Particle Radiation Therapy With Immunotherapy for Advanced Hepatocellular Carcinoma: Emerging Evidence and Remaining Questions

The recent study by Kuo YH and colleagues [1] addresses a clinically important and timely question: whether the addition of proton beam therapy to first-line atezolizumab plus bevacizumab can improve outcomes in patients with advanced hepatocellular carcinoma (HCC). In an era in which immune checkpoint inhibitor–based combination therapy has become the standard of care for advanced HCC, the potential role of integrating particle radiation therapy into systemic treatment strategies remains an area of active investigation. HCC continues to pose a substantial global health challenge and accounts for the third highest number of cancer-related deaths worldwide [2]. Although systemic treatment options for advanced HCC have expanded considerably with the advent of immune checkpoint inhibitor–based therapies, clinical outcomes remain suboptimal in a substantial proportion of patients. Treatment allocation for HCC is commonly guided by the Barcelona Clinic Liver Cancer (BCLC) staging system, which integrates tumour burden, liver functional reserve, and patient performance status [3]. Within this framework, systemic therapy represents the cornerstone of management for patients with intermediate-stage disease unsuitable for locoregional approaches as well as those with advanced-stage HCC [3]. Several landmark randomised controlled trials (RCTs) have established the clinical benefit of immune-based combination regimens. The combination of atezolizumab and bevacizumab (Atez/Bev), consisting of a programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor (VEGF) inhibitor, demonstrated superior progression-free survival (PFS) and overall survival (OS) compared with sorafenib in patients with advanced HCC [4]. Likewise, the dual immune checkpoint blockade with durvalumab and tremelimumab—targeting PD-L1 and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), respectively—was shown to confer an OS advantage over sorafenib [5]. More recently, the combination of nivolumab and ipilimumab, inhibiting programmed death-1 (PD-1) and CTLA-4 pathways, achieved improved survival outcomes compared with sorafenib or lenvatinib [6]. Collectively, these data have led to the incorporation of immune checkpoint inhibitor–based combination therapies as preferred first-line systemic treatment options for patients with advanced HCC who have not previously received systemic therapy, as reflected in contemporary clinical practice guidelines [3, 7]. Particle radiation therapy, including proton beam therapy (PBT) and carbon ion radiotherapy (CIRT), has demonstrated excellent local tumour control with an acceptable safety profile in patients with HCC [8, 9]. A large prospective multicenter registry study [8] conducted in Japan evaluated 567 patients who received PBT between May 2016 and June 2018. In this cohort [8], the median age was 71 years, 437 patients (75.9%) were male, the median tumour size was 35 mm, and approximately 80% of patients had Child–Pugh class A liver function. The cumulative local recurrence rates at 1, 2, 3, and 4 years were 3.5% (95% confidence interval [CI], 1.8–5.1), 8.8% (95% CI, 6.1–11.6), 10.8% (95% CI, 7.7–14.0), and 11.9% (95% CI, 8.5–15.3), respectively. The corresponding OS rates were 83.8% (95% CI, 80.5–86.6), 68.5% (95% CI, 64.5–72.2), 58.2% (95% CI, 53.9–62.2), and 50.1% (95% CI, 44.9–55.0), with a median OS of 48.8 months. Grade ≥ 3 adverse events occurred in 27 patients (4.7%), most commonly liver failure (n = 7) and dermatitis (n = 7). Furthermore, a systematic review [9] including 1516 patients from 17 studies—comprising 11 PBT studies, 2 combined PBT/CIRT studies, and 4 CIRT-only studies—reported favourable outcomes. Across the included studies [9], the mean number of lesions was 1.13 (range, 1–1.32), the median tumour size was 47.5 mm (range, 25–90 mm), and approximately 70% of patients had Child–Pugh class A liver function. The pooled weighted local control rates were 86%, 89%, 87%, and 89% at 1, 2, 3, and 5 years, respectively, while the corresponding OS rates were 86%, 62%, 59%, and 35%. Adjusted morbidity rates were low, with acute grade 3 toxicities observed in 6% of patients and late grade 3 toxicities in fewer than 4%, without treatment-related mortality. Moreover, comparative studies support the clinical relevance of particle radiation therapy. A RCT comparing PBT (n = 72) with radiofrequency ablation (RFA; n = 72) demonstrated a 2-year local PFS rate of 94.8% with PBT and 83.9% with RFA, meeting the predefined criteria for non-inferiority [10]. In addition, propensity score–matched retrospective analyses comparing PBT versus RFA [11] and CIRT versus RFA [12] reported comparable clinical outcomes. Finally, our multicenter retrospective study comparing surgical resection with CIRT in Japan showed no significant differences in recurrence-free survival or OS between the two modalities [13]. Collectively, these findings suggest that particle radiation therapy represents a viable alternative to established standard treatments for selected patients with early-stage HCC. The potential benefit of adding locoregional treatments, such as transarterial chemoembolization (TACE) or radiation therapy, to systemic therapy for patients with advanced HCC remains an area of active investigation and debate. In this context, the LAUNCH trial [14] compared PFS and OS between patients treated with lenvatinib plus TACE and those receiving lenvatinib monotherapy, demonstrating significantly prolonged PFS (hazard ratio [HR] 0.45, 95% CI 0.33–0.61, p < 0.001) and improved OS (HR 0.43, 95% CI 0.34–0.55, p < 0.001) with the combination approach. In contrast, the SORAMIC trial [15], which evaluated sorafenib with or without selective internal radiation therapy (SIRT), failed to show a survival benefit with the addition of SIRT. The IMPACT study [16], a RCT comparing Atez/Bev with or without TACE, is currently ongoing in Japan and is expected to provide further insights into the role of combined locoregional and systemic strategies in the immunotherapy era. With respect to radiation therapy, the NRG Oncology/RTOG 1112 phase III trial [17] demonstrated that the addition of stereotactic body radiotherapy (SBRT) to sorafenib significantly prolonged PFS and yielded a clinically meaningful, although not statistically significant, improvement in OS compared with sorafenib alone. Taken together, despite the excellent local control achieved with particle radiation therapy in early-stage HCC, its added value when combined with systemic therapy for advanced-stage disease has not yet been conclusively established. In this regard, the study reported by Kuo YH et al. [1]—although retrospective in nature—provides compelling evidence that the addition of proton beam therapy to first-line Atez/Bev treatment is associated with a clear and clinically meaningful improvement in survival outcomes. Because Atez/Bev is currently established as the standard first-line immunotherapy for advanced HCC, findings indicating a survival benefit with the addition of proton beam therapy are of particular clinical relevance. In addition to its local effects, radiotherapy has been reported to modulate the tumour immune microenvironment, potentially enhancing the activity of immune checkpoint inhibitors. Experimental and clinical observations have suggested increased cytotoxic T-cell infiltration and activation of the PD-1/PD-L1 pathway following irradiation, providing a plausible mechanistic rationale for combination strategies [18, 19]. Future prospective RCTs are warranted to determine whether the integration of particle radiation therapy can consistently enhance the therapeutic benefit of systemic treatment, to identify patient subgroups most likely to derive benefit, and to establish optimal treatment sequencing and protocols for combining systemic therapy with particle radiation therapy. The authors have nothing to report. The authors declare no conflicts of interest. This article is linked to Kuo et al. paper. To view this article, visit https://doi.org/10.1111/liv.70465. The authors have nothing to report.