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More Data Back Metformin in Prostate Cancer. 24% reduced mortality. Journal of Clinical Oncology

 

    Diabetic men with prostate cancer lived significantly longer and were significantly less likely to die of prostate cancer when treated with metformin.
    Point out that the mortality benefits were unaffected by type of cancer therapy.

Diabetic men with prostate cancer lived significantly longer and were significantly less likely to die of prostate cancer when treated with metformin, data from a large retrospective cohort study showed.

Each 6 months of cumulative metformin treatment was associated with a 24% reduction in the hazard for prostate cancer mortality, reported David Margel, MD, PhD, of the University of Toronto, and colleagues.

A similar association was observed with all-cause mortality, which declined over time after the first 6 months. The mortality benefits were unaffected by type of cancer therapy, they wrote online in the Journal of Clinical Oncology.

Cumulative use of other diabetes drugs did not significantly affect all-cause or prostate cancer-specific mortality, the authors added.

”Consistent with current guidelines, metformin should be considered first-line therapy among patients with prostate cancer and diabetes, not only for diabetes control but possibly to improve cancer prognosis,” they concluded.

”These results suggest that metformin may further improve survival as an adjunct therapy, even among those already receiving optimal cancer treatments,” the authors continued. ”Metformin may be ideal for secondary prevention because it is inexpensive, safe, and well tolerated.”

The results provide a conceptual framework for interventional studies of metformin in prostate cancer, similar to those already begun in breast cancer, Margel and colleagues said. The authors of an accompanying editorial agreed.

”We agree with Margel et al that their findings clearly are insufficient to warrant recommendations to institute metformin treatment in men with prostate cancer,” wrote Kathryn L. Penney, ScD, and Meir J. Stampfer, MD, DrPH, of Brigham and Women’s Hospital and Harvard School of Public Health.

”However, their results provide a compelling rationale for conducting a large-scale long-term randomized trial of metformin in men with clinically localized disease to reduce prostate cancer-specific mortality as an urgent research priority, ” the editorialists added.

The findings add to a growing volume of evidence that metformin has anticancer properties that span a wide range of cancer types. As delineated by Margel and colleagues, the anticancer potential has a strong scientific rationale that includes:

    Direct or indirect effects on cancer cell proliferation and apoptosis

    Inhibition of the adenosine monophosphate-activated protein kinase activator

    Indirect inhibition of the mammalian target of rapamycin pathway
    A possible association with autophagic cell death

Despite the theoretical support, studies of metformin’s impact on prostate cancer risk have yielded inconsistent results, the authors continued. Because of the slow-growing nature of prostate cancer, post-intervention treatment might favorably affect disease progression and survival. Margel and colleagues hypothesized that increasing duration of metformin exposure after prostate cancer diagnosis would be associated with lower all-cause and disease-specific mortality.

They queried the Ontario Diabetes Database to identify all men 66 or older with newly diagnosed diabetes from March 1, 1997 and March 31, 2008. They cross-referenced the results with data from the Ontario Cancer Registry on men who had newly diagnosed prostate cancer after diagnosis of diabetes.

The authors pointed out that ”we used cumulative use of anti-diabetic medications as our main exposure. We believe that because metformin may work by preventing progression, simply analyzing whether a patient was exposed to metformin or not may not capture its effect. This method also allows evaluating a dose-response effect, strengthening evidence for a causality.”

Search of the registries produced a study group of 3,837 patients, who had a median age of 75 at prostate cancer diagnosis. During a median follow-up of almost 5 years, 1,343 of the men died, including 291 deaths attributed to prostate cancer. Investigators found that 976 patients had high-grade tumors at diagnosis (Gleason score ≥8) and 2,167 had high-volume tumors (>30%).

The patients’ medical records showed that 1,251 men were treated with metformin before diagnosis of prostate cancer and 1,619 afterward. Treatment with metformin lasted a median of 19 months before prostate cancer diagnosis and 8.9 months after diagnosis. Metformin use was continuous in 858 patients and periodic or sporadic in 761 cases.

By multivariable analysis, each 6 months of metformin therapy was associated with a 24% reduction in prostate cancer-specific mortality (hazard ratio 0.76, 95% CI 0.64-0.89) compared with men who did not receive metformin. Metformin users had a 24% lower all-cause mortality during the first 6 months of treatment with the diabetes drug (95% CI 0.70-0.82), decreasing to 7% with 24 to 30 months of metformin treatment (95% CI 0.91-0.96).

Among 850 men receiving metformin monotherapy, each additional 6 months of treatment was associated with a 44% reduction in the hazard for disease-specific mortality (95% CI 0.51-0.70) and a 20% reduction in all-cause mortality (HR 0.77-0.85).

The authors noted some limitations including the observational nature of the study and the reliance on administrative data that did not contain information on ”reason for drug discontinuation, severity of diabetes, laboratory data, body mass index, exercise, smoking status, and [prostate cancer] stage.”

Consistent with prior studies, the investigators also found a lower prostate cancer-specific mortality risk among men taking statins. Although their study was not designed to test the association between statin use and mortality, the authors ”believe that our data add to the evidence that statin use is associated with a reduced risk of prostate cancer-related mortality.”

The study is interesting but has inherent shortcomings that limit its generalizability, according to a physician who responded by email to a request for comment.

”Unfortunately, this type of study is only hypothesis-generating,” Jerome Ritchie, MD, of Brigham and Women’s Hospital and Harvard said.

”There are already multiple trials incorporating metformin, either for treatment of recurrent disease or as an adjunct to active surveillance. These trials should provide additional data to help tease out the additive role of metformin in overall prognosis and treatment of prostate cancer.”

The study was supported by a grant from the Canadian Cancer Society Research Institute, and by the Ontario Ministry of Health and Long-Term Care, the Canadian Institutes of Health Research (CIHR), and the Canadian Patient Safety Institute Chair in Patient Safety and Continuity of Care. One co-author was supported by a career investigator award from the Heart and Stroke Foundation of Ontario. Another co-author was supported by an award from the Canadian Diabetes Association/CIHR-Institute of Nutrition, Metabolism and Diabetes.

Stampfer was supported by a grant from the National Cancer Institute. Penney was supported by a Prostate Cancer Foundation Young Investigator Award.

Neither the study authors nor the editorialists reported any conflicts of interest

From http://www.medpagetoday.com

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