TNF抑制剂相关的肿瘤风险：阿达木单抗、依那西普和英夫利昔单抗随机对照试验的荟萃分析

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Pharmacoepidemiol Drug Saf. 2011 Feb;20(2):119-30. doi: 10.1002/pds.2046. Epub 2010 Dec 7. Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Askling J, Fahrbach K, Nordstrom B, Ross S, Schmid CH, Symmons D. Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. johan.askling@ki.se. Abstract PURPOSE: Uncertain short- and long-term cancer risks with anti-TNF therapies is a concern, and led to a recent black box warning. This meta-analysis, requested by the European Medicines Agency, aimed at better assessing short-term risks by using meta-analytic techniques based on individual patient data from all corporate-sponsored randomized controlled trials (RCTs) of adalimumab, etanercept, and infliximab. METHODS: All 74 RCTs of TNF inhibitors of at least 4 weeks duration were provided to independent investigators, including case narratives for events occurring between trial start until 30 days after planned end of treatment and indicating a possible cancer. Relative risks were estimated using Bayesian piecewise exponential models. RESULTS: One hundred thirty (0.84%) of 15 418 individuals randomized to anti-TNF therapy were diagnosed with cancer, compared to 48 (0.64%) of 7486 individuals randomized to comparators. The relative risks associated with all anti-TNF were 0.99 (95%CI 0.61-1.68) for cancers excluding non-melanoma skin cancer (NMSC), and 2.02 (95%CI 1.11-3.95) for NMSC. There were indications of differences in the relative risks for the three anti-TNF drugs, but also of differences across the cancer rates in the three comparator arms for adalimumab, etanercept, and infliximab. CONCLUSIONS: Despite a reassuring overall short-term risk, we could neither refute nor verify that individual anti-TNF therapies affect the short-term clinical emergence of cancer. Despite representing the best available evidence, statistical precision, and differences in baseline cancer risk and reporting detail between trials of adilumumab, etanercept, and infliximab hampered distinction of drug-specific from trial effects, illustrating the challenges in safety-assessments using RCT meta-analyses. Long-term risk assessment requires observational studies.

TNF抑制剂相关的肿瘤风险：阿达木单抗、依那西普和英夫利昔单抗随机对照试验的荟萃分析 Askling J,et al.Pharmacoepidemiol Drug Saf. 2011 Feb;20(2):119-30.   目的：TNF抑制剂相关的短期和长期肿瘤风险的不确定性受到关注，最近加以黑框警示。应欧洲药品管理局要求，本项荟萃分析旨在通过荟萃分析方法、采集所有公司资助的阿达木单抗、依那西普和英夫利昔单抗随机对照研究（RCTs）的患者数据，更好地评估短期风险。   方法：所有为期4周以上的74项TNF抑制剂RCTs提交给独立观察者，包括发生于试验开始至治疗结束后30天、提示可能有肿瘤的事件陈述。采用Bayesian分段指数模型评估相对风险。   结果：在15418例随机使用TNF抑制剂的患者中，130例（0.84%）诊断为肿瘤；在7486例随机分入对照组的患者中，48例（0.64%）为肿瘤。除外非黑色素瘤皮肤肿瘤（NMSC），与TNF抑制剂相关的肿瘤相对风险为0.99 (95%CI 0.61-1.68)，NMSC的相对风险为2.02 (95%CI 1.11-3.95)。3种TNF抑制剂的肿瘤相对风险有所差别，但其对照组亦有差别。   结论：虽然总体短期风险不大，但我们既不能反驳、也不能证实各TNF抑制剂对短期发生肿瘤的影响。尽管这是目前已有的最佳证据，但这三种TNF抑制剂试验的统计精度、基线期肿瘤风险差异和报告详情阻碍了药物特异性风险的区分，这是对采用RCT荟萃分析评估安全性的挑战。长期风险评估需要观察性研究。