Is stereotactic body radiation therapy feasible in hepatocellular carcinoma with portal vein tumor thrombosis?

Abstract

Hepatocellular carcinoma (HCC) with portal venous tumor thrombosis (PVTT) carries a poor prognosis and limited therapeutic options. Khosla et al presented a retrospective study of 30 patients with unresectable HCC and predominantly advanced PVTT (VP3/VP4) treated with stereotactic body radiation therapy (SBRT) at 30-50 Gy in 5-6 fractions in World Journal of Hepatology. SBRT achieved an 83.3% response rate with a median overall survival of 13 months and acceptable toxicity, including no grade 4 events. These findings support SBRT as a safe and effective locoregional treatment for HCC with PVTT and highlight its potential role within multidisciplinary care.

Key Words: Hepatocellular carcinoma; Portal venous tumor thrombosis; Stereotactic body radiation therapy; Radiotherapy; Liver cancer

Core Tip: Portal vein tumor thrombosis is a common and challenging presentation in hepatocellular carcinoma with significantly limited treatment options. This retrospective study highlighted the safety and efficacy of stereotactic body radiation therapy as a locoregional treatment in patients with unresectable hepatocellular carcinoma and portal vein tumor thrombosis. With an encouraging response rate of 83.3% and a median overall survival of 13 months, stereotactic body radiation therapy demonstrates promising early outcomes and minimal toxicity, supporting its role as a viable therapeutic option in this difficult-to-treat population.

This editorial refers to "Stereotactic body radiation therapy in patients with unresectable hepatocellular carcinoma and portal vein tumor thrombosis" by Khosla et al, 2025; https://dx.doi.org/10.4254/wjh.v17.i12.110993.

---

INTRODUCTION

According to global statistics from 2025, liver cancer remains one of the most lethal malignancies worldwide. In the United States an estimated 42240 new cases and 39090 deaths from liver cancer are expected[1]. In hepatocellular carcinoma (HCC), the absence of early-stage symptoms frequently leads to delayed diagnosis. HCC is often complicated by portal venous tumor thrombosis (PVTT), which is present in 44%-62% of cases at initial diagnosis. PVTT severely limits therapeutic options, and the optimal management strategy for this population remains undefined[2].

STEREOTACTIC BODY RADIATION THERAPY IN HCC WITH PVTT

PVTT renders HCC unresectable and excludes patients from eligibility for liver transplantation[3]. Systemic therapy using targeted agents and/or immunotherapy remains the standard of care for patients with HCC presenting with metastatic disease or macrovascular invasion[4,5]. However, locoregional approaches remain essential for patients with unresectable HCC (uHCC) or limited performance status[6-9]. The goal of locoregional therapies, including stereotactic body radiation therapy (SBRT), is to restore portal vein patency by reducing tumor thrombus, thereby improving portal blood flow and enhancing the effectiveness of systemic treatments[3,10]. Transarterial chemoembolization is frequently contraindicated in extensive PVTT due to the risk of hepatic ischemia, emphasizing the need for safer local treatment options in this setting[7]. External beam radiotherapy can restore portal venous flow through tumor thrombus recanalization in approximately 15%-33% of patients with rates varying according to the specific technique used[11].

The choice of external beam radiotherapy dose and its safety profile are closely related to baseline liver function assessed using the Child-Pugh classification. Evidence on post-radiation liver decompensation is largely derived from SBRT studies that typically exclude patients with Child-Pugh B8 or Child-Pugh C disease because of their increased sensitivity to radiation-induced hepatic toxicity compared with patients with Child-Pugh A disease[12]. Advanced PVTT, particularly VP3/VP4 involvement of the right or left portal vein, the main portal vein, or the superior mesenteric vein, carries a very poor prognosis with a median survival of approximately 2.2 months under the best supportive care. These patients frequently exhibit impaired liver function, and the addition of systemic therapy may further compromise hepatic reserve[2].

Khosla et al[3] recently published a study in World Journal of Hepatology, which reported a retrospective series of 30 patients with uHCC and predominantly VP3/VP4 PVTT in whom SBRT delivered at doses of 30-50 Gy in 5-6 fractions achieved an 83% response rate and a median overall survival (OS) of 13 months, consistent with previously published data[6-8]. The cohort included 53.3% Child-Pugh A and 46.6% Child-Pugh B with 60.0% presenting VP4 disease and 26.7% VP3 disease, reflecting a population with preserved to moderately impaired hepatic function.

Given that the liver reserve critically influences treatment tolerance and outcomes, the inclusion criteria included Child-Pugh A-B status, serum bilirubin < 3 mg/dL, Eastern Cooperative Oncology Group performance status 0-2, uninvolved liver volume > 700 mL, and a tumor-to-lumen distance > 5 mm. These parameters were designed to optimize the therapeutic window for SBRT. Dose and fractionation were individualized according to tumor volume and organ-at-risk constraints to ensure an appropriate balance between efficacy and safety. The median tumor diameter was 6.1 cm with a median follow-up of 15 months, and no grade 4 toxicities were reported.

