ADT Increases Risk for Fractures and Cardiovascular-Related Death in Prostate Cancer Patients

Roxanne Nelson

April 30, 2009

April 30, 2009 — Androgen-deprivation therapy (ADT) is a common treatment for men with prostate cancer, but patients who do undergo this therapy are at an increased risk for skeletal fracture, incident diabetes, and cardiovascular-related mortality.

According to an analysis of 14 studies published online April 27 in Cancer, patients who received ADT had a 23% increase in the risk for overall fracture and a 17% increase in cardiovascular-related mortality, compared with men who did not undergo treatment with ADT. Data from 2 large studies also indicated significant elevations in the risk for diabetes.

But lead author Lockwood G. Taylor, MPH, cautioned that although they did observe significant relative risks for skeletal fracture and cardiovascular-related death, the absolute risks for these adverse events are still very low.

"However, our findings do suggest physicians may want to closely monitor their patient's bone mineral density, lipoprofile, and body mass index during and following treatment, especially if the patient is already at risk for skeletal fracture or cardiovascular disease prior to undergoing ADT," said Mr. Taylor, a doctoral candidate in the Division of Epidemiology, University of Texas School of Public Health in Houston.

The benefits of ADT likely outweigh the risks we observed for most patients undergoing ADT.

"While the physician may wish to communicate these risks to the patient, it is imperative to convey that these risks are small in terms of minimal increase in absolute risk," he told Medscape Oncology. "The benefits of ADT likely outweigh the risks we observed for most patients undergoing ADT."

ADT is currently the most common form of treatment for advanced prostate cancer, and is being increasingly used as adjuvant therapy with radiotherapy for localized disease and as salvage therapy for increasing prostate-specific antigen levels after localized treatment. The authors note that although ADT has been successful in improving overall quality of life in patients with advanced prostate cancer, it can cause potential adverse events.

To gain a better understanding of the magnitude of skeletal and cardiovascular adverse effects associated with ADT, Mr. Taylor and colleagues conducted a review that included summary risk estimates for specific outcomes. Their analysis examined 14 studies published from 1966 to 2008 that met their inclusion criteria.

Fracture Risk

There were 5 studies that investigated risk for fracture as a major adverse effect from ADT, 4 of which were retrospective cohort studies. The pooled results yielded a summary random-effects estimate of 1.23 (95% confidence interval [CI], 1.10 - 1.38) and a fixed-effects estimate of 1.17 (95% CI, 1.12 - 1.23).

In addition, 3 studies reported an increased risk for osteoporosis or lower bone mineral density in patients treated with ADT, compared with those who were not. In 2 studies that specifically evaluated osteoporosis as an outcome, there was an elevated association between ADT and osteoporosis. However, the authors note that only 1 of the studies found the association to be statistically significant. The data also indicated that the duration of ADT is associated with osteoporosis and fracture risk; longer duration of ADT is associated with a higher risk.

Diabetes and Cardiovascular Morbidity

Of the 3 studies that investigated incident diabetes and other cardiovascular morbidity secondary to ADT treatment, all reported a significantly increased risk for diabetes or cardiovascular morbidity. The 3 studies were all retrospective cohort studies.

Two of the studies reported significantly increased risk for incident diabetes (between 36% and 49%), but the researchers caution that "further research beyond those 2 studies is needed to confirm the consistency and magnitude of the association."

ADT also increased the risk for cardiovascular morbidity, according to 1 paper in this subgroup. Patients who underwent treatment with ADT had a 20% increased risk for cardiovascular morbidity, compared with men who did not, and the duration of treatment was significantly associated with this risk.

Cardiovascular-Related Mortality

The authors also found that the results of studies investigating cardiovascular-related mortality secondary to ADT were relatively consistent. Of the 4 papers included in this analysis, 2 were retrospective cohort studies and 2 were randomized clinical trials.

The retrospective cohort studies both found significantly increased risks for cardiovascular-related mortality among patients who received ADT treatment, whereas the randomized trials reported slightly elevated but nonsignificant increases in cardiovascular-related mortality secondary to ADT.

The researchers point out that the absolute risk for cardiovascular-related mortality is low. Based on the assumption that the risk for cardiovascular-related mortality among men with prostate cancer who did not receive ADT is 9 or 10 deaths per 1000 person-years, they write, the observed 17% increase in relative risk would result in the increase of the absolute risk to 10.5 or 11.7 deaths per 1000 person-years, respectively, for men who underwent ADT.

Preventive Steps Might Reduce Risk

Even though the absolute risks for fracture and cardiovascular mortality are low, preventive treatments could further reduce the risk for these potentially serious adverse events. "Preventive therapies to reduce these risks, such as lifestyle modifications or drug therapy, may be helpful, especially if the physician recognizes potential precursors to these adverse events, such as decreases in bone mineral density, an abnormal lipid profile, or a marked increase in body mass index," said Mr. Taylor.

The researchers also note that because some patients experience more benefit from ADT than others, physicians should consider each patient's overall health and prostate cancer status when weighing treatment options, and a benefit–risk analysis must be considered.

The study was supported in part by a grant from the Agency for Healthcare Research and Quality.

Cancer. Published online April 27, 2009. Abstract

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