Association Between Androgen Deprivation Therapy Use and Diagnosis of Dementia in Men With Prostate Cancer | Dementia and Cognitive Impairment | JAMA Network Open | JAMA Network
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    2 Comments for this article
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    Not sufficient evidence to convict ADT as a factor in Alzheimer's disease and related dementia
    Seo Baik, PhD and Clement J. McDonald, MD | National Library of Medicine, National Institutes of Health
    Jayadevappa et al(1) reported significant increased risks for Alzheimer’s disease (AD) ( +14%) and dementia (+20%) with ADT treatment and described it as the largest study of its kinds to date. The authors reported a mean follow-up of 8.3 years but did not report the death rate. Their study was meticulously done and used SEER data, in addition to the Medicare sourced data and included cancer stage that SEER data carries.

    In 2018, we reported a similar study of the effect of ADT on AD and dementia. Our study population size was, 1.2 million, 10 times larger
    than Jayadevappa’s study. We used only Medicare data but the age at the diagnosis of prostate cancer (average 75.2), rates of AD (8.9%) and dementia (18.8%) were similar to Jayadevappa’s study(2). We found that the use of ADT had no increased risk for AD and only a miniscule (2%) risk for dementia. We did report our death rate which was 3.7 times the AD rate and 1.4 times the dementia rate we observed. Use of death as a competing risk in survival analyses is recommended when the follow-up is >5 years and/or the death rate is greater than the event rate(3), which was the case in our study and, we assume in theirs because their population was so similar to ours.

    We used a Fine-Gray competing risk model in our analysis; the other study did not. This difference could explain the difference in the results, because censoring patients at death and considering them ‘at risk’ for AD and dementia, will tend to cause an upward bias of the hazard ratio of the AD and the dementia events(3).

    We could not parse how the comorbidity score was calculated from the references given, nor understand how 77% of patients had a ‘zero’ score assuming their death rate was at least as high as ours and given the fact that at least 75% of Medicare fee-for-service beneficiaries aged 75-84 had more than 2 chronic conditions(4). Knowing the AD and dementia rates and death rates for excluded ADT patients (28,588, 31.4%) because of their 2-year cut-off would help us better understand the difference between the two studies.

    Two studies and two different results is the reality with observational studies(5). ADT has been incriminated as a factor in AD/dementia, but the evidence is not sufficient to indict or convict.


    References
    1. 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. doi:10.1001/jamanetworkopen.2019.6562
    2. Baik SH, Kury FSP, McDonald CJ. Risk of Alzheimer’s Disease Among Senior Medicare Beneficiaries Treated With Androgen Deprivation Therapy for Prostate Cancer. J Clin Oncol. August 2017:JCO2017726109. doi:10.1200/JCO.2017.72.6109
    3. Berry SD, Ngo L, Samelson EJ, Kiel DP. Competing risk of death: An important consideration in studies of older adults. J Am Geriatr Soc. 2010;58(4):783-787. doi:10.1111/j.1532-5415.2010.02767.x
    4. Lochner KA, Cox CS. Prevalence of multiple chronic conditions among Medicare beneficiaries, United States, 2010. Prev Chronic Dis. 2013;10:E61. doi:10.5888/pcd10.120137
    5. Madigan D, Ryan PB, Schuemie M, et al. Evaluating the Impact of Database Heterogeneity on Observational Study Results. Am J Epidemiol. 2013;178(4):645-651. doi:10.1093/aje/kwt010
    CONFLICT OF INTEREST: None Reported
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    Response to Drs. Baik SH and McDonald CJ
    Ravishankar Jayadevappa, Ph.D. | University of Pennsylvania
    We thank Drs. Baik and McDonald for their comments and note following strengths of our work (1) and the differences compared to their 2018 article (2). First, our study uses SEER-Medicare data for the period 1996 to 2013, and thus we were able to adjust for some of the clinical variable such as cancer grade at the time of diagnosis. Second, taking advantage of the availability of long-term follow-up data, our cohort consisted of prostate cancer patients receiving androgen deprivation therapy within two years of their diagnosis and potential follow-up of at least ten years. Thus, our study is one of the longest follow-up studies. Finally, our sensitivity analysis and dose effect analysis demonstrated robustness of our results.

    Mortality for ADT group was 69.8% and that for non ADT group was 61.7% (p value <.0001). To address the issue of competing risk due to mortality, we independently assessed the hazard ratios using Fine and Gray method of competing risk analysis. The results were comparable to the ones we have presented (1). To compute Charlson comorbidity index scores, we used algorithm available from SEER-Medicare (4). Charlson Comorbidity Index is a robust summary measure for its component variables using SEER-Medicare data (5). We also assessed the proportion of dementia and Alzheimer’s among patients who were excluded due to receipt of ADT two-year after diagnosis. The proportion were comparable to those observed in our final study cohort (1).

    In conclusion, large cohort analysis such as ours, provides important information regarding the association between use of ADT and dementia and Alzheimer’s. Future studies can explore the causal pathways so that effective clinical interventions can be developed.

