As Dr. Morgans notes, prostate cancer disproportionately affects elderly men with most cases diagnosed in men aged 65-74 and a median age of diagnosis of 66 years of age. Secondly, the proportion of men exposed to androgen-deprivation therapy (ADT) increases with age, particularly in men >80 years of age that may have ADT as their primary therapy in upwards of >35% of cases. According to Dr. Morgans, understanding the complications of systemic therapy for prostate cancer in elderly men is critical.
It is well-established that ADT causes hypogonadal bone loss, leading to increased skeletal response to PTH, and low estrogen altering the balance of osteoclast/osteoblast activity. In fact, hypogonadal bone loss is among the three leading causes of osteoporosis in men in the US, in addition to the incidence of osteoporosis increasing with age. ADT also leads to increased risk of fragility fractures. Indeed, 20-25% of hip fractures occur in men worldwide, with mortality 2x higher than women in the six months post-fracture. In the elderly, hip fracture causes loss of mobility, loss of independence, and increased financial burden. Given these findings, the NCCN Guidelines suggest that patients on ADT should be supplemented with calcium and vitamin D3. Furthermore, there should be consideration for additional pharmacologic therapy if the 10-year probability of hip fracture is >3% or the 10-year probability of major osteoporosis-related fracture is >20%. Finally, all patients should have a baseline bone-density test. In a SEER-Medicare study lead by Dr. Morgans, they found that few men who received ADT underwent bone density testing (6-15% over 8 years), noting disparities for older men, black men and those living in areas of low educational attainment.1
Next, Dr. Morgans highlighted that cardiovascular disease is still the leading cause of death in the US, including 26% of men >65 years of age and 29% for those >85 years of age. But, whether ADT causes cardiovascular disease has been highly controversial. Previous studies have suggested no increased risk for men <65 years of age, however with increased risk in men >65 years of age. Using data from the population-based PCOS, Dr. Morgans and colleagues noted that among 3,112 patients without cardiovascular disease followed prospectively noted that there were no increased odds of cardiovascular disease with short term ADT, however there was significantly increased odds of cardiovascular disease for patients >74 years of age on long-term ADT (HR 1.9, 95%CI 1.0-3.5).2 The NCCN guidelines suggest assessing traditional risk factors for cardiovascular disease using the A (awareness of aspirin) B (blood pressure) C (cholesterol and cigarette) D (diet and diabetes) E (exercise) approach.
There has also been concern regarding the possibility of ADT leading to diabetes mellitus. Dr. Morgans points out that diabetes and complications leads to mortality in 2.8% of men >65 years of age, and 2.0% of men >85 years of age. In a SEER-Medicare study from 2006, GnRH agonist treatment for men with locoregional prostate cancer was associated with an increased risk of incident diabetes (AHR 1.44, p<0.001) . In Dr. Morgans’ study2, short-term ADT was not associated with odds of diabetes, however long-term ADT was significantly associated with odds of diabetes in men >76 years of age (HR 2.1, 95%CI 1.0-4.4).
Finally, dementia has been brought to light as a possible complication of ADT in recent years. Dr. Morgans notes that dementia is associated with mortality in 4.8% of men >65 years of age and 7.5% of patients >85 years of age. Four studies in the last five years have suggested increased risk of dementia in varying populations of men taking ADT. This association is likely part of a spectrum of cognitive decline associated with the normal aging process and may occur in as little as 12 months on ADT. Currently, there are no interventions to reverse cognitive decline for this population, however studies are being developed to address this unmet need in men with prostate cancer. One such study is being developed by Dr. Morgans and her group, the COGCaP schema that will enroll 50 men on abiraterone and 50 men on enzalutamide with primary outcomes being cognitive testing at baseline, 3, 6, and 12 months.
In conclusion, Dr. Morgans notes that ADT is associated with numerous complications that should be considered when caring for prostate cancer survivors. Elderly men are particularly vulnerable to developing complications from ADT that increase morbidity and mortality. Importantly, this may lead to loss of mobility, loss of independence and increased financial burden.
Presented By: Alicia K. Morgans, Vanderbilt University Medical Center, Nashville, TN, USA
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA
1. Morgans AK, Smith MR, O’Malley AJ, et al. Bone density testing among prostate cancer survivors treated with androgen-deprivation therapy. Cancer 2013 Feb 15;119(4):863-870.
2. Morgans AK, Fan KH, Koyama T, et al. Influence of age on incident diabetes and cardiovascular disease in prostate cancer survivors receiving androgen deprivation therapy. J Urol 2015 Apr;193(4):1226-1231.
3. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006;Sep 20;24(27):4448-4456.