2024 AASLD | T+A治疗晚期HCC：疗效预测与静脉曲张出血风险探究

2024年11月15日-19日，美国肝病研究学会年会 (AASLD 2024) 于美国圣迭戈举行。此次会议云集肝病研究领域的最新研究成果与前沿探索，为与会者搭建出一个深化肝病认知、拓宽专业视野的高端学术交流平台。

为便于广大读者及时捕捉学术精髓，肝胆相照平台/肝癌在线特此甄选AASLD热点研究，精心翻译并呈现大会最新动态与核心看点。本篇聚焦“肝癌”这一专题，深入剖析其最新研究进展与临床应用前景。

➢ 背景：在临床试验中，阿替利珠单抗和贝伐珠单抗对晚期肝细胞癌（HCC）表现出良好的疗效。本研究旨在通过全面的真实世界数据验证其在晚期肝细胞癌患者中的疗效和安全性。

• Background: Atezolizumab and bevacizumab have shown promising efficacy in clinical trials for advanced hepatocellular carcinoma (HCC). This study aims to validate these findings with comprehensive real-world data on their efficacy and safety in advanced HCC patients.

➢ 方法：研究者在韩国一家三级癌症中心开展了回顾性队列研究，纳入了111名在2022年5月至2023年6月期间接受阿替利珠单抗和贝伐珠单抗作为一线治疗的晚期肝细胞癌患者。评估了总生存期（OS）、无进展生存期（PFS）、客观缓解率（ORR）、疾病控制率（DCR，按照RECIST v1.1标准）以及安全性。

• Methods: We conducted a retrospective cohort study at a tertiary cancer center in Korea, including 111 patients with advanced HCC treated with atezolizumab and bevacizumab as first-line therapy from May 2022 to June 2023. We assessed overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) according to RECIST v1.1, and the safety profile.

➢ 结果：在患者中，38%存在大血管侵袭，33%呈现高风险特征，包括广泛的门静脉肿瘤血栓、胆管侵犯和显著的肝脏浸润（超过50%）。中位OS为10.6个月（95%置信区间：8.9–13.1个月）。ORR和DCR分别为27%和63%。白蛋白-胆红素（ALBI）等级和甲胎蛋白（AFP）水平是OS的重要预测因子，其中AFP还与PFS和ORR相关。联合放疗对PFS和ORR产生了积极影响。腹膜种植的患者也表现出良好的治疗反应。安全性分析结果与临床试验中的观察一致。

• Results: Among the patients, 38% had macrovascular invasion, and 33% presented high-risk features, including extensive portal vein tumor thrombosis, bile duct invasion, and significant liver infiltration (over 50%). The median OS was 10.6 months (95% confidence interval: 8.9–13.1 months). The ORR and DCR were 27% and 63%, respectively. Albumin-Bilirubin (ALBI) grade and Alpha-fetoprotein (AFP) levels were significant predictors of OS, with AFP also associated with PFS and ORR. Combined radiotherapy positively impacted PFS and ORR. Patients with peritoneal seeding exhibited a favorable response. The safety profile was consistent with that observed in clinical trials.

➢ 结论：阿替利珠单抗和贝伐珠单抗在晚期肝细胞癌中的真实世界应用验证了其疗效。研究还发现，ALBI等级、AFP水平、联合放疗和腹膜种植是影响临床预后的重要因素。

• Conclusion: The real-world application of atezolizumab and bevacizumab for advanced HCC has validated their efficacy. The study identified ALBI grade, AFP levels, combined radiotherapy, and the presence of peritoneal seeding as significant prognostic factors affecting clinical outcomes.

➢ 背景：根据IMbrave150试验，阿替利珠单抗联合贝伐珠单抗（AteBeva）成为不可切除肝细胞癌（HCC）的标准治疗。然而，该临床试验未纳入急性静脉曲张出血 (AVB) 或有高风险食管静脉曲张病史的患者，关于AteBeva在此类患者中的疗效和安全性的真实世界数据仍然稀缺。本研究旨在评估AteBeva的治疗效果和安全性，并识别治疗过程中食管静脉曲张出血的风险因素。

• Background: Following the IMbrave150 trial, atezolizumab plus bevacizumab (AteBeva) emerged as the gold standard for unresectable hepatocellular carcinoma (HCC). However, given the exclusion criteria of the trial, including no history of acute variceal bleeding (AVB) or high-risk esophageal varices, real-world data on AteBeva's efficacy and safety in patients with such histories remain scarce. We aimed to assess the therapeutic effect and safety of AteBeva and identify risk factors for AVB during treatment in Korea.

