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Heterogeneity in adverse events related to atezolizumabbevacizumab for hepatocellular carcinoma reported in realworld studies
真实世界研究中报告的与 atezolizumabbevacizumab 治疗肝细胞癌相关的不良事件的异质性

Authors  作者Claudia Campani, Dimitrios Pallas, Sabrina Sidali, ..., Pierre Nahon, Nathalie Ganne-Carrié, Jean-Charles Nault Correspondence
克劳迪娅·坎帕尼、迪米特里奥斯·帕拉斯、萨布丽娜·西达利、...、皮埃尔·纳洪、娜塔莉·甘纳-卡里埃、让-查尔斯·诺特通信

naultjc@gmail.com (J.-C. Nault).
naultjc@gmail.com （J.-C.诺特）。
Graphical abstract  图形摘要

Highlights:  突出：

  • Systematic review analyzed 30 studies on 3,867 patients with HCC treated with atezolizumab-bevacizumab.
    系统评价分析了 30 项研究，涉及 3,867 名接受阿替利珠单抗-贝伐珠单抗治疗的 HCC 患者。
  • High variability in adverse event reporting across studies available in the literature.
    文献中可用的研究中不良事件报告的差异很大。
  • Severe adverse events like bleeding, thrombosis, and perforation are often underreported.
    出血、血栓形成和穿孔等严重不良事件经常被低估。
  • Need for standardized and thorough adverse event reporting in clinical practice.
    临床实践中需要标准化和彻底的不良事件报告。

Impact and implications:
影响和启示：

Considering the demonstrated safety of atezolizumabbevacizumab in randomized-controlled trials, this metaanalysis offers valuable insights into reported occurrences of adverse events. Our study highlights significant heterogeneity among studies, underscoring the need to improve adverse event recording. Understanding the incidence and severity of treatment-related adverse events beyond clinical trials is essential for prompt intervention and may help in preventing treatment discontinuation and complications, potentially leading to better outcomes without significantly compromising quality of life due to adverse events.
考虑到 atezolizumabbevacizumab 在随机对照试验中证明的安全性，该荟萃分析为报告的不良事件发生提供了有价值的见解。我们的研究强调了研究之间显着的异质性，强调了改进不良事件记录的必要性。了解临床试验之外治疗相关不良事件的发生率和严重程度对于及时干预至关重要，并可能有助于预防治疗中断和并发症，从而有可能带来更好的结果，而不会因不良事件而显着影响生活质量。

Heterogeneity in adverse events related to atezolizumabbevacizumab for hepatocellular carcinoma reported in realworld studies
真实世界研究中报告的与 atezolizumabbevacizumab 治疗肝细胞癌相关的不良事件的异质性

Claudia Campani 1 , 2 , † 1 , 2 , † ^(1,2,†){ }^{1,2, \dagger}, Dimitrios Pallas 3 , † 3 , † ^(3,†){ }^{3, \dagger}, Sabrina Sidali 1 1 ^(1){ }^{1}, Olga Giouleme 4 4 ^(4){ }^{4}, Lorraine Blaise 1 , 3 1 , 3 ^(1,3){ }^{1,3}, Véronique Grando 1 , 3 1 , 3 ^(1,3){ }^{1,3}, Gisele Nkontchou 1 , 3 1 , 3 ^(1,3){ }^{1,3}, Alix Demory 1 , 3 1 , 3 ^(1,3){ }^{1,3}, Pierre Nahon 1 , 3 1 , 3 ^(1,3){ }^{1,3}, Nathalie Ganne-Carrié 1 , 3 1 , 3 ^(1,3){ }^{1,3}, Jean-Charles Nault 1 , 3 , ∗ 1 , 3 , ∗ ^(1,3,**){ }^{1,3, *}
克劳迪娅·坎帕尼 1 , 2 , † 1 , 2 , † ^(1,2,†){ }^{1,2, \dagger} ， 迪米特里奥斯·帕拉斯 3 , † 3 , † ^(3,†){ }^{3, \dagger} ， 萨布丽娜·西达利 1 1 ^(1){ }^{1} ， 奥尔加·朱莱姆 4 4 ^(4){ }^{4} ， 洛林·布莱斯 1 , 3 1 , 3 ^(1,3){ }^{1,3} ， 维罗妮克·格兰多 1 , 3 1 , 3 ^(1,3){ }^{1,3} ， 吉赛尔·恩孔丘 1 , 3 1 , 3 ^(1,3){ }^{1,3} ， 阿利克斯·德莫里 1 , 3 1 , 3 ^(1,3){ }^{1,3} ， 皮埃尔·纳洪 1 , 3 1 , 3 ^(1,3){ }^{1,3} ， 娜塔莉·甘纳-卡里 1 , 3 1 , 3 ^(1,3){ }^{1,3} ， 让-查尔斯·诺 1 , 3 , ∗ 1 , 3 , ∗ ^(1,3,**){ }^{1,3, *}

