Transarterial Chemoembolization Combined with Sorafenib and Iodine-125 Seed Brachytherapy for Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: A Retrospective Controlled Study
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and its prognosis is significantly worsened by the presence of portal vein tumor thrombus (PVTT). PVTT is observed in 10% to 40% of HCC patients at diagnosis and is associated with poor survival outcomes. Sorafenib, a multikinase inhibitor, is the first-line treatment for advanced HCC, including cases with PVTT. However, its efficacy remains modest, necessitating the exploration of combination therapies to improve outcomes. Transarterial chemoembolization (TACE) combined with sorafenib (TACE-S) has shown promise in some studies, but its ability to control PVTT remains limited, with an objective response rate (ORR) of only 9.7%. Recent advancements in brachytherapy, particularly the use of iodine-125 (125I) seeds, have demonstrated significant reductions in tumor thrombus with minimal complications. This study aimed to evaluate the efficacy and safety of combining TACE-S with 125I seed brachytherapy (TACE-S-I) in HCC patients with PVTT.
The study was conducted at a single institution and included patients diagnosed with HCC and PVTT between January 2015 and December 2018. Patients were retrospectively divided into two groups: those who received TACE-S-I and those who received TACE-S alone. The inclusion criteria were age between 18 and 75 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Child-Pugh class A or B, and the presence of PVTT confirmed by dynamic contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) within seven days before treatment. Exclusion criteria included main portal vein obstruction without collateral vessels, PVTT extending into the superior mesenteric vein or hepatic vein/vena cava, prior treatment with sorafenib or systemic chemotherapy, additional malignancies, and severe comorbidities such as heart or kidney dysfunction or coagulation disorders.
In the TACE-S-I group, sorafenib was administered at a dose of 400 mg twice daily, starting 3 to 5 days after TACE. The 125I seeds were implanted into the PVTT under CT guidance 3 to 14 days after TACE, based on pre-operative planning. Patients who declined brachytherapy received TACE-S alone. Follow-up was conducted at 4- to 6-week intervals, with repeat TACE or 125I seed implantation performed as clinically indicated. Sorafenib dosage adjustments or discontinuation were based on toxicity.
PVTT was classified into three types: type A (involving the main portal vein), type B (involving the first-order portal vein branch), and type C (involving the second- or lower-order portal vein branch). The primary endpoint of the study was overall survival (OS), defined as the time from the initial TACE until death. Secondary endpoints included tumor response, time to tumor progression (TTP), and adverse events (AEs). Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors (RECIST), with PVTT response classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). AEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
A total of 194 patients were assessed for eligibility, with 23 excluded based on the criteria. The final study population comprised 171 patients: 74 in the TACE-S-I group and 97 in the TACE-S group. Baseline characteristics were well-balanced between the two groups. The median follow-up duration was 16.0 months in the TACE-S-I group and 10.0 months in the TACE-S group. The mean number of TACE procedures was 5.6 in the TACE-S-I group and 3.9 in the TACE-S group. In the TACE-S-I group, 47 patients underwent repeated 125I seed implantation, with an average of 1.7 procedures per patient. The median duration of sorafenib administration was 15.5 months in the TACE-S-I group and 9.5 months in the TACE-S group.
The study demonstrated significantly better tumor responses in the TACE-S-I group compared to the TACE-S group. The ORR for PVTT was 58.1% in the TACE-S-I group versus 11.3% in the TACE-S group (P < 0.001). Similarly, the ORR for intrahepatic tumors was 59.5% in the TACE-S-I group versus 30.9% in the TACE-S group (P < 0.001). Subgroup analyses revealed higher ORRs for both PVTT and intrahepatic tumors in patients with type B/C PVTT in the TACE-S-I group. The median TTP was 12.0 months in the TACE-S-I group and 5.0 months in the TACE-S group (P < 0.001), with significantly longer TTP observed in type B/C PVTT patients in the TACE-S-I group.
Survival outcomes were markedly improved in the TACE-S-I group. The median OS was 23.5 months in the TACE-S-I group versus 12.0 months in the TACE-S group (P < 0.001). The 1-, 2-, and 3-year survival rates were 73%, 50%, and 24% in the TACE-S-I group, compared to 54%, 20%, and 14% in the TACE-S group, respectively. Subgroup analyses showed no significant difference in survival for type A PVTT patients between the two groups, but significantly longer OS was observed for type B/C PVTT patients in the TACE-S-I group. Multivariate analyses identified treatment modality (TACE-S-I vs. TACE-S), PVTT type (A vs. B/C), and alpha-fetoprotein (AFP) level (≥400 ng/mL vs. <400 ng/mL) as independent prognostic factors for OS.
The study also evaluated the safety profile of the two treatment regimens. Most AEs were sorafenib-related, and the incidence of overall AEs (94.6% in the TACE-S-I group vs. 91.8% in the TACE-S group) and grade ≥3 AEs (33.8% in the TACE-S-I group vs. 28.9% in the TACE-S group) were comparable between the two groups (P = 0.471 and P = 0.490, respectively). These findings suggest that the addition of 125I seed brachytherapy did not significantly increase the risk of AEs.
Despite its promising results, the study had limitations. Its retrospective nature and treatment preferences may have introduced selection bias. Additionally, the visibility of 125I seeds on imaging precluded blinded assessment of tumor response, potentially introducing bias. These limitations highlight the need for randomized clinical trials to validate the findings.
In conclusion, TACE-S-I demonstrated superior efficacy in HCC patients with first- or lower-order branch PVTT compared to TACE-S alone. Patients treated with TACE-S-I achieved significantly better tumor responses, longer TTP, and improved OS. The extent of PVTT was a critical prognostic factor, with type B/C PVTT patients deriving the greatest benefit from TACE-S-I. The safety profile of TACE-S-I was comparable to that of TACE-S, indicating that the combination therapy is a viable treatment option for this challenging patient population. Future studies should focus on optimizing brachytherapy techniques, particularly for type A PVTT, and exploring additional combination therapies to further enhance outcomes.
doi.org/10.1097/CM9.0000000000001537
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