The multicenter retrospective study reviewed and analyzed clinical data from patients with HCC and concomitant PVTT treated with HAIC combined with SBRT (HAIC-SBRT group) or HAIC alone (HAIC group) from three medical centers in China between September 2019 and June 2022. The Institutional Ethics Committee waived the need for informed consent due to the retrospective nature of this study. The participating centers in this study are listed in Supplementary Table 1. All written treatment informed consent was obtained prior to HAIC treatment.

All HCC diagnoses were confirmed according to the criteria of the American Association for the Study of Liver Diseases (AASLD) or the European Association for the Study of the Liver (EASL) or by liver biopsy (20, 21). Inclusion criteria were as follows: (1) age 18–65 years; (2) Eastern Cooperative Oncology Group performance status (ECOG PS) score 0-1; (3) clear radiological evidence of portal vein tumor thrombosis; (4) liver function ALBI grade 2 or Child-Pugh A-B grade; (5) adequate hematologic, with leukocyte count < 3.0 × 10^9/L, neutrophil count < 1.5 × 10^9/L, platelet count < 75 × 10^9/L, and hemoglobin < 85 g/L. Exclusion criteria included: (1) missing clinical data; (2) loss to follow-up for more than 6 months; (3) presence of other malignancies; (4) prior treatment other than HAIC.

All hepatic artery catheterization procedures were performed by at least two experienced interventional radiologists under digital subtraction angiography (DSA). The process was as follows: After local anesthesia, the femoral artery was punctured using the modified Seldinger technique, and a 5F vascular sheath was placed. A 5F Yashiro catheter (Terumo, Tokyo, Japan) was inserted through the sheath into the hepatic artery, and arteriography was performed to identify the tumor-supplying arteries and their branches. Subsequently, a microcatheter (ASAHI, Tokyo, Japan) was placed in the target tumor-feeding artery and secured externally. Following the hepatic artery catheterization, the mFOLFOX6 regimen was administered, consisting of: Oxaliplatin at a dose of 85 mg/m² intravenously over 2 hours on day 1; Leucovorin at a dose of 400 mg/m² intra-arterially over 2 hours on day 1; Fluorouracil at a dose of 400 mg/m² given by intra-arterial injection, followed by a continuous infusion of 2400 mg/m² over 46 hours, all delivered through the microcatheter. Dose adjustments were made in cases of persistent or severe treatment-related adverse reactions, with treatment resumed once the patient’s condition stabilized. The HAIC procedures were repeated every four weeks, the total number of HAIC treatment cycles did not exceed 6 sessions. Post-treatment, a full abdominal enhanced CT scan was conducted every eight weeks for treatment evaluation.

SBRT simulation was performed within 1–2 days after the completion of the first HAIC cycle (continuous infusion). The entire SBRT course, with a total dose of 36–40 Gy delivered in 5 fractions on an every-other-day schedule, was executed and completed within 2–4 weeks after the first HAIC session. Subsequent HAIC cycles continued at the predetermined frequency (once every 4 weeks). SBRT was performed as follows: Four-dimensional computed tomography(4D CT) was employed in the treatment planning process to account for respiratory motion. The gross tumor volume (GTV), delineated through dynamic enhanced CT or MRI, encompassed both the portal vein tumor thrombus (PVTT) and the contiguous primary hepatic lesion. In cases where the primary disease was large, multicenter, or diffuse, rendering the entire tumor volume extensive and precluding the sparing of adequate normal liver from high radiation doses, only the PVTT was considered as the GTV. The internal target volume (ITV) was established to accommodate the range and position of the tumor throughout the breathing cycle, and the planning target volume (PTV) was generated with a uniform expansion of the ITV by 3 to 5 mm. Manual adjustments were made to the PTV to minimize bowel overlap when necessary. The initial prescribed dose to the PTV was 40 Gy administered in five fractions, utilizing 6 MV X-rays via a linear accelerator weekly (Varian Medical Systems). In instances where the PTV was in close proximity to the bowel or sufficiently large to pose challenges in meeting the dose-volume constraints of the organs at risk, the dose was adjusted to a range of 36 to 39 Gy across 5 to 6 fractions.

The dose-volume constraints for organs at risk were as follows: for the liver, the constraint was set at ≥ 700 mL of uninvolved liver (liver minus GTV) receiving < 15 Gy, or alternatively, ensuring that the percentage of normal liver volume receiving more than 15 Gy (V₁₅) did not exceed one-third of the total normal liver volume (V_total); the maximum dose to 1 mL of the stomach, small bowel, or duodenum was restricted to < 25 Gy; for the spinal cord, the maximum dose to 1 mL was limited to < 15 Gy; and for the kidneys, V₁₅ was required to be less than one-third of V_total.

