“Staging the Aging” When Considering Androgen Deprivation Therapy for Older Men With Prostate Cancer

Abstract

It is becoming increasingly clear that androgen deprivation therapy (ADT) is overused in treating prostate cancer. Since Huggins et al revealed that lowering testosterone levels could slow the growth of prostate cancer, its ability to alter the trajectory of prostate cancer growth has overshadowed the recognition of its alteration of other tissues. In many respects, the focus on the role of ADT in prostate cancer has overshadowed its impact on other areas of the body. Although athletes have long recognized the role of testosterone in improving muscle strength and overall energy levels, physicians treating older men with prostate cancer have been slower to recognize the converse effect of ablating testosterone on causing accelerated frailty. ADT was known to adversely impact quality of life (QOL) from the beginning of its use. It has long been known that testosteronedeplete men experience hot flashes, weakness, and fatigue. When ADT was introduced for overt metastatic disease, such QOL impacts were an acceptable trade-off for slowing the growth of cancer and improving life expectancy in men with advanced disease. However, when indications for ADT use was extended from men with metastasis to use for biochemical cancer recurrence (BCR), for adjuvant therapy with external-beam radiation, and for primary therapy for older men, improvements in life expectancy have been uncertain, particularly for lower-grade cancer. Also, newer evidence is suggesting that primary ADT for older men with prostate cancer may actually be lowering disease-specific life expectancy. Thus questions about the adverse impact of ADT on older men are mounting. Prostate cancer is largely a disease of older men. A majority of patients are older than 65 years, and most of the deaths from prostate cancer are in this age group. As a consequence, any treatments for prostate cancer need to consider their impact in an older population. Prostate cancer is an excellent example of a disease that requires the insight from both oncology and geriatrics. In particular, it is important to consider the impact of treatments on age-associated conditions, such as functional impairments, cognitive impairment, comorbidities, and geriatric syndromes. The recognized number of comorbidities that ADT adversely impacts continues to accumulate. The first to be commonly recognized was bone disease. Smith et al convincingly demonstrated that ADT led to osteoporosis. As a consequence, it is now standard to order bone densitometry and to place men on bisphosphonates when ADT is initiated if bone mineral loss is present or if it develops on treatment. Newer studies have shown additional effects on so-called geriatric comorbidities, such as functional losses, cognitive impairment, and falls. These consequences have led to the suggestion that ADT can be a significant contributing cause to a new syndrome, known as the androgen deprivation syndrome. As a result, attention has shifted to understanding the ways ADT affects other prevalent comorbidities of older men. Recently, its potential contribution to cardiovascular disease (CVD), lipid profiles, and diabetes mellitus (DM) has been raised. Given that more older men with prostate cancer will die of CVD than prostate cancer, giving men with (low-grade) prostate cancer a treatment that might exacerbate CVD is concerning. To date, there has been conflicting information regarding the contribution of ADT to CVD and diabetes in older men. An association has been shown for ADT with CVD, fatal myocardial infarction, and DM. In contrast, analyses of randomized controlled trials have found no dose-response relationship of ADT to CVD or between neoadjuvant ADT and fatal cardiac events. Although many of these studies are reasonably large, there are limited numbers of outcome events, and the conclusions are therefore uncertain. Finally, there is mounting data regarding the impact of ADT on metabolic alterations, such as worsening lipid profiles and increased insulin resistance, although nothing directly indicating an association with DM. In short, mixed information exists about the role of ADT in worsening CVD or DM. Given the prevalence of these conditions in older men, the group who are most likely to receive ADT, it is crucial that this be understood. In this context, the article by Alibhai et al in this issue of Journal of Clinical Oncology contributes vitally important information to this debate. This is the highest-quality data to appear to date on the impact of ADT on the incidence of diabetes. This is an impressive use of a large (n 19,079) administrative database, with standardized disease definitions, to assess the relationship of ADT to these preidentified outcomes. Along with previously validated algorithms to assess outcomes, the authors use propensity scoring matching techniques to control for age, medication use, income, prior cancer treatments, and other comorbidities. Overall, they do as much as can be done with observational data to assess the association between treatment with ADT for at least 6 months and the outcomes of interest. The most novel finding is the increase in well-characterized incident diabetes in those men undergoing ADT. There was an adjusted hazard ratio of 1.26 (95% CI, 1.16 to 1.36) for the development of new DM, with a number needed to harm due to the use of ADT of 91. This JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 21 JULY 2