Combination of SBRT and Immunotherapy in Small Hepatocellular Carcinoma (HSBRT2402)

Stereotactic Body Radiotherapy With or Without Adjuvant Immunotherapy for Small Hepatocellular Carcinoma: An Open-label, Randomized, Phase II Trial

For inoperable small hepatocellular carcinoma (HCC), stereotactic body radiotherapy (SBRT) is an effective and safe local treatment. Despite satisfactory local control rate, the incidence of recurrence out the field remains substantial, with 2-year PFS of 31.9% to 60.9%. Therefore, a more effective treatment mode is urgently needed. Immune checkpoint inhibitors targeting PD-1/PD-L1 have shown substantial clinical benefits in advanced HCC as well as resected high-risk HCC. Recently, the combination of immunotherapy with SBRT has shown promising activity in HCC, but its utility in small HCC is unclear. The aim of this study was to investigate the efficacy and safety of SBRT followed by sintilimab (an anti-PD-1 antibody) in patients with recurrent or residual small HCC.

A total of 140 patients with recurrent or residual small HCC will be stratified according to tumor diameter (≤3 vs. >3 cm) and tumor type (recurrent vs. residual) and randomly assigned (1:1) to receive stereotactic body radiotherapy (SBRT) with or without adjuvant sintilimab for 6 cycles (200 mg, once every 3 weeks, with the first dose within 1 week after the completion of SBRT).

Inclusion Criteria:

1. Histologically confirmed hepatocellular carcinoma or diagnosed by American Association for the Study of Liver Disease criteria;
2. Presence of recurrent or residual HCC lesions without vascular invasion or extrahepatic metastasis confirmed by CT or MRI, the sum of the maximum diameter of lesions ≤5 cm, total number of lesions were ≤2, and at least one of which is measurable according to the RECIST 1.1 Criteria;
3. Previous molecular targeted therapy or intravenous chemotherapy is allowed, but the interval of drug withdrawal was at least 6 months prior to protocol therapy;
4. Age at diagnosis 18 to 75 years;
5. Eastern Cooperative Oncology Group performance status ≤ 2
6. Child-Pugh class A liver function;
7. Normal liver volume greater than 700 ml;
8. Estimated life expectancy ≥24 weeks;
9. The function of important organs meets the following requirements: a. white blood cell count (WBC) ≥ 3.0×109/L, absolute neutrophil count (ANC) ≥ 1.5×109/L; b. platelets ≥ 50×109/L; c. hemoglobin ≥ 9g/dL; d. serum albumin ≥ 2.8g/dL; e. total bilirubin ≤ 1.5×ULN, ALT, AST and/or AKP ≤ 2.5×ULN; f. serum creatinine ≤ 1.5×ULN or creatinine clearance rate >60 mL/min;
10. Ability to understand the study and sign informed consent.

Exclusion Criteria:

1. Patients who have previously been treated with immune checkpoint inhibitors;
2. Patients with extrahepatic metastasis disease;
3. A history of abdominal radiotherapy;
4. Known or suspected allergy or hypersensitivity to monoclonal antibodies;
5. Patients who have a preexisting or coexisting bleeding disorder;
6. Female patients who are pregnant or lactating;
7. Inability to provide informed consent due to psychological, familial, social and other factors;
8. A history of malignancies other than hepatocellular carcinoma before enrollment, excluding non-melanoma skin cancer, in situ cervical cancer, or cured early prostate cancer;
9. A history of diabetes for more than 10 years and poorly controlled blood glucose levels;
10. Patients who cannot tolerate radiotherapy due to severe cardiac, lung, liver or kidney dysfunction, or hematopoietic disease or cachexia;
11. Active autoimmune diseases, a history of autoimmune diseases (including but not limited to these diseases or syndromes, such as colitis, hepatitis, hyperthyroidism), a history of immunodeficiency (including a positive HIV test result), or other acquired or congenital immunodeficiency diseases, a history of organ transplantation or allogeneic bone marrow transplantation;
12. A history of interstitial lung disease or non-infectious pneumonia;
13. A history of active pulmonary tuberculosis infection within 1 year or a history of active pulmonary tuberculosis infection more than 1 year ago but without formal anti-tuberculosis treatment;
14. Presence of active hepatitis B (HBV DNA ≥ 2000 IU/mL or 104 copies/mL), hepatitis C (positive for hepatitis C antibody, and HCV-RNA levels higher than the lower limit of the assay);
15. Any unstable situation that may endanger the safety and compliance of patients.