JHEP Reports 2024. vol. 6 | 1-13
JHEP 报告 2024。第 6 卷 |1-13
Background & Aims: Safety data for patients with hepatocellular carcinoma (HCC) treated with atezolizumab-bevacizumab in the real-world setting remain uncertain. Thus, the aim of this study was to evaluate the incidence of adverse events (AEs) in patients with HCC treated with atezolizumab-bevacizumab in the literature.
背景和目的：在现实环境中接受阿替利珠单抗-贝伐珠单抗治疗的肝细胞癌 （HCC） 患者的安全性数据仍不确定。因此，本研究的目的是评估文献中接受阿替利珠单抗-贝伐珠单抗治疗的 HCC 患者的不良事件 （AE） 发生率。
Methods: In this systematic review and meta-analysis, we searched PubMed for original studies reporting percentages of AEs in patients with HCC receiving atezolizumab-bevacizumab between 2020 to 2023, using the search terms “Atezolizumab/Bevacizumab”, “HCC” and “Adverse events”. We summarized the incidence of AEs and performed a meta-analysis in order to evaluate the incidence of AEs reported in the literature.
方法：在这项系统评价和荟萃分析中，我们检索了 PubMed 的原始研究，其中报告了 2020 年至 2023 年间接受阿替利珠单抗-贝伐珠单抗治疗的 HCC 患者 AE 百分比，使用搜索词“Atezolizumab/贝伐珠单抗”、“HCC”和“不良事件”。我们总结了 AE 的发生率并进行了 meta 分析，以评估文献中报道的 AE 的发生率。
Results: A total of 30 studies ( 3,867 patients) were included. The analysis revealed heterogeneity in AE reporting, with arterial hypertension, proteinuria, and fatigue being the most frequently reported AEs whereas incidence of bleeding was reported in 66.7 % 66.7 % 66.7%66.7 \% of the studies and rare immune-related AEs were reported in 26.7 % 26.7 % 26.7%26.7 \% of the studies. The meta-analysis revealed pooled incidence rates of 79 % 79 % 79%79 \% for any grade AEs: 56 % 56 % 56%56 \% for grade 1 / 2 1 / 2 1//21 / 2 and 30 % 30 % 30%30 \% for grade ≥ 3 ≥ 3 >= 3\geq 3. While the pooled rates of hypertension, anorexia, bleeding, pruritus, rash, and thyroid dysfunction were similar to those reported in the IMbrave150 trial, higher rates were observed in the literature for proteinuria, fatigue, ALT and AST elevations and gastrointestinal perforation. For grade ≥ 3 ≥ 3 >= 3\geq 3 AEs, the percentages were consistent with the IMbrave150 trial, except for lower incidences of arterial hypertension and thrombosis in the literature. The exposure-adjusted incidence rates for proteinuria ( 55.7 % 55.7 % 55.7%55.7 \% ), hypertension ( 45.3 % 45.3 % 45.3%45.3 \% ) and fatigue ( 33.6 % 33.6 % 33.6%33.6 \% ) were high. Heterogeneity was observed in the analysis of AEs across articles within the same cohorts of patients.
结果：共纳入 30 项研究（3,867 名患者）。分析显示 AE 报告存在异质性，动脉高血压、蛋白尿和疲劳是最常报告的 AE，而出血发生率在研究 26.7 % 26.7 % 26.7%26.7 \% 中报告 66.7 % 66.7 % 66.7%66.7 \% ，罕见的免疫相关 AE 在研究中报告。荟萃分析揭示了任何级别 AE 的 79 % 79 % 79%79 \% 汇总发生率： 56 % 56 % 56%56 \% 分级 1 / 2 1 / 2 1//21 / 2 和 30 % 30 % 30%30 \% 分级 ≥ 3 ≥ 3 >= 3\geq 3 。虽然高血压、厌食、出血、瘙痒、皮疹和甲状腺功能障碍的合并发生率与 IMbrave150 试验中报告的相似，但在文献中观察到蛋白尿、疲劳、ALT 和 AST 升高以及胃肠道穿孔的发生率更高。对于分级 ≥ 3 ≥ 3 >= 3\geq 3 AE，百分比与 IMbrave150 试验一致，但文献中动脉高血压和血栓形成的发生率较低。蛋白尿 （ 55.7 % 55.7 % 55.7%55.7 \% ）、高血压 （ 45.3 % 45.3 % 45.3%45.3 \% ） 和疲劳 （ 33.6 % 33.6 % 33.6%33.6 \% ） 的暴露调整发生率较高。在同一患者队列中，跨文献的 AE 分析观察到异质性。
Conclusion: We observed a significant variability in AE reporting for atezolizumab-bevacizumab treatment in HCC in the literature, underscoring the need for standardized reporting practices.
结论：我们在文献中观察到阿替利珠单抗-贝伐珠单抗治疗 HCC 的 AE 报告存在显着差异，强调了标准化报告实践的必要性。
© 2024 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
© 2024 作者。由 Elsevier B.V. 代表欧洲肝脏研究协会 （EASL） 出版。这是一篇 CC BY 许可证 （http://creativecommons.org/licenses/by/4.0/） 下的开放获取文章。

