二甲双胍可能阻断前列腺癌进展

加拿大一项对3,837例男性糖尿病患者的回顾性研究显示，二甲双胍似乎可延缓、甚至阻断前列腺癌的进展。该研究发表于《临床肿瘤学杂志》(J. Clin. Oncol. 2013 Aug 5 [doi: 10.1200/JCO.2012.46.7043])。

这并不是首项提示这种广泛应用的降糖药物可能具有很强抗癌作用的研究。已有数十项研究观察了二甲双胍对前列腺肿瘤、乳腺癌、脑癌、子宫癌、结直肠癌、胰腺癌、皮肤癌、血液科恶性疾病和甲状腺癌的作用。

该研究的数据来自安大略省保管的医疗保健数据库，包括安大略肿瘤注册和安大略糖尿病数据库。这些男性患者诊断前列腺癌时的中位年龄为75岁，中位随访4.64年。约有1/4（976例）表现为高级别肿瘤，接近60%（2,167例）为大体积肿瘤。35%（1,343例）的患者于研究期间死亡；7.6%（291例）的死亡原因为前列腺癌。“总之，分别有1,251例 (32.6%)和1,619 例(42.2%)患者在诊断前列腺癌之前和之后暴露于二甲双胍。诊断前的中位暴露时间为19个月，诊断后的中位暴露时间为8.9个月，”主要研究者David Margel医生及其团队指出。

结果显示，接受二甲双胍治疗的时间越长，对前列腺癌进展的阻止作用越强；在诊断后每多治疗6个月，前列腺癌死亡率降低24%［校正危险比（aHR）为0.76］。在最初的6个月内，全因死亡率降低了24%(aHR, 0.76)，但相关性随时间进展而减弱；在诊断后24~30个月，二甲双胍与全因死亡率降低7% (aHR, 0.93)相关。尽管一些男性患者使用其他降糖药物，如磺脲类、噻唑烷二酮类等，有时也会使用胰岛素，但仅二甲双胍可改善前列腺癌预后，并且与合并抗肿瘤治疗无关。

“我们无法推断，在非糖尿病人群中也将看到相似的获益，但结果提示，二甲双胍作为一种辅助治疗，可能提高生存率，即使是在已接受合理抗肿瘤治疗的患者中。”二甲双胍可能无法阻止良性细胞向恶性细胞的转变，但可能“通过降低胰岛素水平或直接影响癌细胞增生和凋亡，间接影响癌细胞。研究者认为，应该进行一项使用二甲双胍延缓前列腺癌进展的干预性研究。

Margel医生在研究期间担任多伦多大学的泌尿肿瘤科研究员，目前为以色列Petah-Tikva Rabin医学中心的泌尿科医生。

该项目由安大略省卫生和长期治疗部资助。作者披露无相关利益冲突。

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By: M. ALEXANDER OTTO, Internal Medicine News Digital Network

Metformin appears to have slowed, or perhaps even halted, the progression of prostate cancer in a retrospective, Canadian study of 3,837 diabetic men.

The study was published in the Journal of Clinical Oncology.

The longer the men were on the drug, the better they did; for each additional 6 months of treatment following diagnosis, prostate cancer mortality dropped 24% (adjusted hazard ratio 0.76). There was a 24% reduction in all-cause mortality in the first 6 months, as well (aHR, 0.76), but the association faded with time; 24-30 months out from diagnosis, metformin was associated with an all-cause mortality reduction of 7% (aHR, 0.93).

Although some of the men used other diabetes drugs such as sulfonylureas, thiazolidinediones, and insulin some of the time, only metformin improved prostate cancer outcomes, regardless of concomitant cancer treatments.

"We cannot conclude" that a nondiabetic population would see similar benefits, but the results "suggest that metformin may ... improve survival as an adjunct therapy, even among those already receiving optimal cancer treatments. We believe an interventional study of the use of metformin to delay progression in prostate cancer is warranted," wrote Dr. David Margel, a uro-oncology fellow at the University of Toronto when the study was conducted, and now a urologist at the Rabin Medical Center in Petah-Tikva, Israel (J. Clin. Oncol. 2013 Aug 5 [doi: 10.1200/JCO.2012.46.7043]).

Dr. Margel and his team are not the first to suggest that the ubiquitous diabetes drug might also be a potent cancer fighter. Metformin is being tested in dozens of trials not only for prostate tumors, but also for breast, brain, lung, uterine, colorectal, pancreatic, skin, blood, and thyroid cancers.

It probably doesn’t stop benign cells from turning cancerous, but may "influence cancer cells indirectly by decreasing insulin levels or directly by influencing cancer cell proliferation and apoptosis," the investigators wrote.

Study data came from health care databases kept by the province of Ontario, including the Ontario Cancer Registry and Ontario Diabetes Database.

The men were a median of 75 years old at diagnosis, and followed for a median of 4.64 years. About a quarter (976) presented with high-grade tumors, and almost 60% (2,167) with high-volume tumors. Thirty-five percent (1,343) died during the study period; prostate cancer was responsible for 7.6% (291) of the deaths.

"Overall, 1,251 (32.6%) and 1,619 (42.2%) were exposed to metformin before and after [prostate cancer] diagnosis, respectively. Patients were exposed to metformin for a median of 19 months before diagnosis and 8.9 months after diagnosis," Dr. Margel and his team noted.

The Ontario Ministry of Health and Long-Term Care funded the project. The authors have no conflicts of interest.

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It’s time for a clinical trial

The authors provide a convincing case for a causal interpretation ... [and] a compelling rationale for conducting a large-scale long-term randomized trial of metformin in men with clinically localized disease. The potential benefits of metformin could exceed those of existing drug therapies, particularly given its safety profile. Based on the strong evidence of this well-executed study, metformin ... may potentially be a safe and effective secondary prevention strategy for prostate cancer (J. Clin. Oncol. 2013 Aug 5 [doi: 10.1200/JCO.2013.50.7715]).

Interestingly, although postdiagnostic use of metformin was highly significant, the association of cumulative metformin use before prostate cancer diagnosis with prostate cancer death was null. As prostate cancer date of diagnosis is a rather arbitrary point in the progression of the disease, this discrepancy between the impact of pre- and postdiagnostic use is perplexing and warrants further study.

Kathryn Penney, Sc.D., is a medical epidemiologist at Brigham and Women’s Hospital in Boston. Dr. Meir Stampfer is professor of nutrition and epidemiology at Harvard Medical School, Boston. They reported no relevant conflicts of interest.