The primary endpoint of this study is overall survival (OS), calculated from the initial definitive diagnosis of HCC to the patient’s death or the last follow-up. Tumor response is evaluated according to the modified Response Evaluation Criteria in Solid Tumors 1.1 (mRECIST 1.1) criteria, by two radiologists independently. Image-based assessments categorize results into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). The secondary endpoint is progression-free survival (PFS), calculated from the initial definitive diagnosis of HCC to the first image-based evaluation as PD according to mRECIST 1.1.The third endpoint is tumor response, including the objective response rate (ORR), the proportion of patients evaluated as CR and PR during imaging follow-up, and the disease control rate (DCR), the proportion of patients evaluated as CR, PR, and SD during imaging follow-up. Adverse events are documented and assessed according to the Common Terminology Criteria for Adverse Events 5.0 (CTCAE 5.0) criteria.

Propensity score matching (PSM) with 1:1 ratio were utilized to mitigate baseline disparities, with a tolerance threshold of 0.02 for matching. The covariates incorporated into the balancing process encompassed age, gender, ECOG PS score, comorbidities, HBsAg status, cirrhosis presence, ascites, Child-Pugh classification, ALBI grade, alpha-fetoprotein (AFP) levels, maximum tumor diameter, tumor number, extrahepatic metastasis and HAIC sessions.

All statistical analysis was conducted using R software (RStudio version 4.2.2). For continuous variables adhering to a normal distribution, the mean ± standard deviation was used for representation and analyzed via Student’s t-test. For non-normally distributed continuous variables, the median was utilized for representation and analyzed using the Mann-Whitney U test. Categorical variables were expressed as percentages and analyzed using either the chi-square test or Fisher’s exact test. The Kaplan-Meier method was employed to estimate overall survival (OS) and progression-free survival (PFS) curves between groups in both the overall and matched cohorts. Univariate and multivariate analysis based on Cox proportional hazards regression model was applied to identify independent risk factors affecting OS and PFS. Covariates with a P-value < 0.1 in the univariate analysis were collectively included in the multivariate analysis.

A two-tailed P-value < 0.05 was considered statistically significant.

After qualification review, a total of 253 HCC patients with PVTT who received HAIC combined with SBRT treatment (n = 79) or HAIC-alone treatment (n = 174) met the inclusion criteria and were enrolled. The enrollment case screening flowchart is shown in Figure 1. In the overall cohort, the majority of enrolled patients had general characteristics such as positive HBsAg (93.3%), ECOG PS 0 (91.7%), age ≤ 65 years (91.3%), and male (88.5%). The average age and tumor diameter in the HAIC-SBRT group were 49.1 ± 11.2 years and 10.5 ± 3.5 cm, respectively, while in the HAIC group, they were 51.4 ± 11.6 years and 11.1 ± 3.9 cm, respectively. The HAIC-SBRT group had a significantly higher proportion of patients with ascites and ALBI grade 1. After 1:1 propensity score matching, the above differences were eliminated, and a total of 146 PSM cohort patients were obtained. Baseline conditions before and after propensity matching are shown in Table 1.

In the overall cohort, the median OS for the HAIC-SBRT group and the HAIC group was 24.5 months and 11.9 months, respectively (HR: 0.49, 95% CI: 0.32-0.74; P < 0.0001). The median PFS was 10.4 months and 6.8 months, respectively (HR: 0.65, 95% CI: 0.47-0.91; P = 0.0062). After propensity matching to balance differences between groups, the median OS and PFS for the HAIC-SBRT group were 24.5 months and 10.3 months, respectively, both significantly better than the 12.2 months (HR: 0.50, 95% CI: 0.31-0.79; P < 0.0001) and 6.9 months (HR: 0.67, 95% CI: 0.45-0.99; P = 0.010) for the HAIC group. In the matched cohort, the 6, 12, and 24-month OS rates for the HAIC-SBRT group were 84.9%, 60.3%, and 15.1%, and the 6, 12, and 18-month PFS rates were 68.5%, 34.2%, and 12.3%, all significantly higher than the 71.2%, 45.2%, and 7.8% for OS and 45.2%, 20.5%, and 11.0% for PFS in the HAIC group (all P < 0.001). The propensity matching adjusted and unadjusted Kaplan-Meier survival curves were exhibited in Figure 2.

In the HAIC-SBRT group, due to varying tumor burdens among patients, the GTV scope was determined through multidisciplinary team(MDT) consensus, selecting either “intrahepatic lesion plus PVTT” or “PVTT only.” This approach aimed to avoid exceeding the tolerance limits of normal liver tissue and prevent radiation-induced liver disease or insufficient preservation of functional liver reserve, which could result from delivering radical radiation doses to all intrahepatic tumor. In this study cohort, among HCC patients in the HAIC-SBRT group, the median OS for those with “intrahepatic tumor-PVTT” and “PVTT-only” as the GTV scope was 20.8 months and 24.5 months(HR: 1.18, 95% CI: 0.55 to 2.54; P = 0.271), respectively. The median PFS was 11.4 months and 9.6 months(HR: 1.19, 95% CI: 0.69 to 2.04; P = 0.102), respectively. No statistically significant differences were observed in either outcome. The Kaplan-Meier curves stratified by GTV scope are presented in Supplementary Figure 2.