Introduction  介绍

The combination of monoclonal antibodies targeting PD-L1 (programmed death-ligand 1) (atezolizumab) and VEGF (vascular endothelial growth factor) (bevacizumab) represents the new first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). 1 , 2 1 , 2 ^(1,2){ }^{1,2} In the IMbrave150 trial, the atezolizumab-bevacizumab combination demonstrated improvements in overall survival (OS), progression-free survival (PFS) and objective response rate, as well as patient-reported outcomes compared to sorafenib. 3 , 4 3 , 4 ^(3,4){ }^{3,4} Adverse events (AEs) of any grade occurred in 98 % 98 % 98%98 \% of patients treated with atezolizumab-bevacizumab vs. 99 % 99 % 99%99 \% in patients treated with sorafenib with 49 % 49 % 49%49 \% experiencing severe AEs vs. 33 % 33 % 33%33 \% in the sorafenib arm. The most common treatment-related AEs were proteinuria, arterial hypertension, increased aspartate aminotransferase (AST), and fatigue with a percentage of AEs leading
靶向 PD-L1（程序性死亡配体 1）（atezolizumab）和 VEGF（血管内皮生长因子）（贝伐珠单抗）的单克隆抗体组合代表了不可切除肝细胞癌（HCC）患者新的一线护理标准。 1 , 2 1 , 2 ^(1,2){ }^{1,2} 在 IMbrave150 试验中，与索拉非尼相比，阿替利珠单抗-贝伐珠单抗联合疗法在总生存期（OS）、无进展生存期（PFS）和客观缓解率以及患者报告的结果方面有所改善。 3 , 4 3 , 4 ^(3,4){ }^{3,4} 接受阿替利珠单抗-贝伐珠单抗治疗的患者与 99 % 99 % 99%99 \% 接受索拉非尼治疗并出现严重 AE 33 % 33 % 33%33 \% 的患者 49 % 49 % 49%49 \% 与索拉非尼组相比，发生了任何级别 98 % 98 % 98%98 \% 的不良事件 （AE）。最常见的治疗相关 AE 是蛋白尿、动脉高血压、天冬氨酸转氨酶 （AST） 升高和疲劳，其中一定比例的 AE 导致
to treatment withdrawal of 22 % . 3 , 4 22 % . 3 , 4 22%.^(3,4)22 \% .^{3,4} The most common immunemediated AEs were rash (22%) and thyroid dysfunction ( 19 % ) . 3 , 4 ( 19 % ) . 3 , 4 (19%).^(3,4)(19 \%) .^{3,4} While a high rate of AST increase was also observed (53%), not all cases could be adjudicated to atezolizumab and immune-related hepatitis. Moreover, the percentage of corticosteroid use for immune-related AEs was not reported. In the atezolizumab-bevacizumab arm, there were six cases of bleeding, five gastrointestinal and one non-gastrointestinal hemorrhage, with a single case of intraperitoneal hemorrhage among patients treated with sorafenib. However, eligibility for IMbrave 150 trial was restricted to patients without prior exposure to systemic therapy, with preserved liver function (Child-Pugh A), and optimal control of portal hypertension. 3 , 4 3 , 4 ^(3,4){ }^{3,4} For this reason, the safety data remain uncertain for patients treated with atezolizumab-bevacizumab in the real-world setting, including rare AEs such as gastrointestinal perforation, bleeding, thrombosis and immune-related AEs requiring
