For RA treatment by biologic agents, TNF inhibitors with cancer risk???

By: MARY ANN MOON,  Oncology Report Digital Network The use of biologic agents to treat rheumatoid arthritis doesn't appear to be associated with an increased risk of malignancy, compared with either placebo or with other disease-modifying drugs, according to a report in the Sept. 5 issue of JAMA. In a meta-analysis of 63 randomized clinical trials of at least 24 weeks' duration involving 29,423 adults with RA, there was no increase in the risk of cancer in general or in the risk of specific cancers. "Additional systematic reviews of observational studies are needed to establish risk in the longer term," said Dr. Maria A. Lopez-Olivo of the University of Texas M.D. Anderson Cancer Center, Houston, and her associates. They described their study as the first systematic review and meta-analysis to assess the risk of any type of malignancy solely in RA patients who were taking any of the nine biologic agents approved for such use: abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, or tocilizumab. There has been concern that these agents could raise cancer risk because they interfere with the immune system. Some data have implicated tumor necrosis factor (TNF) inhibitors in particular, prompting the Food and Drug Administration to recommend adding a warning label citing an excess of cases of spontaneous lymphoma among children and adolescents taking TNF inhibitors. "While trials in RA are relatively short and cannot evaluate the risk over longer-term exposure as observational studies do, we thought there was a need to conduct an updated meta-analysis of RCTs [randomized controlled trials] because of the older reports of the possible increase in malignancies and the more recent FDA advisory for TNF inhibitors, mostly based on studies in children," the researchers noted. In the RCTs included in this meta-analysis, sample sizes ranged from 20 to 1,399 subjects. Most study subjects (79%) were white, and 76% were women. The mean duration of RA ranged from less than 1 year to 13 years. Pharmaceutical companies sponsored 56 of the 63 trials, and another 3 did not disclose their funding sources. The remaining four trials were funded by national organizations, but the agents they used were provided free of charge by manufacturers. "There is evidence that industry-sponsored trials may overestimate the treatment effect and could possibly also overestimate safety," acacording to Dr. Lopez-Olivo and her associates. A total of 15,989 study subjects were assigned to take biologic agents plus methotrexate and/or other disease-modifying antirheumatic drugs, while 3,615 were assigned to take the biologic agents alone and 9,819 served as control subjects who were given placebos. A total of 211 malignancies developed during the trials, in 0.77% of the combination-therapy group, 0.64% of the monotherapy group, and 0.66% of the control group. These differences were not significant, the investigators said (JAMA 2012;308:898-908). Skin cancers accounted for 48 of the malignancies (which included 4 melanomas), 14 were lymphomas, 26 were not specified, and 5 were hematologic nonlymphomas. The remaining 118 malignancies were solid tumors affecting a wide variety of organs including the adrenal glands, bladder, breast, GI system, liver, lung, ovary, pancreas, prostate, kidney, testes, thyroid, tongue, and uterus. Thus there was no pattern involving a specific type of cancer. Similarly, there was no pattern involving any of the individual biologic agents, Dr. Lopez-Olivo and her associates said. "The only increased risk of malignancy we observed was in patients with RA treated with TNF inhibitors plus methotrexate at 52 weeks, for all cancers combined." However, this effect was not consistent across the three separate analytical methods the researchers used, did not occur in patients taking TNF inhibitors as monotherapy, and did not occur at any of the other three time points assessed. The study findings "suggest that biologic, disease-modifying agents may be generally safe with respect to risk of malignancy in the short term," but their safety in RA patients who have concomitant cancer or risk factors for cancer remains unknown, the researchers said. No sponsors were involved with this study, and no financial conflicts of interest were reported.

抗风湿生物制剂似乎不增加恶性肿瘤风险 发布时间：2012-9-6 来源：药品资讯网信息中心《美国医学会杂志》(JAMA)9月5日发表的一项Meta分析显示，与安慰剂或其他缓解疾病抗风湿药(DMAD)相比，使用生物制剂治疗类风湿性关节炎(RA)并不会增加患者发生恶性肿瘤的风险(JAMA 2012;308:898-908)。 这项Meta分析由德克萨斯大学M.D. Anderson癌症中心的Maria A. Lopez-Olivo博士及其同事进行，共纳入63项为期至少24周的随机临床试验，涉及29,423例RA成人患者，目的是评价使用以下9种生物制剂是否会增加发生恶性肿瘤的风险：阿巴西普、阿达木单抗、阿那白滞素、塞妥珠单抗、依那西普、戈利木单抗、英夫利昔单抗、利妥昔单抗和托珠单抗。 在该Meta分析纳入的随机临床试验中，样本量从20例至1,399例不等。大部分(79%)受试者为白人，76%为女性。RA平均病程为1年以下至13年。63项试验中的56项由药企资助，3项未披露资金来源，其余4项由国家机构资助，但所用的药物均由药企免费提供。证据显示，药企资助的试验可能会高估疗效及安全性。共有15,989例受试者接受生物制剂+甲氨蝶呤和(或)其他DMAD联合治疗，3,615例受试者接受生物制剂单药治疗，9,819例使用安慰剂的受试者作为对照。 在这些试验期间，共观察到211例恶性肿瘤，联合治疗组、单药治疗组和对照组的恶性肿瘤发生率分别为0.77%、0.64%和0.66%，差异不显著。48例恶性肿瘤为皮肤癌(包括4例黑色素瘤)，14例为淋巴瘤，26例未指明，5例为非淋巴瘤血液性肿瘤。其余118例恶性肿瘤为累及以下器官的实体瘤：肾上腺、膀胱、乳腺、胃肠道系统、肝、肺、卵巢、胰腺、前列腺、肾、睾丸、甲状腺、舌和子宫。可见并无涉及某种特定类型癌症的模式。 同样，也无涉及某种特定生物制剂的模式。恶性肿瘤风险增加的情况仅见于52周时接受TNF抑制剂+甲氨蝶呤治疗的RA患者。这种效应在研究者进行的3项独立分析中并无一致性，并且未见于接受TNF抑制剂单药治疗的患者，也未见于另外3个时间点。 该Meta分析结果表明，从短期恶性肿瘤风险来看，生物制剂的安全性一般较好，但这些药物在合并癌症或癌症危险因素的RA患者中的安全性尚不清楚。未来尚需对观察性研究做进一步系统评价，以明确这些药物的远期风险。 该Meta分析未获药企资助，并且研究者声明无经济利益冲突。