蛋白尿与接受阿替利珠单抗和贝伐单抗治疗的不可切除肝细胞癌预后改善的相关性以及血清血管内皮生长因子D水平的预测作用：一项多中心回顾性研究

Association of proteinuria with improved prognosis in unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab, and the predictive role of serum vascular endothelial growth factor D levels: A multicenter retrospective study.

作者信息

Yang Zijian, Suda Goki, Sho Takuya, Maehara Osamu, Ohara Masatsugu, Yoda Tomoka, Fu Qingjie, Sasaki Takashi, Kohya Risako, Yoshida Sonoe, Hosoda Shunichi, Kitagataya Takashi, Kawagishi Naoki, Nakai Masato, Natsuizaka Mitsuteru, Ogawa Koji, Ohnishi Shunsuke, Yamamoto Yoshiya, Baba Masaru, Yamada Ren, Kobayashi Tomoe, Chen Minhu, Sakamoto Naoya

机构信息

Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.

Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

出版信息

Hepatol Res. 2025 Mar;55(3):433-443. doi: 10.1111/hepr.14139. Epub 2024 Nov 25.

DOI:10.1111/hepr.14139

PMID:39584803

Abstract

AIM

Atezolizumab/bevacizumab is a first-line therapy for unresectable hepatocellular carcinoma (HCC). Among several adverse events, grade ≥2 proteinuria is considered a significant adverse event that may cause bevacizumab interruption. Studies have shown that proteinuria might predict improved prognosis, although data are scarce and the association remains controversial, and the mechanisms and predictive factors remain unclear. We aimed to clarify these.

METHODS

In this multicenter retrospective study, we screened patients with HCC treated with atezolizumab/bevacizumab. The prognostic impact of grade ≥2 proteinuria was examined in patients with proper clinical data and preserved serum for growth factor analysis. For biomarker analysis predicting proteinuria, baseline serum vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D levels were analyzed.

RESULTS

This study included 75 patients, and 32 (42.7%) experienced grade ≥2 proteinuria. No significant differences were observed between those with or without proteinuria, except for aspartate transaminase and alanine transaminase levels. Time-dependent Cox proportional hazards analysis revealed that grade ≥2 proteinuria was significantly associated with better prognosis (hazard ratio 0.221; 95% confidence interval 0.082-0.592; p = 0.003). In biomarker analysis, low baseline serum VEGF-C and VEGF-D levels were significantly associated with proteinuria, and multivariate analysis demonstrated that baseline serum VEGF-D level was significantly associated with grade ≥2 proteinuria (hazard ratio 0.101; 95% confidence interval 0.029-0.357; p < 0.001).

CONCLUSIONS

Grade ≥2 proteinuria in patients with unresectable HCC treated with atezolizumab/bevacizumab indicates a better prognosis, and baseline serum VEGF-D levels can help predict its occurrence. These findings can help in managing adverse events and prognosis in advanced HCC treated with atezolizumab/bevacizumab.

摘要

目的

阿替利珠单抗/贝伐珠单抗是不可切除肝细胞癌（HCC）的一线治疗方案。在多种不良事件中，≥2级蛋白尿被视为可能导致贝伐珠单抗中断的严重不良事件。研究表明，蛋白尿可能预示预后改善，尽管数据稀少且这种关联仍存在争议，其机制和预测因素也尚不清楚。我们旨在阐明这些问题。

方法

在这项多中心回顾性研究中，我们筛选了接受阿替利珠单抗/贝伐珠单抗治疗的HCC患者。对具有适当临床数据且保存了血清用于生长因子分析的患者，研究≥2级蛋白尿对预后的影响。为了分析预测蛋白尿的生物标志物，检测了基线血清血管内皮生长因子（VEGF）-A、VEGF-C和VEGF-D水平。

结果

本研究纳入75例患者，其中32例（42.7%）出现≥2级蛋白尿。除天冬氨酸转氨酶和丙氨酸转氨酶水平外，有或无蛋白尿患者之间未观察到显著差异。时间依赖性Cox比例风险分析显示，≥2级蛋白尿与更好的预后显著相关（风险比0.221；95%置信区间0.082 - 0.592；p = 0.003）。在生物标志物分析中，低基线血清VEGF-C和VEGF-D水平与蛋白尿显著相关，多因素分析表明基线血清VEGF-D水平与≥2级蛋白尿显著相关（风险比0.101；95%置信区间0.029 - 0.357；p < 0.001）。