Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related deaths, with an estimated 906,000 new cases and 830,000 deaths worldwide in 2020 [1]. Portal vein tumor thrombosis (PVTT) is a frequent complication of HCC that is associated with aggressive tumor biology and poor prognosis, with a median survival of only a few months [2-4]. PVTT is classified as an advanced-stage (Barcelona Clinic Liver Cancer [BCLC] stage C) and is typically not amenable to locoregional treatment. Systemic therapy is the first line of treatment for patients with PVTT [5,6]. Multikinase inhibitors, such as sorafenib and lenvatinib, are the mainstay systemic agents that provide modest survival benefits for patients with BCLC stage C disease. However, pooled analyses of randomized sorafenib trials have shown that major vascular invasion is associated with poor survival in all patient subgroups [7]. Although preliminary studies have suggested that lenvatinib may yield better outcomes than sorafenib in patients with PVTT [8], a randomized phase III trial in patients with HCC found no significant difference in overall survival between the two drugs in the presence of PVTT [9].

The phase III IMbrave150 trial demonstrated that the combination of atezolizumab, an immune checkpoint inhibitor (ICI) targeting programmed death-ligand 1, and bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, significantly improved survival outcomes in patients with advanced HCC compared to sorafenib [10]. Therefore, atezolizumab plus bevacizumab (atezo/bev) has been established as the first-line treatment for advanced HCC [5,6]. Updated data from the IMbrave150 trial showed that the superior efficacy of atezo/bev over sorafenib was maintained, regardless of the presence of PVTT [11], suggesting that patients with advanced HCC and PVTT can also benefit from atezo/bev therapy. Nevertheless, response rates remain low, with only about one-quarter of patients with PVTT achieving an objective response to atezo/bev [11].

Since HCC is a radiosensitive malignancy; therefore, external beam radiotherapy (EBRT) has been clinically employed for the local control of PVTT [12]. Advances in imaging and radiation delivery have made radiation therapy (RT) increasingly feasible for patients with PVTT who often have limited hepatic reserve [13]. A recent meta-analysis reported an objective response rate (ORR) of 50.4% for conventional EBRT, either alone or in combination with other treatment modalities [14]. Current guidelines from the American Society for Radiation Oncology conditionally recommend EBRT as a treatment option for HCC with macrovascular invasion, either as a monotherapy or in sequence with systemic or catheter-based therapies [15].

The combination of radiation and ICIs has been actively investigated for several solid tumors [16]. In HCC, phase I/II trials combining ICIs with EBRT have demonstrated promising survival outcomes and acceptable safety profiles, including those in patients undergoing PVTT [17-20]. Recent small studies using combined ICIs and intensity-modulated radiotherapy (IMRT) for PVTT reported variable response rates (ORR, 49-77%) [21-23]. However, it remains unclear whether the addition of EBRT enhances the efficacy of atezo/bev therapy in patients with HCC and PVTT. Therefore, the aim of this study was to evaluate the efficacy and safety of EBRT in HCC patients with PVTT receiving atezo/bev treatment.

HCC with PVTT remains a major clinical challenge because of its potential for microscopic dissemination. Even limited portal vein involvement can preclude curative-intent treatments, whereas invasion of the main trunk or first-order branches is associated with poor prognosis and rapid disease progression [27]. Although ICIs have demonstrated improved treatment outcomes compared with tyrosine kinase inhibitors (TKIs), the overall response rates remain suboptimal [7,9]. Given the limitations of the current systemic therapies for PVTT, combining locoregional and systemic treatments may yield synergistic effects by addressing both rapid local progression and multifocal tumor growth. However, conventional EBRT, which is constrained by the risk of radiation-induced liver injury, has shown response rates of less than 30% [28]. In contrast, SBRT and IMRT have demonstrated improved tumor control and favorable toxicity profiles [15]. Therefore, these modalities may serve as effective adjuncts to systemic therapy for PVTT.

Historically, RT has been explored as a strategy to enhance the limited efficacy of standard TKI-based treatments for PVTT [29,30]. These observed synergistic anticancer effects may be partially explained by the ability of sorafenib to modulate the radiosensitivity of HCC cells [31,32]. Moreover, ionizing radiation can stimulate both local and systemic immune-mediated antitumor responses, suggesting that EBRT may potentiate the effects of ICIs [16,17,33]. Recent case series and single-arm studies have reported promising outcomes of combined radiation and immunotherapy in patients with PVTT [18,22,34,35]. Despite the increasing role of EBRT as a primary radiation modality, there is a lack of retrospective or prospective studies specifically evaluating the combination of EBRT with atezo/bev, the current first-line treatment for unresectable HCC.

This single-center retrospective study evaluated the effect of EBRT in patients receiving atezo/bev therapy and found that the addition of radiotherapy was not associated with a significant survival benefit across all types of PVTT. However, when patients with Vp4 invasion were excluded, the combination of EBRT with systemic therapy was associated with significantly improved PFS and OS compared to atezo/bev alone.