➢ 方法：本回顾性研究纳入了2020年9月至2022年12月期间在天主教医疗中心七家医院接受AteBeva治疗的所有晚期HCC患者。对患者进行随访至2023年12月，分析了治疗效果、安全性和AteBeva相关的静脉曲张出血。使用Kaplan-Meier和Cox模型进行时间事件分析。

• Methods: This retrospective study enrolled all patients diagnosed with advanced HCC who received AteBeva from seven centers of the Catholic Medical Center between September 2020 and December 2022. Patients were followed up until December 2023, and therapeutic efficacy, safety, and AteBeva-related variceal bleeding were analyzed. Time-to-event analyses were conducted using Kaplan-Meier and Cox models.

➢ 结果：共有154名接受AteBeva治疗的患者被纳入分析。基线特征显示，患者的中位年龄为64.0岁（范围：56.0-73.0），其中男性占85.1%。最常见的病因是乙型肝炎病毒感染（62.2%）和酒精相关性肝病（26.5%）。客观缓解率（ORR）为38.3%，疾病控制率（DCR）为70.9%。中位总生存期（OS）为14.0个月（95% CI：8.5-19.5），中位无进展生存期（PFS）为5.0个月（95% CI：3.9-6.1），中位进展时间（TTP）为3.0个月（95% CI：2.3-3.7）。

多变量分析确定了与OS和AteBeva治疗后静脉曲张出血相关的变量。在多变量分析中，与OS相关的变量包括东部合作肿瘤学组（ECOG）表现状态、肝硬化、Child-Pugh评分、最大肝内肿瘤大小和治疗持续时间。在接受 AteBeva 治疗后发生所有级别胃肠道出血事件的患者中，有 40 人 (26.0%) 受到影响，包括静脉曲张出血（n=23，14.9%）。在多变量分析中，与AteBeva治疗后静脉曲张出血相关的变量包括Child-Pugh评分和AteBeva治疗前预防性内镜套扎术 (EBL) 引起的溃疡。

• Results: One hundred fifty-four patients treated with AteBeva were included. Baseline characteristics revealed a median age of 64.0 years (range: 56.0-73.0), with 85.1% male. The most common etiologies were hepatitis B virus infection (62.2%) and alcohol-related liver disease (26.5%). The Objective Response Rate (ORR) was 38.3%, and the Disease Control Rate (DCR) was 70.9%. Median overall survival (OS) was 14.0 months (95% CI: 8.5-19.5), median progression-free survival (PFS) was 5.0 months (95% CI: 3.9-6.1), and median time-to-progression (TTP) was 3.0 months (95% CI: 2.3-3.7). 

Multivariable analysis identified variables associated with OS and varix bleeding after AteBeva. In multivariable analysis, variables associated with OS were the Eastern Cooperative Oncology Group (ECOG) performance status, liver cirrhosis, Child-Pugh class, largest intrahepatic tumor size, and treatment duration. Among the patients who underwent all grades of gastrointestinal bleeding events after AteBeva, 40 (26.0%) were affected, including varix bleeding (n = 23, 14.9%). In multivariable analysis, variables associated with varix bleeding after AteBeva were Child-Pugh score and ulceration from prophylactic endoscopic band ligation (EBL) before AteBeva.

➢ 结论：基线的Child-Pugh评分和治疗前预防性EBL引起的溃疡是静脉曲张出血的风险因素。对于接受AteBeva治疗的患者，特别是那些接受过预防性EBL治疗的患者，监测和处理EBL后的溃疡至关重要。需要进一步的大规模研究来验证这些发现。

• Conclusion: Child-Pugh score at baseline and ulceration from prophylactic EBL before AteBeva were identified as risk factors for varix bleeding. Monitoring and managing ulceration post-EBL are essential for patients receiving AteBeva, particularly those with prophylactic EBL. Further large-scale studies are warranted to validate these findings.