到治疗停止最常见的 22 % . 3 , 4 22 % . 3 , 4 22%.^(3,4)22 \% .^{3,4} 免疫介导的 AE 是皮疹 （22%） 和甲状腺功能 ( 19 % ) . 3 , 4 ( 19 % ) . 3 , 4 (19%).^(3,4)(19 \%) .^{3,4} 障碍虽然也观察到 AST 增加率很高 （53%），但并非所有病例都可以判定为 atezolizumab 和免疫相关性肝炎。此外，没有报告皮质类固醇用于免疫相关不良事件的百分比。在阿替利珠单抗-贝伐珠单抗组中，接受索拉非尼治疗的患者中有 6 例出血，5 例消化道出血，1 例非消化道出血，腹腔内出血 1 例。然而，IMbrave 150 试验的资格仅限于之前未接受过全身治疗、肝功能保留 （Child-Pugh A） 且门静脉高压症得到最佳控制的患者。 3 , 4 3 , 4 ^(3,4){ }^{3,4} 因此，在现实环境中接受阿替利珠单抗-贝伐珠单抗治疗的患者的安全性数据仍不确定，包括罕见的不良事件，如胃肠道穿孔、出血、血栓形成和需要的免疫相关不良事件
corticosteroids. 5 − 8 5 − 8 ^(5-8){ }^{5-8} Accurate and consistent reporting of AEs is crucial for evaluating the safety profile of any therapeutic regimen, guiding clinical decision-making, and informing patient management. The analysis of incidence of AEs in studies from patients treated in the real-world setting is also useful to identify potential new toxicity signals not reported in the phase III clinical trials. The incidence of the different AEs associated with systemic treatments in other solid cancers across studies published in the literature is highly heterogeneous, both for lower grade and more severe AEs. 9 − 11 9 − 11 ^(9-11){ }^{9-11} Inconsistencies in the reporting of AEs can stem from differences in study design (retrospective vs. prospective, monocentric, multicentric), sample size, patient demographics, and the way AEs are collected. These discrepancies complicate the interpretation of safety data and can obscure the true incidence and severity of AEs. However, this issue was not studied in patients with advanced HCC treated with systemic treatment.
皮质 类固醇。 5 − 8 5 − 8 ^(5-8){ }^{5-8} 准确、一致的不良事件报告对于评估任何治疗方案的安全性、指导临床决策和为患者管理提供信息至关重要。在现实环境中接受治疗的患者研究中分析 AE 的发生率也有助于识别 III 期临床试验中未报告的潜在新毒性信号。在文献中发表的研究中，与其他实体癌的全身治疗相关的不同 AE 的发生率是高度异质的，无论是低级别还是更严重的 AE。AE 报告的 9 − 11 9 − 11 ^(9-11){ }^{9-11} 不一致可能源于研究设计（回顾性与前瞻性、单中心、多中心）、样本量、患者人口统计学以及 AE 收集方式的差异。这些差异使安全数据的解释变得复杂，并可能掩盖 AE 的真实发生率和严重程度。然而，这个问题没有在接受全身治疗的晚期 HCC 患者中进行研究。
We aimed to perform a systematic review and meta-analysis of the literature to assess the frequencies of AEs reported in studies evaluating atezolizumab-bevacizumab in patients with advanced HCC in order to evaluate the need for a more precise standardization of A E A E AEA E reports in the literature.
我们旨在对文献进行系统评价和 meta 分析，以评估评估 atezolizumab-bevacizumab 治疗晚期 HCC 患者的研究中报告的 AE 的频率，以评估文献中报告更 A E A E AEA E 精确标准化的必要性。