None of the evaluated clinical or dosimetric factors [including age, baseline alpha-fetoprotein (AFP), bilirubin, Child-Pugh class, albumin-bilirubin score, or gross tumor volume/planning target volume size and volume] were associated with differences in survival outcomes[3]. Conversely, in a separate cohort of 80 patients with HCC treated with SBRT, predominantly with VP2/VP3 PVTT, OS was independently influenced by tumor stage, age, cirrhosis status, AFP levels, and hemoglobin levels[13]. Ultimately, the limited tolerance of uninvolved liver tissue remains the principal barrier to dose intensification in HCC with PVTT. Notably, improved outcomes appear to be associated with a biologically effective dose ≥ 58 Gy₁₀, and responders to radiation therapy demonstrate longer survival than non-responders (median OS 10.7 months vs 5.3 months)[6].

In the phase I and II trials conducted by Bujold et al[9], SBRT achieved a 1-year local control rate of 87% and a median OS of 17 months. However, significant toxicity was observed with seven treatment-related deaths (five due to liver failure) among 102 patients despite a mean liver dose of 18.1 Gy. Although local control was acceptable, many patients experienced out-of-field progression, underscoring the need to integrate SBRT with systemic therapies[8]. Proton beam therapy offers the advantage of delivering high radiation doses while providing superior sparing of adjacent healthy tissues, and several studies have reported excellent clinical outcomes with this modality[14].

The addition of cadonilimab and lenvatinib to SBRT has demonstrated encouraging efficacy with manageable toxicity in patients with VP3/VP4 PVTT, and early declines in serum AFP or protein induced by vitamin K absence or antagonist II at 6 weeks may serve as useful prognostic biomarkers[2]. As demonstrated in the cohort published in World Journal of Hepatology by Khosla et al[3], incorporation of PVTT subclassification (VP3/VP4) helped clarify which patient subgroups derive the greatest survival benefit and should be validated in larger studies. The central challenge in administering SBRT for HCC remains the protection of surrounding normal liver parenchyma.

A prospective study of patients with HCC and macrovascular invasion treated with radiosurgery evaluated treatment-related predictors and clinical outcomes. Among the 139 patients with available response data, portal vein recanalization was identified as a significant prognostic factor for OS. Responders demonstrated a median OS of 18.40 months compared with 9.34 months in non-responders. The greatest survival benefit was observed in patients achieving complete recanalization (30 months), whereas those with partial or no recanalization had markedly shorter survival (12-14 months; P = 0.002). Performance status also correlated with outcomes as patients with Eastern Cooperative Oncology Group 0 exhibited superior survival and higher recanalization rates. Radiation-induced liver disease occurred in 24% of treated patients[10].

Future research in the management of HCC with PVTT will require the development of treatment algorithms that integrate both thrombus burden and baseline liver function. Patient selection remains critical for identifying those most likely to benefit from intensified multimodal approaches. Key priorities include refining dose and fractionation strategies, clarifying the mechanisms of radiation-induced immune activation, and determining the optimal sequencing and integration of SBRT with immunotherapy or targeted therapies, whether delivered concurrently or sequentially. Equally important will be improving the management of overlapping toxicities and establishing predictive biomarkers to guide patient selection and enhance immune-mediated responses.

CONCLUSION

Appropriate patient selection is fundamental when considering SBRT for HCC with PVTT. The greatest benefit is consistently observed in patients with Child-Pugh A disease and carefully selected Child-Pugh B7 patients along with preserved performance status. In this population, particularly among those with extensive VP3/VP4 involvement, SBRT has emerged as a clinically meaningful modality capable of achieving durable local control under strict dosimetric constraints. Beyond reducing tumor thrombus, SBRT can promote portal vein recanalization and improve portal permeability, thereby enhancing hepatic perfusion and facilitating more effective delivery of systemic agents.

These physiological advantages, together with advances in image guidance, real-time motion management, and conformal dose delivery, increasingly position SBRT as a potential standard component of multidisciplinary care for uHCC with PVTT. Nevertheless, the retrospective design of most studies, small sample sizes, and limited case numbers restrict generalizability and preclude definitive conclusions. Even so, the available evidence remains hypothesis-generating and highlights the practical value of SBRT in a clinical setting with few effective therapeutic alternatives. Overall, current results demonstrate encouraging efficacy with acceptable toxicity, reinforcing SBRT as a well-tolerated and impactful treatment option in this high-risk population when patients are rigorously selected and treatment is tailored to hepatic reserve and anatomical considerations.