Managing the Side Effects of Androgen-Deprivation Therapy

Androgen-deprivation therapy (ADT) is a widely accepted treatment for men with advanced or metastatic prostate cancer. The goal of ADT is to reduce testosterone production to castrate levels, and this can be achieved surgically via orchiectomy or chemically, using hormonal agents. Gonadotropin-releasing hormone (GnRH) or luteinizing hormone releasing hormone (LHRH) agents are typically used, but they have come under increasing scrutiny for their toxic side effects. In May, the FDA announced that it would be reviewing the safety of commonly prescribed GnRH agonists and issued a series of recommendations for patients and physicians considering their use.

At the Third Annual Interdisciplinary Prostate Cancer Congress (IPCC) in New York City in March 2010, co-chair Leonard G. Gomella, MD, Bernard W. Godwin Professor of Prostate Cancer, chairman of the Department of Urology, and associate director of clinical affairs at the Jefferson Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, discussed ADT-related toxicities and current trends in managing them. Gomella noted that ADT is increasingly being used at earlier stages of prostate disease. “With ADT being used more and more in nonmetastatic prostate cancer, there is the potential for men to be exposed to these agents longer. We have concerns that are growing, and probably appropriately, over the potential side effect profile.”

HISTORY OF ADT

ADT begins with physicians Charles Huggins and C.V. Hodges, who disclosed the relationship between androgen and prostate cell proliferation in 1941 and reported on the effects of androgen deprivation on prostate tumors. In the intervening decades, ADT has drastically evolved, with hormonal agents replacing surgical castration as the patientpreferred treatment for prostate cancer. Since GnRH receptors and GnRH agonists were discovered in the 1970s, they have become the mainstay in treating advanced prostate cancer. Gomella said, “These agents chronically suppress testosterone by desensitizing the pituitary to the release of luteinizing hormones, resulting in the down-regulation of the GnRH receptors.”

Historically, GnRH agents have been used in men with advanced disease, but they are increasingly being used in other settings. For example, Gomella noted that while concurrent administration of radiation and hormone therapy was almost unheard of in the 1990s, it became commonplace for patients with high-risk prostate cancer after multiple studies indicated it improved survival. Another growing trend is administering ADT to men with nonmetastatic disease or disease that appears to be progressing based on rising levels of prostate-specific antigen (PSA).

Gomella said data support this, and he pointed to a 1997 pivotal study conducted by the Medical Research Council (N = 938) that compared immediate versus deferred hormone treatment in locally advanced or asymptomatic metastatic prostate cancer. Men were randomized to receive orchiectomy or an LHRH analogue immediately or only after an indication occurred. Patients in the delayed treatment group were more likely to experience progression from M0 to M1 disease (P <.001), metastatic pain, and death. Messing and colleagues conducted a similar study and found that after median follow-up of 7.1 years, only 15% of the 47 men who received immediate adjuvant androgen ablation died compared with 35% of the 51 randomized to delayed treatment (P <.02).

Many controversies remain regarding early versus delayed treatment in prostate cancer, some of which are specific to ADT. Earlier use might translate to longer use in some cases, and these drugs are associated with a host of toxicities due partly to fluctuating hormonal levels. Gomella encouraged a risk-benefit analysis of ADT. “We have to remember that ADT is a therapeutic intervention. Data show that it does extend the life, but we have to balance the risks and benefits with the side effect profile,” he said.

MAJOR ADVERSE EFFECTS WITH ADT

Gomella said men prescribed an LHRH analogue might be alarmed at the laundry list of side effects included in the prescribing information: loss of libido, respiratory disorders, muscle weakness, weight gain, appetite changes, dry eyes, testicular atrophy, body hair loss, gynecomastia/breast tenderness, hot flushes, osteoporosis, metabolic syndrome, and more. “A lot of people think, ‘Gee, these are really bad. Look at all of the horrible things that can happen,’” said Gomella. Some are more common than others and some are manageable, he added.

Vasomotor Instability

Between 50% to 80% of men taking an LHRH analogue will experience some degree of vasomotor instability, or hot flashes, which may be accompanied by sweating, chills, and reddening of the skin. Some episodes occur spontaneously, while others appear to develop in response to environmental triggers. Hot flashes are more common in the first few weeks after starting ADT, when hormone levels are fluctuating.