Material and methods  材料和方法

Search strategy  搜索策略

A systematic search for records from 14 May 2020 to 25 October 2023 in PubMed Central was performed using different combinations of the following keywords: “Atezolizumab plus Bevacizumab” AND “Hepatocellular Carcinoma”, OR “Atezolizumab plus Bevacizumab” AND “HCC”, OR “Atezolizumab and Bevacizumab” AND Hepatocellular Carcinoma", OR “Atezolizumab and Bevacizumab” AND “HCC”, OR “AtezolizumabBevacizumab” AND “Hepatocellular Carcinoma” AND “Adverse events”, OR “Atezolizumab-Bevacizumab” AND “HCC” AND “Adverse events”, OR “Atezolizumab-Bevacizumab” AND “Hepatocellular Carcinoma”, OR “Atezolizumab-Bevacizumab” AND “HCC”. This study was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines. 12 12 ^(12){ }^{12}
使用 2020 年 5 月 14 日至 2023 年 10 月 25 日在 PubMed Central 中系统搜索以下关键字的不同组合进行记录：“Atezolizumab 加贝伐珠单抗”和“肝细胞癌”，或“Atezolizumab 加贝伐珠单抗”和“HCC”，或“Atezolizumab 和贝伐珠单抗”和肝细胞癌“，或”Atezolizumab 和贝伐珠单抗“和”HCC“，或”Atezolizumab 贝伐珠单抗“和”肝细胞癌“和”不良事件“， 或“阿替珠单抗-贝伐珠单抗”和“HCC”和“不良事件”，或“阿替珠单抗-贝伐珠单抗”和“肝细胞癌”，或“阿替珠单抗-贝伐珠单抗”和“HCC”。本研究是根据 PRISMA（系统评价和荟萃分析的首选报告项目）指南进行的。 12 12 ^(12){ }^{12}

