他汀类药物或可降低前列腺癌死亡率

一项英国大型男性队列研究显示，在前列腺癌诊断后使用他汀类药物与全因死亡率和前列腺癌相关死亡率降低相关。在诊断前也使用他汀类药物的患者中观察到的风险降幅最大(J. Clin Oncol. 2014; 32:5-11)。

这项研究由蒙特利尔犹太总医院的Oriana Yu医生及其同事进行，入组的是从一个大型人群电子数据库中回顾找到的11,722例男性(平均年龄71.3岁)。所有男性在1998年4月1日至2009年12月31日间首次被诊断非转移性前列腺癌。在平均随访4.4年间，3,499例男性死亡，其中1,791例死于前列腺癌。

结果显示，前列腺癌诊断后使用他汀类药物的患者的前列腺癌死亡风险降低24%[风险比(HR) 0.76]，全因死亡风险降低14%(HR 0.86)。诊断后使用他汀类药物还与远处转移风险降低相关(HR 0.77)。

在诊断前也使用他汀类药物的患者中，前列腺癌相关死亡和全因死亡的相应HR分别为0.55和0.66，而在只有诊断后才使用他汀类药物的患者中，前列腺癌相关死亡和全因死亡的相应HR分别为0.82和0.91。

在累计疗程和剂量方面观察到量效关系，疗程越长和累计剂量越高，HR就越显示出保护性。例如，使用他汀类药物少于1年的患者和使用他汀类药物≥3年的患者的校正后HR分别为0.99和0.61。累计剂量＜365 mg的患者和累计剂量≥1,096 mg的患者的校正后HR分别为0.84和0.57。

越来越多的证据表明，他汀类药物具有抗肿瘤作用。观察性研究已探讨了他汀类药物使用与前列腺癌转归之间的关联，但研究结果不一致，并且没有一项研究专门探讨诊断前使用他汀类药物是否会影响所观察到的诊断后使用他汀类药物与转归之间的关联。当前研究观察到的前列腺癌诊断前使用他汀类药物对这一关联的影响可通过以下因素解释。

•诊断前使用他汀类药物的患者的肿瘤特征可能较好，因此前列腺癌转归较好。然而，该研究发现，与未使用他汀类药物的患者相比，诊断前使用他汀类药物的患者更可能具有较高的Gleason评分。
•在诊断前使用他汀类药物的患者中，他汀类药物使用时间最长，这与该研究中的情况一样。
•前列腺癌诊断前使用他汀类药物的男性可能不同于诊断后使用他汀类药物的男性。具体而言，后一组可能是因为某种治疗，如雄激素剥夺治疗，而需要使用他汀类药物。已知雄激素剥夺治疗可增加脂质水平，并且通常应用于晚期前列腺癌患者，这些都会导致他汀类药物的作用变得更加弱。

该研究获加拿大卫生研究所支持。Yu医生声明无经济利益冲突。一位研究者声明是阿斯利康等公司的顾问。

随刊述评：研究结果可能促使他汀类药物使用增加

哈佛公共卫生学院的Lorelei A. Mucci医生和Meir J. Stampfer医生表示，该研究得出的最新重要结果证明他汀类药物使用与前列腺癌相关死亡风险降低相关。虽然一项2012年的荟萃分析和之后的5项流行病学研究均观察到这种关联，但Yu医生的研究明确表明有必要确定化学预防药物发挥作用的具体时间窗。关注药物治疗的时间窗可能有助于消除流行病学研究之间的明显差异，并且对于指导随机研究的设计至关重要。目前要进行随机一级预防研究的话，既不可能也不可行，因为需要在诊断前检验他汀类药物的使用，而且此类研究的样本量必须够大且持续时间必须够长。另一方面，对进行前列腺切除术的男性进行术前新辅助治疗研究可能有助于阐明他汀类药物在局部肿瘤环境中的分子机制。此外，对行政医学数据库中的长期转归数据进行分析也可能有用。当前研究结果可能足以促使一些临床医生对处于心血管疾病预防临界点的男性患者使用他汀类药物。Mucci医生和Stampfer医生均声明无经济利益冲突(J. Clin. Oncol. 2014;32: 1-2)。

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By: SHARON WORCESTER, Cardiology News Digital Network

The use of statins following a prostate cancer diagnosis was associated with a decrease in all-cause and prostate cancer–related mortality risks in a large cohort of men from the United Kingdom.

