Androgen Deprivation May Raise Risk of Cardiovascular Death, Adding Toremifene May Improve Lipid & Bone Profiles

KISSIMMEE, FL—Use of androgen-deprivation therapy may increase the risk of death from heart disease in older men with localized prostate cancer, while toremifene may improve lipid profiles and bone mineral density in men with advanced prostate cancer receiving the therapy, according to separate studies reported here at the Prostate Cancer Symposium. “Men of advanced age should be considered for cardiovascular evaluation prior to treatment with androgen-deprivation therapy,” said Henry K. Tsai, MD, a resident physician in the Harvard Radiation Oncology Program and lead author of the study linking androgen-deprivation therapy to an increased risk of cardiovascular death. Since the study was retrospective, a prospective clinical trial is needed to confirm a cause-and-effect relationship, Dr. Tsai stressed at the Symposium, which was cosponsored by the American Society of Clinical Oncology, the American Society of Therapeutic Radiology and Oncology, and the Society of Urologic Oncology. The study included 3,636 men with localized prostate cancer in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database, a national longitudinal registry. Of these men, 735 received androgen-deprivation therapy for a median duration of 4.1 months, while the rest did not receive anti-hormone therapy. The men were all free of cardiovascular disease at the time of initial treatment with surgery, external-beam radiation therapy, brachytherapy, or cryotherapy. Their median age was 64, and they were followed for a median of 4.0 years. Both the duration of androgen-deprivation therapy and age were significant predictors of cardiac mortality at five years in an analysis that controlled for age and baseline coronary artery disease risk factors, including hypertension, diabetes, body mass index, and smoking status. In addition, the duration of androgen therapy was a significant predictor of shorter time to all-cause mortality in an analysis that controlled for pretreatment PSA level, Gleason score, and tumor category. When stratified by age, the association between anti-hormone therapy and death from cardiac disease remained significant in men 65 years of age and older, but not in younger men. Specifically, men 65 and older who were taking androgen-deprivation therapy had a 3% risk of death from cardiac disease over five years, compared with a 0.9% risk for patients 65 and older who did not receive the therapy. Caution Advised Oncologists “need to be more judicious than in the past and carefully assess patients to determine if the risks of androgen-deprivation therapy outweigh the benefits,” said the moderator of a news conference that featured the study, Eric A. Klein, MD, Head of the Section of Urologic Oncology and Professor of Surgery at the Cleveland Clinic. Additionally, studies should be performed to determine if combining anti-hormone therapy with low-dose aspirin, statins, and other drugs used to prevent cardiovascular disease could benefit these patients, he said. But until such studies are performed, caution should be exercised, as there could be drug-drug interactions between androgen-deprivation therapy and antiplatelet or lipid-lowering agents, he said. “We won't know until we do those studies.” The findings from this study are surprising, he added. “We knew being on androgen-deprivation therapy for as little as three to six months increases the chance of metabolic syndrome and bone problems, but we never really knew that it could kill people, and that is what this is saying. “This does not mean we should abandon androgen-deprivation therapy,” he added, pointing out that it successfully lowers levels of testosterone in the body. Toremifene Improves Lipid, Skeletal Profiles Toremifene, a selective estrogen-receptor modulator, appeared to improve lipid profiles and increase bone mineral density among men on androgen-deprivation therapy for advanced prostate cancer, said the lead researcher of the toremifene studies, Matthew R. Smith, MD, PhD, Director of Research in the Genitourinary Unit of Oncology at Massachusetts General Hospital Cancer Center. The drug is also being studied for the prevention of prostate cancer, and it is already on the market for use in the treatment of breast cancer. The new results both emerged from planned interim analyses of a trial at 150 centers in the United States and Mexico of 1,392 patients with advanced cancer age 50 years and older who were randomized to 80 mg/day of oral toremifene or placebo for two years. The protocols specified interim analysis of the first 200 patients at 12 months. Patients who took toremifene experienced an 8% reduction in total cholesterol, compared with a 1% decline in the placebo group, and a 13% decrease in triglycerides, compared with a 7% increase in the placebo group. Toremifene use was also connected with changes in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. Patients in the toremifene group experienced an 8% decrease in LDL cholesterol versus a 1% increase in the placebo arm and a 1% increase in HDL cholesterol compared with a 5% decline in the placebo arm. There was a 7% drop in the total cholesterol/HDL cholesterol ratio in the drug arm versus a 6% increase in the placebo group. All the individual differences in the lipid