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androgen deprivation therapy (ADT)

Pharmacologic therapy to diminish circulating levels of androgen, in particular plasma testosterone, through use of: 1) androgen angonists 2) GnRH analogs Indications: - treatment of androgen-sensitive prostate cancer Dosage: - intermittent androgen deprivation (8 months on treatment, repeated when the PSA reached 10 ng/mL after a hiatus of at least 2 months) as effective as continuous therapy (with either drugs or orchiectomy) [5] Monitor: - bone mineral density with Dexa scan annually [8] Adverse effects: - increased risk of diabetes mellitus type 2 [3] - can worsen glycemic control in patients with diabetes mellitus type 2 [8] - impact on cardiovascular disease controversial [8] - increased risk of cardiovascular disease [1] - no increased risk of cardiovascular mortality [4] - can unfavorable alter lipid panels [8] - decline in physical function [2] - sarcopenia [6] - cognitive impairment [14] - a single-nucleotide polymorphism, rs1047776 in GNB3, seems to accelerate cognitive impairment [14] - increased risk of new onset dementia (RR=2.3), 7.9% vs 3.5% within 5 years [17]; 22% vs 16% in 8 years [21] - may increase risk of Alzheimer's disease, 13% vs 9% in 8 years [21] - excess risk for acute kidney injury [7] - osteoporosis [8] - increased risk for venous thromboembolism [12] - gynecomastia - hot flushes - anemia [8] Complications: - loss of NCOR2 expression may accelerate resistance to androgen deprivation therapy in prostate cancer [22] - osteoporotic fracture [19] Management: - prevention & treatment of osteoporosis [8] - calcium & vitamin D supplementation [8] - bisphosphonate therapy [8,10] - not indicated in the absence of bone metastases [8] ? - presumptively indicated if Dexa bone mineral density shows osteoporosis [8] - increases bone mineral density at lumbar spine, femoral neck, & total spine [18] - may reduce osteoporosis, fractures - no trials have been powered to detect a decrease in fractures [18] - does not increase survival, slow disease progression, improve quality of life, diminish pain [12] - denosumab reduced radiographic vertebral fractures in one study [18] - raloxifene increases bone mineral density at the hip & femoral neck [11] - exercise of no benefit in improving bone mineral density [18] - docetaxel with androgen-deprivation therapy results in longer survival in men with metastatic prostate cancer [13]

Related

androgen insufficiency (hypoandrogenism, testosterone deficiency) androgen or anabolic steroid androgen receptor antagonist; androgen receptor signaling inhibitor (ARSI)