Treatment options include estrogens, megestrol acetate (Megace), clonidine (Catapres), progesterones (eg, depot medroxyprogesterone acetate [MPA; Depo Provera]), antidepressants (eg, venlafaxine [Effexor] and paroxetine), neuromodulators (eg, gabapentin), and alternative therapies (eg, soy and acupuncture). Although there are several possibilities for treating hot flashes, Gomella said data supporting their use are limited. One study comparing multiple agents in men with ADT-associated hot flashes found that diethylstilbestrol plus megestrol acetate eliminated them in 70% of patients, and for 20%, the drugs more than halved the severity of the events. The most common complaints with these drugs were gynecomastia and nausea. Patients

in the study preferred oral megestrol acetate, which was associated with fewer side effects.

A pilot study administered 150-mg or 400-mg doses of MPA, a derivative of the female progesterone, to 50 men with ADT-related hot flashes. Symptoms improved for 91% of the men, and approximately half (46%) saw their hot flashes subside completely after only 1 or 2 injections. Despite the clinical benefits, Gomella said men for whom he has prescribed

MPA have had insurance issues. “Unfortunately, they have had to lay the dollars out of their pocket for the medication.” Hot flashes do not routinely require treatment. A significant percentage of patients who experience hot flashes find them tolerable. Gomella suggested using a grading system developed by his colleague Mark Moyad, MD, to help assess when vasomotor instability

requires treatment.

Metabolic Syndrome

Metabolic syndrome—a cluster of conditions that includes insulin insensitivity, central obesity, muscle wasting, dyslipidemia, and hypertension&mdash;is one of the most serious complications of ADT. Gomella said metabolic syndrome seems to account for the increased risk of diabetes and cardiovascular disease in men receiving ADT. Increased abdominal fat and insulin sensitivity are known triggers for diabetes in men. Orchiectomy has been found to increase the risk of diabetes, but not the risk of myocardial infarction (MI).

The data linking ADT with diabetes have been consistent over the years, while the data associating ADT with increased cardiovascular risk are less so. Gomella said, “Where it gets really controversial is the MI risk, and this is something that is unsettled.” He noted that studies published several years ago showed that men on LHRH analogue therapy had an increased risk of MI but that subsequent studies contradicted these findings, suggesting that the risk might not be as significant as previously believed.

A review of the literature, conducted by representatives from the American Heart Association, the American Urological Association, and the American Cancer Society, was published in the February 16 issue of Circulation, and concluded that despite the inconsistent evidence, ADT does appear to exacerbate cardiac risk factors and increase the risks of heart attack and heart failure. They issued an advisory, supported by the American Society for Radiation Oncology, recommending oncologists weigh these risks when prescribing ADT and calling for additional trials to study the possible link. The authors said an annual assessment of blood glucose and lipid levels was reasonable but did not recommend altering current ADT strategies, leaving it to the discretion of the treating physician.

The advisory prompted the FDA to initiate a review of specific GnRH agonists used in prostate cancer to determine whether they increase the risks of cardiovascular disease and diabetes. Medications under review include leuprolide acetate (Eligard, Lupron, and Viadur), nafarelin (Synarel), triptorelin pamoate (Trelstar), histrelin (Vantas), and goserelin (Zoladex). The FDA is advising careful evaluation of cardiovascular and diabetes risk factors before prescribing GnRH treatment. The agency said patients currently receiving ADT with GnRHs should be monitored for possible diabetes and cardiovascular disease and make lifestyle changes to reduce their risk of these complications.

Osteoporosis

Loss of bone mineral density (BMD) is a common side effect of ADT. Gomella pointed to studies showing a dramatic increase in the risk of fractures with orchiectomy and decreased BMD following LHRH analogue treatment and surgical castration. He noted that the advanced age of many men receiving ADT for prostate cancer might contribute to this complication, adding that many men are osteoporotic or osteopenic at initial diagnosis. “There are a lot of normal things that happen in the aging male that may be overlapping with the use of therapies such as LHRH analogue therapy,” he said.

Several drugs are available for men with osteoporosis, though not all are approved specifically for men with metastatic prostate cancer. Gomella listed teriparatide (Forteo), toremifene (Fareston), and denosumab (Prolia) as possible therapeutic options. Denosumab is under priority review by the FDA for men with prostate cancer. While estrogens correct osteoporosis in men, Gomella said they have a significant side effect profile that many men find intolerable. Bisphosphonates reduce skeletal-related events in men, but they are not indicated for male osteoporosis. Gomella said clinicians should encourage patients to take vitamin D and calcium supplements, do resistance exercises, and stop smoking. BMD testing is also warranted.

Loss of Libido/Impotence

Prostate cancer itself does not cause erectile dysfunction (ED), or impotence, but many of the treatments for the disease do. Gomella said a similar risk of erectile dysfunction was seen in men following 2 years of ADT, radiation therapy, or radical prostatectomy in Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a longitudinal observational study of 438 men with early-stage prostate cancer.

