推荐剂量下抗 TNF-α 治疗成人类风湿关节炎的癌症风险：一项意向治疗和方案分析的荟萃分析。

BACKGROUND

The risk of malignancies on TNF-α antagonists is controversial. The aim of this survey was to assess cancer risk on TNF-α antagonists in adult rheumatoid arthritis patients, including the five marketed drugs (infliximab, etanercept, adalimumab, golimumab and certolizumab) used in line with the New Drug Application. Furthermore, the relative interest of modified intention to treat or per protocol analyses to assess such sparse events remains unknown.

METHODOLOGY/PRINCIPAL FINDINGS: Data sources were MEDLINE, CENTRAL, ISI Web of Science, ACR and EULAR meeting abstracts, scientific evaluation of the drugs leading to their marketing approval, and clinicaltrials.gov, until 31 December 2012.We selected double-blind randomized controlled trials in adult rheumatoid arthritis patients, including at least one treatment arm in line with New Drug Application. We performed random effect meta-analysis, with modified intention to treat and per protocol analyses. Thirty-three trials were included. There was no excess risk of malignancies on anti-TNF-α administered in line with New Drug Application in the per protocol model (OR, 0.93 95%CI[0.59-1.44]), as well as in the modified intention to treat model (OR, 1.27 95%CI[0.82-1.98]). There was a non-significant tendency for an excess non-melanoma skin cancer risk in both models (respectively, 1.37 [0.71-2.66] and 1.90 [0.98-3.67]). With fixed effect Peto model restricting to trials during at least 52 weeks, the overall cancer risk was respectively 1.60 [0.97-2.64] and 1.22 [0.72-2.08]. Whatever the model, modified intention to treat analysis led to higher estimations than per protocol analysis. The later may underestimate the treatment effect when assessing very sparse events and when many patients dropped out in placebo arms. In metaregression, there was no differential risk among the five drugs.

CONCLUSIONS/SIGNIFICANCE: This study did not find any evidence for an excess cancer risk on TNF-α antagonists in adult rheumatoid arthritis patients, but an excess cancer risk after several years of exposure cannot be ruled out. Both modified intention to treat and per protocol analyses should be presented in such safety analyses.

背景

TNF-α 拮抗剂的恶性肿瘤风险存在争议。本研究旨在评估 TNF-α 拮抗剂在成年类风湿关节炎患者中的癌症风险，包括新适应证中使用的五种已上市药物（英夫利昔单抗、依那西普、阿达木单抗、戈利木单抗和培塞利珠单抗）。此外，评估此类罕见事件时，意向治疗或方案分析的相对优势仍不清楚。

方法/主要发现：数据来源包括 MEDLINE、CENTRAL、ISI Web of Science、ACR 和 EULAR 会议摘要、导致药物上市的药物科学评价以及 clinicaltrials.gov，截至 2012 年 12 月 31 日。我们选择了成年类风湿关节炎患者的双盲随机对照试验，包括至少一个符合新适应证的治疗组。我们进行了随机效应荟萃分析，包括意向治疗和方案分析。共纳入 33 项试验。在方案模型（OR，0.93；95%CI[0.59-1.44]）和意向治疗模型（OR，1.27；95%CI[0.82-1.98]）中，符合新适应证的抗 TNF-α 治疗并未增加恶性肿瘤风险。在两种模型中，非黑色素瘤皮肤癌风险均有增加的趋势（分别为 1.37；95%CI[0.71-2.66]和 1.90；95%CI[0.98-3.67]）。采用固定效应 Peto 模型限制在至少 52 周的试验中，总体癌症风险分别为 1.60；95%CI[0.97-2.64]和 1.22；95%CI[0.72-2.08]。无论采用哪种模型，意向治疗分析的估计值均高于方案分析。当评估非常罕见的事件且许多患者在安慰剂组中脱落时，方案分析可能低估了治疗效果。在元回归中，五种药物的风险无差异。

结论/意义：本研究未发现 TNF-α 拮抗剂在成年类风湿关节炎患者中存在癌症风险增加的证据，但不能排除数年暴露后的癌症风险增加。此类安全性分析应同时呈现意向治疗和方案分析。