CyberKnife SBRT plus lenvatinib and tislelizumab versus doublet systemic therapy for hepatocellular carcinoma with macrovascular invasion: A real-world IPTW-adjusted study.
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BACKGROUND & PURPOSE: Macrovascular invasion (MVI) in hepatocellular carcinoma (HCC) confers extremely poor prognosis. While lenvatinib plus tislelizumab is an active targeted-immunotherapy regimen, local control of tumor thrombus remains suboptimal. Stereotactic body radiotherapy (SBRT) delivered via CyberKnife offers highly conformal local treatment and may have immunomodulatory effects. We evaluated whether adding CyberKnife SBRT to doublet systemic therapy was associated with improved outcomes in HCC with MVI. MATERIALS & METHODS: This real-world retrospective study included 116 HCC patients with MVI (Triple group: CyberKnife SBRT + lenvatinib + tislelizumab, n = 50; Doublet group: lenvatinib + tislelizumab, n = 66) - selected from a screened pool of 215 patients between June 2021 and June 2024. Stabilized inverse probability of treatment weighting (IPTW), with the propensity score derived from a multivariable logistic regression including nine baseline covariates and, as additional sensitivity analyses, an expanded 18-covariate model and a gradient-boosted-machine propensity score, balanced the measured baseline covariates (all standardized mean differences <0.10 after weighting). Primary endpoints were the confirmed objective response rate (ORR, mRECIST, requiring a confirmatory scan ≥4 weeks after the first documented response) and local progression-free survival (LPFS, defined as radiographic progression of a prespecified index local lesion - the macrovascular tumor thrombus with its contiguous primary hepatic tumor - or death; the index lesion corresponded to the SBRT-treated target in the Triple Group and to the anatomically corresponding lesion followed with identical criteria in the Doublet Group). Secondary endpoints included progression-free survival (PFS), overall survival (OS), detailed organ-at-risk dosimetry, hepatic safety (CTCAE v5.0 plus Child-Pugh/ALBI tracking), and treatment exposure. RESULTS: The observed confirmed ORR was 68.0% (34/50) in the Triple Group versus 37.9% (25/66) in the Doublet Group; the stabilized IPTW-weighted ORR was 71.1% versus 37.6% (P < 0.001). Median LPFS was 15.1 versus 7.8 months (HR = 0.42, 95%CI: 0.27-0.64, P < 0.001). Median PFS (11.1 vs. 6.4 months; HR = 0.46, 95%CI: 0.30-0.71, P < 0.001) and OS (23.0 vs. 15.6 months; HR = 0.57, 95%CI: 0.36-0.92, P = 0.022) also favored the Triple Group. Estimates for LPFS, PFS, and OS were directionally consistent in a common fixed landmark analysis at day 28 and in a time-dependent Cox model. Grade ≥ 3 adverse events were comparable (28.0% vs. 24.2%, P = 0.648), with no classic radiation-induced liver disease and two cases of non-classic RILD in the Triple Group. CONCLUSION: In this selected cohort of patients with advanced HCC, MVI, preserved performance status, and Child-Pugh A/B7 liver function, the addition of CyberKnife SBRT to lenvatinib and tislelizumab was associated with higher confirmed response rates, longer local control, and prolonged PFS and OS, without a clear excess of severe toxicity. These findings support prospective evaluation of CyberKnife SBRT as a local-treatment component of first-line combined-modality therapy in carefully selected patients with HCC and MVI.