射波刀立体定向放射治疗联合仑伐替尼和替雷利珠单抗对比双药系统治疗伴有大血管侵犯的肝细胞癌：一项真实世界IPTW调整研究

摘要(中文译文)

大血管侵犯（MVI）在肝细胞癌（HCC）中预示着极差的预后。尽管仑伐替尼联合替雷利珠单抗是一种有效的靶向-免疫治疗方案，但瘤栓的局部控制仍不理想。通过射波刀实施的立体定向体部放疗（SBRT）可提供高度适形的局部治疗，并可能具有免疫调节效应。我们评估了在双药全身治疗基础上加用射波刀SBRT是否与伴MVI的HCC患者预后改善相关。这项真实世界回顾性研究纳入116例伴MVI的HCC患者（三联组：射波刀SBRT+仑伐替尼+替雷利珠单抗，n=50；双药组：仑伐替尼+替雷利珠单抗，n=66）——从2021年6月至2024年6月期间筛查的215例患者池中选取。采用稳定化逆概率治疗加权（IPTW），倾向性评分由包含九个基线协变量的多变量logistic回归得出，并作为额外敏感性分析，采用扩展的18协变量模型和梯度提升机倾向性评分，使测得的基线协变量达到均衡（加权后所有标准化均数差<0.10）。主要终点为确认的客观缓解率（ORR，mRECIST标准，要求在首次记录缓解后≥4周进行确认性扫描）和局部无进展生存期（LPFS，定义为预先指定的索引局部病灶——大血管瘤栓及其相邻的原发性肝肿瘤——的影像学进展或死亡；索引病灶在三联组对应SBRT治疗的靶区，在双药组对应解剖学相应病灶并以相同标准随访）。次要终点包括无进展生存期（PFS）、总生存期（OS）、详细的危及器官剂量学、肝脏安全性（CTCAE v5.0加Child-Pugh/ALBI追踪）和治疗暴露。观察到的确认ORR在三联组为68.0%（34/50），双药组为37.9%（25/66）；稳定化IPTW加权后ORR为71.1%对37.6%（P<0.001）。中位LPFS为15.1个月对7.8个月（HR=0.42，95%CI：0.27-0.64，P<0.001）。中位PFS（11.1个月对6.4个月；HR=0.46，95%CI：0.30-0.71，P<0.001）和OS（23.0个月对15.6个月；HR=0.57，95%CI：0.36-0.92，P=0.022）也均有利于三联组。在第28天进行的共同固定界标分析和时间依赖性Cox模型中，LPFS、PFS和OS的估计值方向一致。≥3级不良事件相当（28.0%对24.2%，P=0.648），三联组无经典放射性肝病，有2例非经典放射性肝病。在这一经选择的晚期HCC、MVI、体能状态保留且Child-Pugh A/B7肝功能患者队列中，在仑伐替尼和替雷利珠单抗基础上加用射波刀SBRT与更高的确认缓解率、更长的局部控制以及延长的PFS和OS相关，且未出现明显的严重毒性增加。这些发现支持在精心选择的伴MVI的HCC患者中，将射波刀SBRT作为一线联合模态治疗中局部治疗组成部分进行前瞻性评估。

Abstract

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. This real-world retrospective study included 116 HCC patients with MVI (Triple group: CyberKnife SBRT + lenvatinib + tislelizumab, = 50; Doublet group: lenvatinib + tislelizumab, = 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. 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% ( < 0.001). Median LPFS was 15.1 versus 7.8 months (HR = 0.42, 95%CI: 0.27-0.64, < 0.001). Median PFS (11.1 vs. 6.4 months; HR = 0.46, 95%CI: 0.30-0.71, < 0.001) and OS (23.0 vs. 15.6 months; HR = 0.57, 95%CI: 0.36-0.92, = 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%, = 0.648), with no classic radiation-induced liver disease and two cases of non-classic RILD in the Triple Group. 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.

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