvatinib with or without PD-1 antibody as the first-line treatment, regorafenib combined with another PD-1 antibody will be used for second-line treatment.
progression-free survival, PFS
PFS is defined as the time from treatment to the first confirmed disease progression based on imaging assessment according to the RECIST v1.1 criteria.
objective response rate，ORR
The ratio of patients achieving the best efficacy of the corresponding interventions, including complete response (CR) and partial response (PR), to all patients in the arm.
overall survival, OS
OS is defined as the time from treatment beginningto death from any cause
Incidence of adverse events (safety )
Treatment-related adverse events are evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE 5.0)
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