Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide.^1-3 Surgical removal and liver transplantation are preferred, however, only 30% of patients are eligible for curative treatment at presentation.¹ Stereotactic body radiotherapy (SBRT) is a promising local treatment modality that has been included in recent international guidelines as an alternative therapy for HCC.^1,3 A local retrospective study led by researchers from the Department of Surgery, School of Medicine, LKS Faculty of Medicine of the University of Hong Kong (HKUMed) compared the clinical benefits of immunotherapy plus SBRT (SBRT-IO) with SBRT alone in patients with nonmetastatic, unresectable HCC.¹ SBRT-IO was found to be associated with more optimal survival outcomes and tumor response rate compared to SBRT alone.¹

SBRT is a type of external beam radiotherapy that exposes the tumor to precise, high fractional doses of radiation, thereby yielding local control of HCC lesions for up to 90%.² Previous studies have established the efficacy and safety of SBRT as a treatment for early-stage HCC and bridging treatment before liver transplantation.^1,3 Nevertheless, some patients may develop intra-hepatic or distant metastasis even if radiation can ablate the tumor, which supports the rationale of combining SBRT with systematic therapy in unresectable HCC.¹ Preclinical studies have suggested SBRT’s non-antagonistic relationship with checkpoint inhibitors and its role as a modulator of the tumor microenvironment, while a phase II trial has demonstrated favorable survival outcomes in patients with unresectable HCC under a combined treatment of transarterial chemoembolization (TACE) and SBRT followed by anti-PD-L1 antibody.¹ Although increasingly more studies have shown the promising efficacy and safety profile of SBRT-IO, this study was the first to compare the benefits of SBRT-IO with SBRT-alone in patients with unresectable HCC.¹

This retrospective study included 100 Hong Kong patients with nonmetastatic, unresectable HCC who were diagnosed and treated at two local hospitals between 2016 and 2022.¹ The study population had ≤3 tumor nodules, ≥700mL of uninvolved liver, a Child-Pugh score of A5 to B7, absence of extrahepatic metastasis, ascites, or encephalopathy, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, adequate liver, renal and bone marrow functions, and no prior systemic therapy.¹ Seventy patients received SBRT only (SBRT-alone), while 30 patients were treated with intravenous nivolumab (3mg/kg) starting from 14 days (+/-3 days) after completing SBRT (SBRT-IO).¹ Nivolumab was given every 2 weeks until the development of grade ≥3 immune-related adverse events (irAEs), progression or patients’ refusal.¹ Median number of cycles of nivolumab was 9 cycles (IQR: 5-12 cycles) over a median duration of 4.2 months (IQR: 2.3-5.5 months), while the median dose of SBRT prescribed was 30 Gy in 5 fractions (range: 25-45 Gy in 5 fractions) in both groups (p=0.408).¹

Clinical endpoints of this study included but were not limited to overall survival (OS), time to progression (TTP), local control (LC), objective response rate (ORR) per modified response evaluation criteria in solid tumors (mRECIST), disease control rate (DCR), the incidence of Child-Pugh score progression by ≥2, percentage of patients who had curative surgery done after successful downstaging, the pattern of disease progression, and radiological response per RECIST v1.1.¹ Propensity score matching was used to adjust for potential confounding effects of treatment and selection bias.¹

After propensity score matching, 25 and 50 patients from the SBRT-IO and SBRT-alone groups were selected.¹ The SBRT-IO group had significantly better 1-year (92% vs. 74%), 2-year (82% vs. 54%), and 3-year OS (64% vs. 33%) than the SBRT-alone group (p=0.034).¹ The 1-year (69% vs. 59%), 2-year (69% vs. 41%), and 3-year TTP (61% vs. 33%) in the SBRT-IO group were also more desirable than in the SBRT-alone group (p=0.057).¹ The ORR of the SBRT-IO group per mRECIST was significantly higher than that of the SBRT-alone group (88% vs. 50%, p=0.001), while a trend of better DCR was also observed in the SBRT-IO group (88% vs. 66%, p=0.121).¹ SBRT-IO was also associated with less treatment failure at 24 months (28% vs. 56%, p=0.022) and 36 months (32% vs. 62%, p=0.014).¹ The benefits of SBRT-IO were observed in both patients with and without macrovascular invasion (MVI).¹

There were no significant differences in the rates of grade ≥3 treatment-related adverse events (TRAEs) or safety concerns between the 2 arms.¹ SBRT-IO was associated with a significantly higher treatment discontinuation rate (p=0.003), which was consistent with that reported in previous checkpoint inhibitor studies in HCC patients.¹

In summary, the findings of this study illustrated the promising potential of SBRT-IO as a treatment option for patients with unresectable HCC.¹ The remarkable tumor response rate of SBRT-IO also facilitated tumor downsizing, which translated to additional survival advantages.¹ To validate the survival benefits of SBRT-IO, supplementary clinical data from future prospective, randomized, controlled studies will be required.¹