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.