There were an estimated 164,690 new cases of prostate cancer diagnosed in 2018, which represented approximately 19% of all new cancer diagnoses in men.1 Androgen deprivation therapy (ADT) is one of the mainstays of treatment in prostate cancer, either alone or in combination with other agents or treatment modalities. ADT includes gonadotropin-releasing hormone (GnRH) agonists (eg, leuprolide, goserelin) or GnRH antagonists (degarelix).2,3
As with any treatment, there are concerns about both the short-term and long-term side effects of ADT in men. Commonly experienced side effects include sexual dysfunction (erectile dysfunction, decreased libido); bone fractures and osteoporosis; hot flashes; diabetes; and coronary artery disease.3
Dementia is another potential adverse event associated with ADT that has recently come under more scrutiny. There are several purported mechanisms that could explain the link between ADT and dementia. These include the increased risk of vascular disease (such as diabetes and coronary disease), and decreased levels of testosterone, which can lead to reduced neuronal growth and repair.2
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To further evaluate this possible association, a retrospective cohort study was recently conducted by Jayadevappa and colleagues.2 This study analyzed data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database of the National Cancer Institute. The study included patients who were 66 years or older and were diagnosed with either localized or advanced prostate cancer between 1996 and 2003.
The first 2-year period after diagnosis was considered the “treatment phase” and was reviewed for the number of ADT doses received (1-4, 5-8, and >8 doses). The authors reviewed and included diagnosis codes for both Alzheimer dementia (AD) and dementia.
A total of 154,089 patients met study criteria, of which 62,330 received ADT within 2 years of diagnosis. Patients treated with ADT were more likely to be diagnosed with AD compared those who did not receive ADT (13.1% vs 9.4%; absolute difference 3.7%, 95% CI 3.3-3.9%, P <.001).
Patients treated with ADT had a higher hazard ratio (HR) for developing AD (HR, 1.14; 95% CI, 1.10-1.18). Similarly, patients treated with ADT had higher rates of dementia (21.6% vs 15.8%; absolute difference 5.8%, 95% CI, 5.4%-6.2%, P <.001) and a higher hazard ratio for dementia (HR, 1.20; 95% CI, 1.17-1.24) compared with those not receiving this medication.
There was also an association between the number of doses of ADT received and the risk of AD and dementia. HRs were the lowest in both the AD (HR, 1.19; 95% CI, 1.15-1.24) and dementia (HR, 1.19; 95% CI, 1.22-1.35) groups in the 1- to 4-dose group. There was a modest, yet statistically significant increase in these HRs in patients receiving more than 8 doses of ADT for AD (HR, 1.24; 95% CI, 1.16-1.34) and dementia (HR, 1.21; 95% CI, 1.15-1.28).
For AD, the number needed to harm was 18 patients (95% CI, 17-19), compared with 10 patients (95% CI, 9.5-11) for dementia. Therefore, the authors concluded that there was an association between ADT exposure and the development of AD or dementia in patients with prostate cancer.
This study has several limitations, including the patient population (Medicare enrollees only), retrospective nature of the study, and potential variability in physician diagnosis and billing codes used for AD and dementia.
A recent study published in Pharmacotherapy conducted a similar type of retrospective cohort study looking at the long-term side effects associated with ADT.3 Similarly, the authors found an increased risk of dementia in patients with prostate cancer treated with ADT compared with those who did not receive ADT (HR, 1.16; 95% CI, 1.13-1.20). In addition to dementia, patients receiving ADT were found to have increased risks of bone fractures (HR, 1.39; 95% CI, 1.35-1.43), diabetes (HR, 1.21; 95% CI, 1.18-1.24), coronary heart disease (HR, 1.12; 95% CI, 1.09-1.14) and acute myocardial infarction (HR, 1.11; 95% CI, 1.08-1.15).
Future studies are needed to confirm this potential link of ADT to dementia in patient with prostate cancer. Ideally, prospective studies would be conducted to further evaluate this potential link. It is important to consider that these types of retrospective studies have shown only association data and not necessarily causation data. In the interim, it is important to discuss this potential association of ADT with dementia with patients whom are candidates for treatment with ADT.
References
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.
- Jayadevappa R, Chhatre S, Malkowicz SB, Parikh RB, Guzzo T, Wein AJ. Association between androgen deprivation therapy use and diagnosis of dementia in men with prostate cancer. JAMA Netw Open. 2019;2(7):e196562.
- Nguyen C, Lairson DR, Swartz MD, Du XL. Risks of major long-term side effects associated with androgen-deprivation therapy in men with prostate cancer. Pharmacotherapy. 2018;38(10):999-1009.
