胺碘酮增加男性癌症风险

根据4月8日在线发表于《癌症》(Cancer)杂志的一项以台湾人群为基础的队列研究结果，抗心律失常药物胺碘酮与癌症风险增加相关，但这种效应仅在男性或较高剂量时有意义。

胺碘酮于1985年通过食品与药品管理局的审批，是一种脂溶性药物，清除半衰期较长，因此在长期治疗之后有大量药物蓄积于软组织中。并且上市后监测数据提示，该药可能增加肺部肿物、甲状腺癌和皮肤癌风险。

这项研究中评估了6,418例接受胺碘酮治疗的患者数据，其中43%为女性，研究中使用的信息来自台湾国立健康保险研究数据库。

结果显示，在中位数为2.6年的随访期间，共有280例患者发生癌症，癌症的类型或部位无显著差异。台湾台北市荣民总医院的Vincent Yi-Fong Su医生及其同事写道：“我们发现，接受胺碘酮治疗的患者较整体人群的癌症风险增高达到了临界统计学意义。”男性或在第1年内应用剂量累计超过180个定义每日剂量的患者“发生癌症的风险显著增高，兼具上述两个因素的患者SIR(标准发生率比)进一步增高，达到1.46(P=0.008)。”尽管所有接受胺碘酮治疗的患者总体癌症风险略有增高(SIR，1.12；95%CI，0.99~1.26；P=0.067)，男性风险增高具有统计学意义(SIR，1.18；95%CI，1.02~1.36；P=0.022)，但女性的风险增高无统计学意义(SIR，0.99；95%CI，0.79~1.23)。

“一个可能的解释为，胺碘酮在女性中的清除率较男性高37%，这是因为男性和女性细胞色素P450 3A4活性和身体脂肪含量不同。”研究中还发现，胺碘酮与癌症风险之间有剂量依赖性关系。经校正年龄、性变和合并疾患之后，发现在累计定义每日剂量为中和高三分位数的患者中，经校正危险比分别为1.70(95%CI，1.02~2.84；P=0.042)和1.98(95%CI，1.22~3.22；P=0.006)。研究者注意到，在胺碘酮治疗后第1年内的癌症发生率增加(SIR，1.32；95%CI，1.05~1.64；P=0.002)，但认为这可能是由监测偏差所致(Cancer 2013 April 8 2013 [doi.wiley.com/10.1002/cncr.27881])。“为了提供对心律失常病因学的初始全面评估并在随访研究中监测胺碘酮的毒性，对于接受胺碘酮治疗的患者进行了更多的医学评估，因此，早期检出导致第1年内癌症发生率呈现增高假象。”

研究者认为，胺碘酮可能增加男性和累计应用较高剂量患者发生癌症的风险，建议在未来的胺碘酮试验中进行更密切的癌症监测。

该研究部分由台湾台北市荣民总医院资助。作者披露无相关利益冲突。

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By: BIANCA NOGRADY, Cardiology News Digital Network

The antiarrhythmic drug amiodarone is associated with an increased risk of cancer, but the effect is significant only in men or at higher doses, according to a Taiwanese population-based cohort study published online April 8 in Cancer.

"We found that there was a borderline significantly increased risk of cancer among patients who received amiodarone compared with the general population," wrote Dr. Vincent Yi-Fong Su of the Taipei (Taiwan) Veterans General Hospital and his colleagues. Patients either of male sex or with more than 180 cumulative defined daily doses within the first year "had a significantly higher risk of developing cancer, and those with both factors had an even greater SIR [standardized incidence ratio] of 1.46 (P = .008)."

While all patients receiving amiodarone had a slight increase in their overall risk of cancer (SIR, 1.12; 95% CI, 0.99-1.26; P = .067), the risk was significantly higher in men (SIR, 1.18; 95% CI, 1.02-1.36; P = .022) but not in women (SIR, 0.99; 95% CI, 0.79-1.23).

"One possible explanation for this difference is that there is a 37% higher clearance rate of amiodarone in females than in males because of differences in cytochrome P450 3A4 activity and the percentage of body fat," the authors reported.

The study also found a dose-dependent relationship between amiodarone and cancer risk. Among patients in the middle and top tertile of cumulative defined daily dose, the adjusted hazard ratios were 1.70 (95% CI, 1.02-2.84; P = .042) and 1.98 (95% CI, 1.22-3.22; P = .006) respectively, after adjustment for age, sex, and comorbidities.

The researchers examined data from 6,418 patients treated with amiodarone, 43% of whom were female, using information from the Taiwan National Health Insurance Research Database.

During the median 2.6-year follow-up, 280 patients developed cancer, with no significant differences found in the type or location of cancer. Amiodarone, approved by the Food and Drug Administration in 1985, is a fat-soluble drug with a long elimination half-life, so large amounts of the drug can build up in the soft tissues after prolonged treatment, and postmarketing surveillance had suggested an increased risk of lung masses, thyroid cancer, and skin cancer.

The researchers noted an increase in the incidence of cancer in the first year after amiodarone therapy (SIR, 1.32; 95% CI, 1.05-1.64; P = .002), although they suggested this may be due to surveillance bias (Cancer 2013 April 8 2013 [doi.wiley.com/10.1002/cncr.27881].

"To provide an initial, thorough evaluation of the etiology of arrhythmias and to monitor the toxicity of amiodarone in follow-up studies, an increased number of medical examinations are performed in patients treated with amiodarone," the authors wrote. "Thus, the cancer incidence within the first year falsely increases due to early detection."

While the study excluded patients with preexisting malignancies, researchers were not able to account for other risk factors, such as obesity, smoking and alcohol use, environmental exposure, and family history of cancer.

The authors concluded that while extensive screening for occult cancers in patients taking amiodarone was not practical, they advocated closer surveillance of cancer events in future amiodarone trials.

The study was partly supported by the Taipei (Taiwan) Veterans General Hospital. The authors reported no relevant financial conflicts.