    References
    1. 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. doi:10.1001/jamanetworkopen.2019.6562
    2. Baik SH, Kury FSP, McDonald CJ. Risk of Alzheimer’s Disease Among Senior Medicare Beneficiaries Treated With Androgen Deprivation Therapy for Prostate Cancer. J Clin Oncol. August 2017:JCO2017726109. doi:10.1200/JCO.2017.72.6109
    3. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med. 2005;352(2):154-164. doi:10.1056/NEJMoa041943.
    4. SEER-Medicare: Selecting the Appropriate Comorbidity SAS Macro. https://healthcaredelivery.cancer.gov/seermedicare/considerations/calculation.html. Accessed on May 2018.
    5.Austin SR, et al. Why summary comorbidity measures such as the Charlson Comorbidity Index and Elixhauser score work, Med Care, 2015 September; 53(9): e65–e72. doi:10.1097/ MLR. 0b013e318297429c.
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    Oncology
    July 3, 2019

    Association Between Androgen Deprivation Therapy Use and Diagnosis of Dementia in Men With Prostate Cancer

    Author Affiliations
    • 1Leonard Davis Institute of Health Economics, Perlman School of Medicine, University of Pennsylvania, Philadelphia
    • 2Perlman School of Medicine, Division of Urology, Department of Surgery, University of Pennsylvania, Philadelphia
    • 3Perlman School of Medicine, Department of Medicine, University of Pennsylvania, Philadelphia
    • 4Perlman School of Medicine, Department of Psychiatry, University of Pennsylvania, Philadelphia
    JAMA Netw Open. 2019;2(7):e196562. doi:10.1001/jamanetworkopen.2019.6562
    Key Points español 中文 (chinese)

    Question  Is androgen deprivation therapy exposure associated with dementia among elderly patients with prostate cancer?

    Findings  In this cohort study of 154 089 elderly men with prostate cancer, androgen deprivation therapy exposure was associated with subsequent diagnosis of Alzheimer disease or dementia over a follow-up period of at least 10 years.

    Meaning  Clinicians must carefully weigh the long-term risks and benefits of exposure to androgen deprivation therapy in patients with a prolonged life expectancy and stratify patients by dementia risk prior to androgen deprivation therapy initiation.

    Abstract

    Importance  The association between androgen deprivation therapy (ADT) exposure and dementia is uncertain.

    Objective  To analyze the association between ADT exposure and diagnosis of Alzheimer disease or dementia among elderly men with prostate cancer.

    Design, Setting, and Participants  This retrospective cohort study used data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results–Medicare linked database. Participants were 154 089 elderly men newly diagnosed with prostate cancer between 1996 and 2003. The analyses were conducted between November 1, 2018, and December 31, 2018.

    Exposure  Androgen deprivation therapy.

    Main Outcomes and Measures  Patients receiving ADT within 2 years of prostate cancer diagnosis were identified. Survival analysis was used to determine the association between ADT exposure and diagnosis of Alzheimer disease or dementia in the follow-up period. Propensity score and instrumental variable approaches were used to minimize measured and unmeasured selection bias. The association by dose of ADT was also examined.

    Results  Of the 295 733 men diagnosed with prostate cancer between 1996 and 2003, 154 089 met the study criteria. Of these, 62 330 (mean [SD] age, 76.0 [6.0] years) received ADT within 2 years of prostate cancer diagnosis, and 91 759 (mean [SD] age, 74.3 [6.0] years) did not receive ADT. Mean (SD) follow-up was 8.3 (4.7) years. Exposure to ADT, compared with no ADT exposure, was associated with a diagnosis of Alzheimer disease (13.1% vs 9.4%; difference, 3.7%; 95% CI, 3.3%-3.9%; P < .001; hazard ratio [HR], 1.14; 95% CI, 1.10-1.18) and dementia (21.6% vs 15.8%; difference, 5.8%; 95% CI, 5.4%-6.2%; P < .001; HR, 1.20; 95% CI, 1.17-1.24). For 1 to 4 doses of ADT, the HR was 1.19 (95% CI, 1.15-1.24) for Alzheimer disease and 1.19 (95% CI, 1.15-1.23) for dementia. For 5 to 8 doses of ADT, the HR was 1.28 (95% CI, 1.22-1.35) for Alzheimer disease and 1.24 (95% CI, 1.19-1.29) for dementia. For more than 8 doses of ADT, the HR was 1.24 (95% CI, 1.16-1.34) for Alzheimer disease and 1.21 (95% CI, 1.15-1.28) for dementia. The number needed to harm was 18 patients (95% CI, 17-19 patients) and 10 patients (95% CI, 9.5-11 patients) for Alzheimer disease and dementia, respectively.

    Conclusions and Relevance  Among elderly patients with prostate cancer, ADT exposure was associated with subsequent diagnosis of Alzheimer disease or dementia over a follow-up period of at least 10 years.

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