profile were statistically significant, Dr. Smith said. As for skeletal problems, patients taking toremifene had significantly increased bone mineral density at the lumbar spine, hip, and femoral neck, compared with men in the placebo group, who lost bone at all three sites. “Cardiovascular disease is a major cause of morbidity and mortality, particularly among older men with prostate cancer,” Dr. Smith said. “The results suggest that toremifene has the potential not only to reduce the risk of fractures in men with advanced prostate cancer but also to improve their lipid profile.” Still, more follow-up is needed, he added. “We need to continue following these patients for 24 months. These results are encouraging but not conclusive.” Longer Follow-Up Needed Oncologists who are using androgen-deprivation therapy (ADT) to treat their patients are seeing more and more metabolic problems and issues with bone mineral density, noted Kevin Kelly, DO, Associate Professor of Medicine and Associate Director of Solid Tumor Clinical Investigation at Yale Cancer Center, when asked to comment on the study. But the real question is what these findings mean long-term, he said: “Will the use of toremifene in fact lower the risk of cardiovascular disease and fractures among men on ADT?” In the past, oncologists were not that concerned about lipid profiles and bone loss, as patients on androgen-deprivation therapy were not expected to live that long, he added. “But now we are starting to give androgen-deprivation therapy to younger men for longer periods of time, 10 or 15 years. As a result, these long-term side effects are becoming more worrisome.” However, more study of toremifene is needed. “We do not yet know about any possible side effects,” he said, noting that another selective estrogen-receptor modulator, raloxifene, has been linked to an increased risk of thromboembolic events. “I am optimistic that toremifene may help combat these [cardiovascular and bone] problems. But until we see longer follow-up with larger number of patients, I would hate for people to start using toremifene for this indication.” ASCO Prostate Abstracts 149, 150, 298 ASCO Updates Guidelines for Hormonal Management of Androgen-Sensitive, Metastatic, Recurrent, or Progressive Prostate Cancer ASCO recently updates its 2004 clinical practice guideline on the best practices for the initial management of androgen-sensitive, metastatic, recurrent, or progressive prostate cancer. The new guideline was published in the April 2 issue of the Journal of Clinical Oncology. Physicians can begin androgen-deprivation therapy (ADT) after a patient's tests show recurrence or progression of prostate cancer or defer therapy until a later time, according to the new guideline. Most often a patient will have no symptoms of prostate cancer at that time. However, all patients should start therapy once they experience symptoms of the disease. The guideline does not strongly recommend the early use of ADT since there was no overall survival difference seen when the results of all the studies were combined. The guideline update addressed whether there is benefit for men with metastatic or progressive prostate cancer from starting early ADT over deferring therapy. The expert panel found a 17% decrease in mortality from prostate cancer, but a 15% increase in mortality from causes not associated with prostate cancer. This indicates no overall survival advantage for patients who are treated with early ADT versus deferred therapy, the lead author of the report, Andrew Loblaw, MD, a radiation oncologist at Toronto-Sunnybrook Regional Cancer Centre, noted in a news release. “There is debate in the medical community regarding the optimal timing for starting androgen-deprivation therapy for prostate cancer. Doctors should discuss with patients the risks and benefits of early androgen deprivation therapy versus deferred therapy. If the patient prefers to defer therapy, he should have regular visits with his doctor every three to six months to monitor the disease.” The guideline update recommends either bilateral orchiectomy or luteinizing hormone-releasing hormones as initial ADT. Additionally, combined androgen blockade (CAB) should be considered in the treatment of locally advanced or metastatic prostate cancer. CAB uses nonsteroidal anti-androgen therapy with an orchiectomy or LHRH to treat prostate cancer. “Overall, survival for men with prostate cancer is greater with the combination of non-steroidal anti-androgen therapy and surgical or medical castration, over one of these treatments alone, although patients may experience increased side effects due to combined therapies, depending on the non-steroidal agent used,” Dr. Loblaw said. Consistent with the 2004 guideline, current data are insufficient to support the use of intermittent androgen blockade outside of clinical trials. Intermittent androgen blockade is hormone therapy given for specified periods and then stopped temporarily according to schedule. This therapy is used to prevent prostate cancer from becoming capable of growing without hormones. The guideline update recommends that if available, clinical trials should be considered for patients with recurrent prostate cancer. The ASCO panel reviewed published literature from January 2003 to March 2006.

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