According to the mRECIST 1.1 criteria, in the overall cohort, the HAIC-SBRT group achieved CR in 1(1.3%) case, PR in 46(58.2%) cases, SD in 23(29.1%) cases, and PD in 9(11.4%) cases, while the HAIC group achieved CR in 1(0.6%) case, PR in 29(16.7%) cases, SD in 88(50.6%) cases, and PD in 56(32.2%) cases (P < 0.001). The ORR and DCR of intrahepatic tumor in the HAIC-SBRT group were 59.5% and 88.6%, respectively, significantly higher than those in the HAIC group, which were 17.2% and 67.8% (both P < 0.001). After propensity matching, the HAIC-SBRT group demonstrated similarly superior anti-tumor efficacy in terms of overall response, ORR, and DCR. In the PSM cohort, the HAIC-SBRT and HAIC-alone groups achieved CR in 1(1.4%) and 1(1.4%) case, PR in 44(60.3%) and 11(15.1%) cases, SD in 20(27.4%) and 42(57.5%) cases, and PD in 8(11.0%) and 19(26.0%) cases, respectively (P < 0.001). The ORR of intrahepatic tumor lesion in the HAIC-SBRT and HAIC-alone groups were 61.6% and 16.4% (P < 0.001), respectively, and the DCR were 89.0% and 74.0% (P = 0.019).In addition, the ORR and DCR of PVTT in the HAIC-SBRT group of PSM cohort were 67.1% and 97.3%, respectively, significantly higher than the 13.7% and 54.8% in the HAIC group (both P < 0.001). The best tumor response before and after propensity matching adjustment is shown in Table 2.

Based on the COX proportional hazards regression model, covariates with a P-value < 0.01 in univariate analysis were jointly included in multivariate analysis. Univariate analysis showed that ALBI grade 2, tumor diameter > 7 cm, tumor number > 3, and HAIC-alone treatment were risk factors associated with worse OS, while AFP level > 400 ng/ml, extrahepatic metastasis, and HAIC-alone treatment were risk factors associated with poorer PFS. Multivariate analysis showed that ALBI grade 2, tumor diameter > 7 cm, and HAIC-alone treatment were independent risk factors affecting OS, while AFP level > 400 ng/ml, extrahepatic metastasis, and HAIC-alone treatment were independent risk factors affecting PFS. The univariate and multivariate analyses based on COX regression are shown in Table 3.

Subgroup analysis revealed that, with the exception of subgroups characterized by female gender, age > 65 years, ECOG PS 0, absence of comorbidities, and HBsAg negativity, the combined HAIC and SBRT regimen exhibited superior overall survival benefits and more effective tumor progression control compared to HAIC treatment alone across all other subgroups. The forest plots illustrating this subgroup analysis are depicted in Figure 3.

During the treatment period, no cases of treatment-related mortality were reported. All treatment-related adverse reactions are detailed in Table 4. Abdominal pain, nausea, and elevated AST were the most frequent Grade 1–2 adverse events observed in both the HAIC-SBRT group and the HAIC group. These symptoms were noticeably alleviated or resolved following appropriate symptomatic management. In the HAIC-SBRT group, the prevalent Grade 3–4 adverse reactions included elevated transaminases (AST elevation: 19.0%; ALT elevation: 10.1%), thrombocytopenia (10.1%), and hyperbilirubinemia (10.1%). For the HAIC group, the primary Grade 3–4 adverse reactions were elevated transaminases (AST elevation: 11.6%; ALT elevation: 7.5%), thrombocytopenia (8.0%), and leukopenia (4.6%). After matching, similarly, abdominal pain, nausea, and elevated AST remained the most frequent Grade 1–2 adverse events in both the HAIC-SBRT and HAIC groups. The most common Grade 3–4 adverse reactions in the HAIC-SBRT group included elevated AST (19.2%), elevated ALT (11.1%), hyperbilirubinemia (10.1%), and thrombocytopenia (9.6%). In the HAIC group, the most frequent Grade 3–4 adverse reactions were elevated AST (16.4%), leukopenia (8.2%), thrombocytopenia (6.8%), and hyperbilirubinemia (6.8%). Treatment-related adverse events after matching are presented in Supplementary Table 2. Statistical analysis revealed no significant differences in Grade 1–2 or Grade 3–4 treatment-related adverse events before and after PSM between the HAIC-SBRT group and the HAIC group.