Study selection and data extraction
研究选择和数据提取

The studies identified by the search were subsequently evaluated according to the following inclusion and exclusion criteria. Inclusion criteria: articles written in English, target population of the original paper was patients with HCC treated with atezolizumab-bevacizumab, general or specific percentages of AEs occurring during atezolizumab-bevacizumab treatment were reported. Exclusion criteria: phase Ib and phase III randomized clinical trial evaluating atezolizumab-bevacizumab, case-reports, systematic reviews and meta-analyses, sub-analyses of phase Ib and phase III trials, articles reporting AEs occurring when atezolizumab-bevacizumab was used in combination with other treatments (e.g. loco-regional treatments), articles reporting AEs occurring when atezolizumabbevacizumab was used as adjuvant treatment, articles reporting AEs occurring during therapy with immune checkpoint inhibitors including atezolizumab-bevacizumab, but where the percentages of AEs for this specific combination, among all the systemic treatments, were not clearly reported.
随后根据以下纳入和排除标准评估检索确定的研究。纳入标准：用英文撰写的文章，原论文的目标人群是接受阿替利珠单抗-贝伐珠单抗治疗的 HCC 患者，报告了阿替利珠单抗-贝伐珠单抗治疗期间发生的 AE 的一般或特定百分比。排除标准：评估 atezolizumab-贝伐珠单抗的 Ib 期和 III 期随机临床试验、病例报告、系统评价和荟萃分析、Ib 期和 III 期试验的子分析、报告 atezolizumab-贝伐珠单抗与其他治疗联合使用时发生的 AE 的文章（例如 局部区域治疗），报告使用 atezolizumabbevacizumab 作为辅助治疗时发生的 AE 的文章，报告免疫治疗期间发生的 AE 的文章检查点抑制剂，包括阿替利珠单抗-贝伐珠单抗，但该特定组合的 AE 百分比在所有全身治疗中没有明确报告。
Published systematic reviews and meta-analyses were screened to ensure that all studies reporting AEs during atezolizumab-bevacizumab were included.
筛选已发表的系统评价和荟萃分析，以确保纳入所有报告阿替利珠单抗-贝伐珠单抗期间 AE 的研究。
Two reviewers (DP and CC) independently screened titles and abstracts of the articles extracted. The full texts of the eligible articles were then independently reviewed. Any discrepancies in article selection were resolved by discussion with a third expert reviewer (JCN). Data extraction from the included studies was then performed independently by two reviewers (DP and CC). The complete list of variables extracted from the included studies are reported in Table S1.
两名审稿人（DP 和 CC）独立筛选了提取的文章的标题和摘要。然后对符合条件的文章的全文进行独立审查。文章选择中的任何差异都通过与第三位专家审稿人 （JCN） 讨论解决。然后由两名评价员（DP 和 CC）独立从纳入的研究中提取资料。从纳入研究中提取的变量的完整列表报告在表 S1 中。
The outcomes of interest were the reporting of AEs and the incidences of these AEs during atezolizumab-bevacizumab treatment. In particular, we recorded general percentages of any AEs regardless of their severity, percentages of any AEs divided by severity grade according to the classification used in each study, and percentages of each specific A E A E AEA E regardless of grade and divided by severity grades. We recorded if frequent potential immune-related AEs, such as rash, hepatitis and thyroid disorder, were reported (and their incidence), as well as less common immune-related AEs (such as colitis, pneumonitis, nephritis, neuropathy, myositis, adrenal insufficiency, hypophysitis and/or rheumatological diseases) and the use of corticosteroids to treat immune-related AEs.
感兴趣的结果是 atezolizumab-贝伐珠单抗治疗期间 AE 的报告和这些 AE 的发生率。特别是，我们记录了任何 AE 的一般百分比，无论其严重程度如何，根据每项研究中使用的分类，将任何 AE 的百分比除以严重程度等级，以及每个特定 A E A E AEA E AE 的百分比，无论其严重程度如何，并除以严重程度等级。我们记录了是否报告了频繁的潜在免疫相关不良事件，如皮疹、肝炎和甲状腺疾病（及其发生率），以及不太常见的免疫相关不良事件（如结肠炎、肺炎、肾炎、神经病变、肌炎、肾上腺皮质功能不全、垂体炎和/或风湿病）以及使用皮质类固醇治疗免疫相关不良事件。