The risk reduction was greatest among those who also used statins prior to their diagnosis, said Dr. Oriana Yu, of Jewish General Hospital, Montreal, and her colleagues.

The findings support experimental evidence suggesting a possible antitumor effect of statins on prostate carcinogenesis. Additional observational studies are needed to confirm the findings before a randomized controlled trial is launched to assess the effects of statins in the adjuvant setting, they said.

The study subjects were 11,722 men (mean age, 71.3 years) who were retrospectively identified from a large population-based electronic database. All were newly diagnosed as having nonmetastatic prostate cancer between April 1, 1998, and Dec. 31, 2009. During a mean follow-up of 4.4 years, 3,499 died, including 1,791 who died from prostate cancer.

Those who used statins after their prostate cancer diagnosis had a 24% decrease in the risk of prostate cancer mortality (hazard ratio, 0.76), and a 14% decrease in the risk of all-cause mortality (HR, 0.86). Statin use post diagnosis also was associated with a decreased risk of distant metastasis (HR, 0.77).

Among those who also used statins prior to their diagnosis, the corresponding hazard ratios for prostate cancer–related and all-cause mortalities were 0.55 and 0.66, compared with 0.82 and 0.91, respectively, for those who only used statins after diagnosis, the researchers reported (J. Clin Oncol. 2014; 32:5-11).

"A dose-response relationship was observed in terms of cumulative duration of use and dose, with the HRs becoming progressively more protective with longer durations of use and higher cumulative doses," they wrote.

For example, the adjusted hazard ratios for those using statins for less than 1 year and for those using statins for 3 or more years were 0.99 and 0.61, respectively. The adjusted hazard ratios for cumulative doses of less than 365 mg and 1,096 mg or more were 0.84 and 0.57, respectively.

Accumulating evidence suggests that statins have antitumor effects. Observational studies have looked at the association between statin use and prostate cancer outcomes, but the findings have been inconsistent, and none have specifically assessed whether prediagnosis use of statins modified the association seen between postdiagnosis use and outcomes, the investigators said.

The findings of an effect modification by prediagnostic use of statins in this study could be explained by several factors.

• Tumor characteristics may be more favorable in those using statins before diagnosis, resulting in improved prostate cancer outcomes, the investigators said. In the current study, however, those using statins before diagnosis were slightly more likely to have higher Gleason scores compared with nonusers.

• Duration of statin use is longest among those who used statins before their diagnosis, as in this study.

• Men who start statins before their prostate cancer diagnosis may differ from those who start after diagnosis. "Specifically, it is possible that the latter group required statins as a consequence of certain treatment, such as androgen deprivation therapy, which is known to increase lipid levels," and typically is prescribed to those with advanced prostate cancer, which would make statins seem to have more modest effects.

This study was supported by the Canadian Institutes of Health Research. Dr. Yu reported having no disclosures. One of her coauthors, Samy Suissa, Ph.D., reported serving as a consultant or adviser for AstraZeneca, Boehringer Ingelheim, and other companies.

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Findings may prompt more statin use

The findings by Dr. Yu and her colleagues add important new information supporting a link between statin use and a lower risk of prostate cancer–related mortality.

While similar associations were seen in a 2012 meta-analysis and in five subsequent epidemiologic studies, the current findings nicely illustrate the need to identify the specific window of timing for the effects of a chemopreventive agent. Attention to timing of an exposure may help resolve apparent discrepancies across epidemiologic studies and is essential in guiding the design of randomized trials.

But where do the findings lead at this point?

A randomized primary prevention trial seems unlikely because of the need to test statin use prior to diagnosis, and because such a trial would have to be large and lengthy – and thus may not be feasible. On the other hand, a pre-prostatectomy, neoadjuvant study of men undergoing surgery could be useful for elucidating the molecular mechanisms of statins on the local tumor environment.

Administrative medical databases with linkage to long-term outcomes might also help.

Meanwhile, as we wait, the current data may be sufficient to sway some clinical decisions toward statin use for men who are on the borderline for cardiovascular disease prevention.

Lorelei A. Mucci, Ph.D., and Dr. Meir J. Stampfer are with the Harvard School of Public Health in Boston. They made their remarks in an editorial that accompanied Dr. Yu’s study (J. Clin. Oncol. 2014;32: 1-2). Both reported having no disclosures.