Previous studies have shown that both the presence and extent of PVTT significantly influence patient outcomes. Among the PVTT classifications, Vp4, which is defined as a tumor thrombus extending into the main portal vein trunk, is associated with the poorest prognosis. This subtype corresponds to the lowest median OS of approximately 4.3 months among patients with HCC and PVTT, underscoring the aggressive nature of the disease at this stage [2,36]. Although limited data exist on the effect of combining RT with systemic therapy in Vp4 cases, the aggressive behavior and rapid progression associated with Vp4 PVTT may limit the efficacy of such combination treatments relative to those in patients with less extensive involvement. The poor prognosis of Vp4 patients may have masked any potential benefits of RT in the overall cohort, highlighting the need for future studies specifically designed for this subgroup. Although this study could not elucidate the mechanistic reasons why additional RT failed to improve clinical outcomes in cases of main trunk invasion, our findings support the selection of appropriate candidates for adjunctive radiotherapy during atezo/bev treatment.

Several mechanisms of synergy between RT and ICIs have been proposed for the treatment of locally advanced solid tumors [33]. First, RT induces immunogenic cell death, leading to the release of tumor-associated antigens that enhance immune recognition and stimulate a robust immune response. Radiation can also upregulate major histocompatibility complex molecules in tumor cells, thereby improving antigen presentation to T cells and promoting stronger T cell activation. Additionally, RT contributes to the proinflammatory tumor microenvironment by releasing cytokines and chemokines that attract immune cells to the tumor site. These mechanisms may also contribute to the abscopal effect, a phenomenon in which localized radiation induces systemic immune responses that reduce the size of distant untreated tumors. Finally, RT may mitigate the immunosuppressive tumor microenvironment, thereby enhancing the therapeutic effects of ICIs. Whether the benefits of additional RT observed in our study reflect these immunogenic mechanisms remains to be elucidated in future research.

Radiation-induced liver injury is a major concern in the use of RT for liver tumors because it can be dose limiting and, in severe cases, can lead to liver failure or death. In the present study, we observed no significant deterioration in hepatic function during EBRT. However, as all patients had well-compensated liver function at baseline (Child-Pugh class A), it remains uncertain whether similar safety and efficacy would apply to patients with decompensated liver disease. Our findings suggest that RT can be safely administered to patients with preserved liver function, particularly when the PVTT is confined to the second-order or more distal portal vein branches.

This study has several limitations. First, owing to its single-center retrospective design and limited sample size, we were unable to establish a causal relationship between combination therapy and observed survival outcomes. This study was also subject to potential selection bias and unmeasured confounding factors. The administration and dosing of RT were determined at the discretion of individual physicians based on varying clinical conditions without a standardized treatment protocol. This variability may have further contributed to the selection bias. For example, the lower baseline ALT levels in the atezo/bev only group suggest better preservation of liver function, indicating a potential physiological advantage at baseline and a potential bias in the selection of patients for RT. Nevertheless, the observation that the atezo/bev group, despite having higher baseline ALT levels, demonstrated superior outcomes supports the potential added therapeutic benefit of RT, which may outweigh the baseline disadvantages.

Second, although the two treatment groups were generally well balanced in terms of baseline characteristics, the small sample size may have limited the statistical power to detect significant differences in PFS or OS. Based on previously reported survival data from larger studies [10,37], detecting a HR of 0.67 for OS, would require approximately 280 patients to achieve 80% power at a 5% significance level. The small sample size in our study increased the likelihood of a type II error, potentially masking the true treatment effect.

Third, while the positive outcomes observed in patients with Vp1-3 PVTT were encouraging, these findings were derived from a subgroup analysis that excluded patients with Vp4 involvement. Therefore, these results should be interpreted with caution when considering the efficacy of combination therapy in a broader population of patients with PVTT. Additionally, the relatively short follow-up duration limited our analysis to 1-year survival outcomes. This abbreviated observation period may have prevented the detection of long-term changes in local tumor characteristics post-RT, hindering a more comprehensive understanding of the mechanistic effects of RT.

Finally, the study population was heterogeneous with respect to prior locoregional therapy. Although the presence or absence of such treatments was not a significant predictor of survival in the multivariate analysis, we were unable to determine whether treatment-naïve patients with PVTT responded differently than those who experienced progression after prior locoregional interventions.

In conclusion, this study found that the addition of RT did not significantly improve the tumor response or survival in an overall cohort of HCC patients with PVTT receiving atezo/bev systemic therapy. However, subgroup analysis revealed improved PFS and OS in patients whose PVTT was limited to Vp1-3. These findings support the hypothesis that, in the absence of main portal vein invasion, the addition of RT may offer clinical benefits when combined with atezo/bev therapy in this patient population. Further prospective studies with larger cohorts and longer follow-up periods are required to validate these results and address the limitations discussed above.