监管机构需要证据证明终点与临床益处相关,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,生物标志物的测量特征频繁。本系统综述的目的是评估癌症恶病质试验中生物标志物终点的频率和多样性。MEDLINE的全面电子文献检索,Embase和Cochrane(1990-2023)完成。符合条件的试验符合以下标准:成人(≥18岁),前瞻性设计,超过40名参与者,使用恶病质干预超过14天,并使用生物标志物作为终点。生物标志物定义为从体液中测定的任何客观指标,包括基于这些测定的评分系统。没有考虑常规血液学和生物化学来监测干预毒性。使用Covidence进行数据提取,报告遵循PRISMA指导(PROSPERO:CRD42022276710)。共评估了5975项研究,其中52项试验(总参与者=6522)包括生物标志物作为终点。大多数研究(n=29,55.7%)包括多种癌症类型。药物干预措施(n=27,51.9%)得到了最多的评价,其次是营养干预(n=20,38.4%)。在整个试验中使用了99种不同的生物标志物,其中,96是从血液中检测的。白蛋白(n=29,55.8%)是最常见的评估,其次是C反应蛋白(n=22,42.3%),白细胞介素-6(n=16,30.8%)和肿瘤坏死因子-α(n=14,26.9%),后者是唯一用于指导样本量计算的生物标志物.在六个试验中,生物标志物被明确列为主要结果。总的来说,在6项或更多试验中使用了12种生物标志物(99种的12.1%)。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)水平在所有三个使用它们的试验中均显着增加。这与主要结果相对应,瘦体重,与药理机制有关。生物标志物主要用作探索性而非主要终点。最常用的生物标志物,白蛋白,由于缺乏对营养干预的反应而受到限制。为了让生物标志物对变化有反应,它必须与干预的作用机制和/或干预改变的潜在恶病质过程有关,如IGFBP-3,IGF-1和anamorelin所见。为了作为端点获得监管部门的批准,必须明确生物标志物与临床获益之间的关系.
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.