Surgical removal of the prostate generally leads to impotence for several months following the procedure, but approximately half the patients will recover function within 1 year and slightly more than half within 2 years. Recovery depends on the extent of nerve damage during the procedure. With radiation therapy, brachytherapy is associated with a 25% to 50% rate of ED and standard external beam radiation causes ED in nearly 50% of patients. Unlike surgery and ADT, where sexual function improves over time, radiation is associated with a slight decline in sexual function over time. Gomella said a similar risk of erectile dysfunction was seen in men following 2 years of ADT, radiation therapy, or radical prostatectomy in CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor), a longitudinal observational study of 438 men with early-stage prostate cancer.

Many options exist for managing ED, including medication (oral and injectable), medical devices, and prostheses. Monotherapy with PDE-5 inhibitors has a response rate of 33% to 80%, said Gomella. Combining PDE-5 inhibitors with other multimodal therapies, such as constriction bands and vacuum pumps, produces a much higher response rate. The choice of treatment for this complication will depend largely on the patient’s medical history and preference.

Psychological Issues

Depression, cognitive disorders such as dementia and memory disturbances, and constitutional symptoms like fatigue and debility are more common in patients receiving ADT, but Gomella hypothesized that this is primarily because these patients are older, with advanced disease and more comorbidities. A study conducted at the University of Texas in Galveston analyzed data for more than 50,000 men with prostate cancer aged >65 years from the Surveillance, Epidemiology, and End Results—Medicare database. Investigators found that men who survived 5 years after diagnosis were more likely to have at least one depressive, cognitive, or constitutional event if they received ADT (31.3% vs 23.7%, respectively; P <.001). After adjusting for variables such as comorbidity, tumor characteristics, and age, the risks associated with ADT were substantially reduced.

Whether these side effects are related to ADT specifically is unclear, said Gomella. “It is a little hard to actually nail the cognitive aspects of the depressive episodes strictly to the ADT. It may contribute a little bit, yes, but there is really no hard data to say it is absolutely a cause and effect.” Cancer in general is associated with higher rates of depression, and one can imagine several circumstances arising from prostate cancer and its treatments that might lead to depression. Clinicians should be open about approaching the subject of depression with their patients.

INTERMITTENT ANDROGEN DEPRIVATION

Intermittent androgen deprivation (IAD) involves alternating androgen ablation with treatment cessation to allow testosterone recovery. The goal is to ameliorate some of the adverse effects associated with continuous ADT. Gomella said for some patients, the “on-again, off-again” strategy might improve quality of life and delay the development of hormone-resistant prostate cancer seen with constant androgen deprivation.

IAD cyclic treatment schedules are arbitrary, with no established guidelines in the United States. “At this point in time, we have absolutely no parameters to follow, and that is a problem,” said Gomella. “The concept [behind IAD] is that patients with advanced prostate cancer are put on ADT for a fixed period of time—maybe 6 months, maybe 9 months, maybe 12 months, or until they get to a PSA nadir. You check their testosterone, and then you stop [therapy]. You and the patient decide when to start him back on ADT.” Gomella said he keeps his patients on hormones for a year to a year and a half initially. He decides with the patient when to resume therapy based on symptoms, baseline PSA, and overall metabolic status.

Gomella said several phase II and phase III trials have demonstrated clinical benefits with IAD, including a recent phase III study by the South European Urologic Group. Investigators randomized 626 men with locally advanced or metastatic prostate cancer to continuous ADT or IAD and found no difference in survival rates between the two groups. The quality of life disparity was the most important benefit observed with IAD. Side effects were more pronounced in the continuous therapy arm; men in the IAD arm reported better sexual function. “The bottom line is that IAD can be considered in some men, but we don’t really have the absolute guidelines yet,” said Gomella.

CONCLUSIONS

While improving survival is obviously the key goal with ADT, the importance of preserving quality of life should not be ignored. Gomella noted that several novel therapies are being investigated for prostate cancer that, on first glance, appear to have a better side effects profile than some of the existing GnRH agonists. In addition, ongoing studies are looking at novel therapeutics and exercise programs designed to reverse bone loss and/or muscle wasting in prostate cancer.

For now, ADT remains the mainstay of treatment in prostate cancer, and more research is needed on the effects of prolonged ADT. “We are seeing more hormonal therapy at all stages, and earlier use of hormone therapy that most of us believe is improving outcomes. We do have some concerns, but there is a lot more we need to look at with androgen deprivation syndrome, really to study it better and in a more organized fashion,” Gomella concluded.