SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide). The first-generation Androgen Receptor (AR) inhibitors act by binding to the Androgen Receptor (AR) and prevent the activation of the AR and subsequent up-regulation of androgen responsive genes. They may also accelerate the degradation of the AR. These agents have a range of pharmacologic activity from being pure anti-androgens to androgen agonists. The second-generation, anti-androgen agents include, ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide) and ERLEADA® (Apalutamide). ZYTIGA® inhibits CYP17A1 enzyme and depletes adrenal and intratumoral androgens, thereby impairing AR signaling. XTANDI® and ERLEADA® compete with Testosterone and Dihydrotestosterone and avidly binds to the Androgen Receptor, thereby inhibiting AR signaling, and in addition inhibits translocation of the AR into the nucleus and thus inhibits the transcriptional activities of the AR.
Androgen Deprivation Therapy (ADT) is often recommended alone or as a part of multimodality therapy, as ADT reduces the likelihood of cancer progression and/or mortality, in high-risk localized, locally advanced, recurrent, or metastatic Prostate cancer. ADT however can be associated with side effects such as fatigue, loss of muscle mass, impotence, anemia, osteoporosis, depression, etc., which in turn can have a significant negative impact on an individual’s quality of life. ADT has also been associated with cognitive dysfunction and there has been conflicting evidence establishing an association between ADT use and diagnosis of Alzheimer disease or Dementia. It has been postulated that lower testosterone levels impair neuron growth and axonal regeneration, in addition to accumulation of abnormally folded β-amyloid protein. With the earlier introduction of ADT in the course of disease progression for patients with Prostate cancer, it is important to discuss the association between ADT and Dementia with patients, which in turn can improve shared decision making around the risks and benefits of ADT in Prostate cancer.
The present study was conducted to analyze the association between ADT exposure and diagnosis of Alzheimer disease or Dementia, among elderly men with Prostate cancer. The authors in this retrospective cohort study used data from the NCI’s Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, and the participants included 154,089 elderly men with newly diagnosed Prostate cancer, between 1996 and 2003. The analyses were conducted in 2018 and patients receiving ADT within 2 years of Prostate cancer diagnosis were identified. In this study, 62,330 men received ADT within 2 years of Prostate cancer diagnosis, and 91,759 men did not receive ADT. Mean follow up was 8.3 years, and survival analysis was used to determine association between ADT exposure and diagnosis of Alzheimer disease or Dementia.
The researchers noted that exposure to ADT, compared with no ADT exposure, was associated with a diagnosis of Alzheimer disease (13.1% vs 9.4%; HR=1.14; P<0.001) and Dementia (21.6% vs 15.8%; HR=1.20; P<0.001). There was a dose-response relationship and patients who received more than 8 doses of ADT were at a significantly higher hazard of diagnosis of both Alzheimer disease and Dementia, than those receiving fewer doses ADT.
The authors concluded that over a follow-up period of at least 10 years, ADT exposure among elderly patients with Prostate cancer was associated with subsequent diagnosis of Alzheimer disease or Dementia. They added that clinicians should carefully weigh the long-term risks and benefits of ADT, in patients with a prolonged life expectancy, and stratify patients based on Dementia risk, prior to ADT initiation. Association Between Androgen Deprivation Therapy Use and Diagnosis of Dementia in Men With Prostate Cancer. Jayadevappa R, Chhatre S, Malkowicz SB, et al. JAMA Netw Open. 2019;2(7):e196562. doi:10.1001/jamanetworkopen.2019.6562