General

hormonal therapy

References

  1. Levine GN et al Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology CA Cancer J Clin. 2010 May-Jun;60(3):194-201 PMID: 20124400 - Levine GN et al Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. Circulation. 2010 Feb 16;121(6):833-40. PMID: 20124128
  2. Alibhai SMH et al. Impact of androgen-deprivation therapy on physical function and quality of life in men with nonmetastatic prostate cancer. J Clin Oncol 2010 Dec 1; 28:5038. PMID: 21041715
  3. FDA MedWatch, 10/20/2010 GnRH Agonists: Label Change - Increased Risk of Diabetes and Cardiovascular Disease (Update) http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm230359.htm
  4. Nguyen PL et al Association of Androgen Deprivation Therapy With Cardiovascular Death in Patients With Prostate Cancer: A Meta-analysis of Randomized Trials JAMA. 2011;306(21):2359-2366 PMID: 22147380 http://jama.ama-assn.org/content/306/21/2359.short - Kelly WK and Gomella LG Androgen Deprivation Therapy and Competing Risks JAMA. 2011;306(21):2382-2383 PMID: 22147384 http://jama.ama-assn.org/content/306/21/2382.short
  5. Crook JM et al Intermittent Androgen Suppression for Rising PSA Level after Radiotherapy N Engl J Med 2012; 367:895-903September 6, 2012 PMID: 22931259 http://www.nejm.org/doi/full/10.1056/NEJMoa1201546 - Sartor O. Androgen deprivation -- continuous, intermittent, or none at all? N Engl J Med 2012 Sep 6; 367:945 PMID: 22931264
  6. Smith MR et al. Sarcopenia during androgen-deprivation therapy for prostate cancer. J Clin Oncol 2012 Sep 10; 30:3271 PMID: 22649143
  7. Lapi F et al. Androgen deprivation therapy and risk of acute kidney injury in patients with prostate cancer. JAMA 2013 Jul 17; 310:289 PMID: 23860987 http://jama.jamanetwork.com/article.aspx?articleid=1713592
  8. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013 - Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016 - Geriatric Review Syllabus, 10th edition (GRS10) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2019
  9. Mohile SG, Mustian K, Bylow K, Hall W, Dale W. Management of complications of androgen deprivation therapy in the older man. Crit Rev Oncol Hematol. 2009 Jun;70(3):235-55. Review. PMID: 18952456
  10. Ito K et al, Cost-Effectiveness of Fracture Prevention in Men Who Receive Androgen Deprivation Therapy for Localized Prostate Cancer Annals of Internal Medicine 2010, 152:621, May 18, 2010 PMID: 20479027 http://www.annals.org/content/152/10/621.abstract
  11. Smith MR, Fallon MA, Lee H, Finkelstein JS. Raloxifene to prevent gonadotropin-releasing hormone agonist- induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab. 2004 Aug;89(8):3841-6. PMID: 15292315
  12. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15 16, 18. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2018. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  13. NIH: News & Events. Dec 5, 2013 NIH-funded study shows increased survival in men with metastatic prostate cancer who receive chemotherapy when starting hormone therapy. http://www.nih.gov/news/health/dec2013/nci-05.htm
  14. Castellino AM Cognitive Impairment Linked to Androgen Deprivation Therapy. Medscape Oncology. May 14, 2015 http://www.medscape.com/viewarticle/844690 - Gonzalez BD et al Course and Predictors of Cognitive Function in Patients With Prostate Cancer Receiving Androgen-Deprivation Therapy: A Controlled Comparison. American Society of Clinical Oncology. May 11, 2015
  15. Lu-Yao GL; Albertsen PC; Moore DF et al Fifteen-Year Survival Outcomes Following Primary Androgen- Deprivation Therapy for Localized Prostate Cancer. JAMA Intern Med. Published online July 14, 2014 PMID: 25023796 http://archinte.jamanetwork.com/article.aspx?articleid=1887061 - Trinh QD and Schrag D Measuring the Effectiveness of Androgen-Deprivation Therapy for Prostate Cancer in the Medicare Population. Adequate Data Are Neither the Same as Nor the Enemy of Perfect Data. JAMA Intern Med. Published online July 14, 2014 PMID: 25023522 http://archinte.jamanetwork.com/article.aspx?articleid=1887059
  16. Nead KT et al. Androgen deprivation therapy and future Alzheimer's disease risk. J Clin Oncol 2016 Feb 20; 34:566. PMID: 26644522 Free Article http://jco.ascopubs.org/content/34/6/566 - McGinty HL. Unlocking electronic medical record data to identify possible connections between cancer and cognitive declines. J Clin Oncol 2016 Feb 20; 34:530. PMID: 26712232 Free Article http://jco.ascopubs.org/content/34/6/530
  17. Nead KT, Gaskin G, Chester C Association Between Androgen Deprivation Therapy and Risk of Dementia. JAMA Oncol. Published online October 13, 2016 PMID: 27737437 http://jamanetwork.com/journals/jamaoncology/article-abstract/2569059 - Walsh CG, Johnson KB Observational Cohort Studies and the Challenges of In Silico Experiments. JAMA Oncol. Published online October 13, 2016 PMID: 27737433 http://jamanetwork.com/journals/jamaoncology/article-abstract/2569057
  18. Alibhai SMH, Zukotynski K, Walker-Dilks C et al Bone Health and Bone-Targeted Therapies for Nonmetastatic Prostate Cancer: A Systematic Review and Meta-analysis. Ann Intern Med. Aug 8, 2017. PMID: 28785760 http://annals.org/aim/article/2647668/bone-health-bone-targeted-therapies-nonmetastatic-prostate-cancer-systematic-review - Farooki A, Scher HI Maintaining Bone Health During Hormonal Therapy for Prostate Cancer. Ann Intern Med. Aug 8, 2017. PMID: 28785765 http://annals.org/aim/article/2648591/maintaining-bone-health-during-hormonal-therapy-prostate-cancer
  19. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005 Jan 14; 352:154. PMID: 15647578 Free Article http://www.nejm.org/doi/full/10.1056/NEJMoa041943
  20. Smith MR, Lee WC, Brandman J et al. Gonadotropin-releasing hormone agonists and fracture risk: a claims-based cohort study of men with nonmetastatic prostate cancer. J Clin Oncol 2005 Nov 1; 23:7897 PMID: 162580
  21. Jayadevappa R, Chhatre S, Malkowicz B et al Association Between Androgen Deprivation Therapy Use and Diagnosis of Dementia in Men With Prostate Cancer. JAMA Netw Open. 2019;2(7):e196562. PMID: 31268539 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2737101 - Harding A Long-Term Androgen Deprivation May Boost Alzheimer's, Dementia Risk. Annals of Long-Term Care. DEc 23, 2019 https://www.managedhealthcareconnect.com/content/long-term-androgen-deprivation-may-boost-alzheimers-dementia-risk - Krasnova A, Epstein M, Marchese M et al Risk of dementia following androgen deprivation therapy for treatment of prostate cancer. Prostate Cancer Prostatic Dis Nov 29, 2019 PMID: 31784699 https://www.nature.com/articles/s41391-019-0189-3
  22. Larkin M Loss, Mutation of NCOR2 Likely Fuels Prostate Cancer Progression, Resistance. Medscape. December 23, 2021 https://www.medscape.com/viewarticle/965465 - Long MD, Jacobi JJ, Singh PK et al Reduced NCOR2 expression accelerates androgen deprivation therapy failure in prostate cancer. Cell Reports 2021. 37(11):110109 https://www.sciencedirect.com/science/article/pii/S221112472101603X