癌症恶病质临床试验中的生物标记终点:恶病质终点系列系统回顾 5》。

IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY
Michael S. Yule, Joshua Thompson, Khachonphat Leesahatsawat, Mariana S. Sousa, Stefan D. Anker, Jann Arends, Trude R. Balstad, Leo R. Brown, Asta Bye, Olav Dajani, Marie Fallon, Marianne J. Hjermstad, Gunnhild Jakobsen, James McDonald, Josh McGovern, Eric J. Roeland, Judith Sayers, Richard J.E. Skipworth, Inger O. Ottestad, Iain Philips, Melanie R. Simpson, Tora S. Solheim, Ola Magne Vagnildhaug, Donald McMillan, Barry J.A. Laird, Ross D. Dolan, the Cancer Cachexia Endpoints Working Group
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引用次数: 0

摘要

监管机构要求有证据表明终点与临床获益相关,然后才能用于批准药物。生物标志物通常被认为是替代终点。在癌症恶病质试验中,生物标志物的测量经常出现。本系统综述旨在评估癌症恶病质试验中生物标志物终点的频率和多样性。我们对 MEDLINE、Embase 和 Cochrane(1990-2023 年)进行了全面的电子文献检索。符合条件的试验需满足以下标准:成人(≥18 岁)、前瞻性设计、参与者超过 40 人、使用恶病质干预措施超过 14 天、使用生物标志物作为终点。生物标志物的定义是通过体液化验得出的任何客观指标,包括基于这些化验结果的评分系统。用于监测干预毒性的常规血液学和生物化学方法不在考虑之列。数据提取采用 Covidence,报告遵循 PRISMA 指南(PROSPERO:CRD42022276710)。共评估了 5975 项研究,其中 52 项试验(总参与人数 = 6522 人)将生物标记物作为终点。大多数研究(n = 29,55.7%)包括多种癌症类型。评估最多的是药物干预(27 项,占 51.9%),其次是营养干预(20 项,占 38.4%)。试验中使用了 99 种不同的生物标志物,其中 96 种是从血液中检测的。白蛋白(29 人,占 55.8%)最常用,其次是 C 反应蛋白(22 人,占 42.3%)、白细胞介素-6(16 人,占 30.8%)和肿瘤坏死因子-α(14 人,占 26.9%),后者是唯一用于指导样本量计算的生物标志物。有六项试验明确将生物标志物列为主要结果。共有 12 种生物标志物(占 99 项试验的 12.1%)在六项或六项以上试验中使用。在同时使用胰岛素样生长因子结合蛋白 3 (IGFBP-3) 和胰岛素样生长因子 1 (IGF-1) 的所有三项试验中,这两种生物标志物的水平均显著升高。这与主要结果(瘦体重)相符,并与药理机制有关。生物标志物主要用作探索性终点而非主要终点。最常用的生物标志物白蛋白因缺乏对营养干预的反应而受到限制。生物标志物要想对变化做出反应,必须与干预措施的作用机制和/或干预措施改变的潜在恶病质过程相关,如 IGFBP-3、IGF-1 和 anamorelin。要作为终点获得监管部门的批准,必须明确生物标志物与临床益处之间的关系。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Biomarker endpoints in cancer cachexia clinical trials: Systematic Review 5 of the cachexia endpoint series

Biomarker endpoints in cancer cachexia clinical trials: Systematic Review 5 of the cachexia endpoint series

Regulatory agencies require evidence that endpoints correlate with clinical benefit before they can be used to approve drugs. Biomarkers are often considered surrogate endpoints. In cancer cachexia trials, the measurement of biomarkers features frequently. The aim of this systematic review was to assess the frequency and diversity of biomarker endpoints in cancer cachexia trials. A comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990–2023) was completed. Eligible trials met the following criteria: adults (≥18 years), prospective design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a biomarker(s) as an endpoint. Biomarkers were defined as any objective measure that was assayed from a body fluid, including scoring systems based on these assays. Routine haematology and biochemistry to monitor intervention toxicity were not considered. Data extraction was performed using Covidence, and reporting followed PRISMA guidance (PROSPERO: CRD42022276710). A total of 5975 studies were assessed, of which 52 trials (total participants = 6522) included biomarkers as endpoints. Most studies (n = 29, 55.7%) included a variety of cancer types. Pharmacological interventions (n = 27, 51.9%) were most evaluated, followed by nutritional interventions (n = 20, 38.4%). Ninety-nine different biomarkers were used across the trials, and of these, 96 were assayed from blood. Albumin (n = 29, 55.8%) was assessed most often, followed by C-reactive protein (n = 22, 42.3%), interleukin-6 (n = 16, 30.8%) and tumour necrosis factor-α (n = 14, 26.9%), the latter being the only biomarker that was used to guide sample size calculations. Biomarkers were explicitly listed as a primary outcome in six trials. In total, 12 biomarkers (12.1% of 99) were used in six trials or more. Insulin-like growth factor binding protein 3 (IGFBP-3) and insulin-like growth factor 1 (IGF-1) levels both increased significantly in all three trials in which they were both used. This corresponded with a primary outcome, lean body mass, and was related to the pharmacological mechanism. Biomarkers were predominately used as exploratory rather than primary endpoints. The most commonly used biomarker, albumin, was limited by its lack of responsiveness to nutritional intervention. For a biomarker to be responsive to change, it must be related to the mechanism of action of the intervention and/or the underlying cachexia process that is modified by the intervention, as seen with IGFBP-3, IGF-1 and anamorelin. To reach regulatory approval as an endpoint, the relationship between the biomarker and clinical benefit must be clarified.

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来源期刊
Journal of Cachexia Sarcopenia and Muscle
Journal of Cachexia Sarcopenia and Muscle MEDICINE, GENERAL & INTERNAL-
CiteScore
13.30
自引率
12.40%
发文量
234
审稿时长
16 weeks
期刊介绍: The Journal of Cachexia, Sarcopenia and Muscle is a peer-reviewed international journal dedicated to publishing materials related to cachexia and sarcopenia, as well as body composition and its physiological and pathophysiological changes across the lifespan and in response to various illnesses from all fields of life sciences. The journal aims to provide a reliable resource for professionals interested in related research or involved in the clinical care of affected patients, such as those suffering from AIDS, cancer, chronic heart failure, chronic lung disease, liver cirrhosis, chronic kidney failure, rheumatoid arthritis, or sepsis.
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