Statistical analysis  统计分析

First, we conducted a descriptive analysis to assess the number of studies reporting each AE, as well as evaluating the characteristics of the included population. For each AE reported in these studies, we evaluated the distribution of percentages by calculating the minimum, maximum, median, and interquartile range (raw data). Distinct analyses encompassing all grades of AEs and each severity grade (grade 1 / 2 1 / 2 1//21 / 2, grade 3 / 4 3 / 4 3//43 / 4, grade 5) were performed. Initially, we performed the analysis by excluding studies from the same research group to eliminate potential overlap. If multiple publications reported on the same study population, the one with the higher number of patients was included. We considered studies to be from the same research group when they were explicitly declared as such or when we identified recurring authors across different papers.
首先，我们进行了描述性分析，以评估报告每种 AE 的研究数量，并评估纳入人群的特征。对于这些研究中报告的每个 AE，我们通过计算最小值、最大值、中位数和四分位数范围（原始数据）来评估百分比分布。进行了涵盖所有级别的 AE 和每个严重程度等级（等级 1 / 2 1 / 2 1//21 / 2 、等级 3 / 4 3 / 4 3//43 / 4 、5 级）的不同分析。最初，我们通过排除来自同一研究组的研究来进行分析，以消除潜在的重叠。如果多篇出版物报告了同一研究人群，则包括患者人数较多的出版物。当研究被明确声明为研究时，或者当我们在不同论文中确定经常出现的作者时，我们认为这些研究来自同一研究组。
In a second step, we conducted a meta-analysis using the meta-packages and metaprop functions of R statistical software version 4.1.1. The proportion of patients experiencing each A E A E AEA E and the corresponding number of patients were extracted from each study along with the total number of patients included in each study. To account for between-study heterogeneity, an inverse variance random-effects model was employed, assuming a common between-study variance. The DerSimonian-Laird estimator was used to estimate the between-study variance ( τ ∼ 2 τ ∼ 2 tau∼2\tau \sim 2 ), which quantifies the amount of heterogeneity among the included studies. Forest plots were generated to visualize the individual study estimates along with the overall pooled estimate, with confidence intervals representing the uncertainty around the pooled estimate.
在第二步中，我们使用 R 统计软件 4.1.1 版的元包和 metaprop 函数进行了荟萃分析。从每项研究中提取经历每种 A E A E AEA E 情况的患者比例和相应的患者数量，以及每项研究中包含的患者总数。为了解释研究之间的异质性，采用了逆方差随机效应模型，假设研究间方差是共同的。DerSimonian-Laird 估计器用于估计研究间方差（ τ ∼ 2 τ ∼ 2 tau∼2\tau \sim 2 ），量化纳入研究之间的异质性。生成森林图以可视化各个研究估计值以及总体汇总估计值，置信区间代表汇总估计值周围的不确定性。
Next, we studied the occurrence of AEs adjusted to the length of exposure to atezolizumab-bevacizumab. For studies where the median treatment duration with atezolizumabbevacizumab was available, the outcome of interest was reported as exposure-adjusted incidence rate. Incidence rates per 100 patient-years were calculated by dividing the total
接下来，我们研究了根据暴露于 atezolizumab-贝伐珠单抗的时间长度调整的 AE 的发生情况。对于有 atezolizumabbevacizumab 治疗中位持续时间的研究，感兴趣的结局报告为暴露调整后的发生率。每 100 个患者年的发病率是通过除以总数来计算的
    • Corresponding author. Address: AP-HP, Avicenne Hospital, Hepatology Unit, Cordeliers Research Center, 125 rue de Stalingrad 93000 Bobigny, France.
      通讯作者。地址：AP-HP，阿维森医院，肝病科，科德利埃研究中心，125 rue de Stalingrad 93000 Bobigny，法国。
    E-mail address: naultjc@gmail.com (J.-C. Nault).
    电子邮件地址：naultjc@gmail.com （J.-C.诺特）。
    † † ^(†){ }^{\dagger} Co first authorship
    † † ^(†){ }^{\dagger} 共同第一作者
    https://doi.org/10.1016/j.jhepr.2024.101190