Collaborative Review - Prostate Cancer Androgen Deprivation Therapy for the Treatment of Prostate Cancer: Consider Both Benefits and Risks

Context: Androgen deprivation therapy (ADT) is increasingly used for the treatment of prostate cancer (PCa), even in clinical settings in which there is no evidence-based proof of prolonged overall survival (OS). ADT, however, may be associated with numerous side effects, including an increased therapy-related cardiovascular mortality. Objective: To discuss different clinical settings in which ADT is currently used and to critically weigh the benefits of ADT against its possible side effects. Evidence acquisition: A MEDLINE search was conducted to identify original articles and review articles addressing the efficacy and side effects of ADT for the treatment of PCa. Keywords consisted of prostate cancer, hormonal therapy, adverse effects, radical prostatectomy, and radiotherapy. The articles with the highest level of evidence for the various examined end points were identified with the consensus of all authors and were reviewed. Evidence synthesis: Even short-term use of ADT may lead to numerous side effects, such as osteoporosis, obesity, sarcopenia, lipid alterations, insulin resistance, and increased risk for diabetes and cardiovascular morbidity. Despite these side effects, ADT is commonly used in various clinical settings in which a clear effect on improved OS has not been shown. Conclusions: ADT is associated with an increased risk of multiple side effects that may reduce quality of life and/or OS. Consequently, these issues should be discussed in detail with patients and their families before initiation of ADT. ADT should be used with knowledge of its potential long-term side effects and with possible lifestyle interventions, especially in settings with the highest risk–benefit ratio, to alleviate comorbidities.

[1]  B. Steen,et al.  Body composition and aging. , 2009, Nutrition reviews.

[2]  A. Heidenreich Management of advanced prostate cancer: gonadotropin-releasing hormone blockers might improve prognosis. , 2008, European urology.

[3]  H. Sandler,et al.  Cardiovascular mortality and duration of androgen deprivation for locally advanced prostate cancer: analysis of RTOG 92-02. , 2008, European urology.

[4]  S. Basaria Androgen deprivation therapy, insulin resistance, and cardiovascular mortality: an inconvenient truth. , 2008, Journal of andrology.

[5]  F. Burkhard,et al.  Good outcome for patients with few lymph node metastases after radical retropubic prostatectomy. , 2008, European urology.

[6]  Matthew R. Smith Osteoclast targeted therapy for prostate cancer: bisphosphonates and beyond. , 2008, Urologic oncology.

[7]  D. Grignon,et al.  Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  A. Zietman,et al.  Metabolic changes during gonadotropin‐releasing hormone agonist therapy for prostate cancer , 2008, Cancer.

[9]  E. Klein,et al.  Androgen deprivation falls as orchiectomy rates rise after changes in reimbursement in the U.S. Medicare population , 2008, Cancer.

[10]  S. Boorjian,et al.  Timing of androgen deprivation therapy and its impact on survival after radical prostatectomy: a matched cohort study. , 2008, The Journal of urology.

[11]  L. Collette,et al.  Using PSA to guide timing of androgen deprivation in patients with T0-4 N0-2 M0 prostate cancer not suitable for local curative treatment (EORTC 30891). , 2008, European urology.

[12]  P. Ebeling Clinical practice. Osteoporosis in men. , 1999, The New England journal of medicine.

[13]  D. Nathan,et al.  Adipocytokines, obesity, and insulin resistance during combined androgen blockade for prostate cancer. , 2008, Urology.

[14]  D. Grignon,et al.  Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  Eduardo Orihuela,et al.  Characteristics of urologists predict the use of androgen deprivation therapy for prostate cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  M. Roach Regarding the influence of adjuvant suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarction: how real is the risk? , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  A. D'Amico,et al.  Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. , 2007, Journal of the National Cancer Institute.

[18]  N. Mottet,et al.  The role of intermittent androgen deprivation in prostate cancer , 2007, BJU international.

[19]  M. Schonlau,et al.  Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer , 2007, Cancer.

[20]  E. Bergstralh,et al.  Long-term outcome after radical prostatectomy for patients with lymph node positive prostate cancer in the prostate specific antigen era. , 2007, The Journal of urology.

[21]  A. D'Amico,et al.  Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  Matthew R. Smith Androgen deprivation therapy for prostate cancer: new concepts and concerns , 2007, Current opinion in endocrinology, diabetes, and obesity.

[23]  A. D'Amico,et al.  Guideline for the management of clinically localized prostate cancer: 2007 update. , 2007, The Journal of urology.

[24]  A. Partin,et al.  Death in patients with recurrent prostate cancer after radical prostatectomy: prostate-specific antigen doubling time subgroups and their associated contributions to all-cause mortality. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  J. Nelson,et al.  Effect of Once-Weekly Oral Alendronate on Bone Loss in Men Receiving Androgen Deprivation Therapy for Prostate Cancer , 2007, Annals of Internal Medicine.

[26]  P. Kantoff,et al.  Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  M. Wirth,et al.  Bicalutamide (Casodex) 150 mg plus standard care in early non-metastatic prostate cancer: results from Early Prostate Cancer Trial 24 at a median 7 years' follow-up , 2007, Prostate Cancer and Prostatic Diseases.

[28]  E. Ferrannini,et al.  Metabolic syndrome: a solution in search of a problem. , 2007, The Journal of clinical endocrinology and metabolism.

[29]  U. Tunn The current status of intermittent androgen deprivation (IAD) therapy for prostate cancer: putting IAD under the spotlight , 2007, BJU international.

[30]  E. Walker-Corkery,et al.  The rising prevalence of androgen deprivation among older American men since the advent of prostate‐specific antigen testing: a population‐based cohort study , 2006, BJU international.

[31]  T. Wilt,et al.  Neo-adjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer. , 2006, The Cochrane database of systematic reviews.

[32]  N. Keating,et al.  Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  T. Tammela,et al.  Tolerability, efficacy and pharmacokinetics of bicalutamide 300 mg, 450 mg or 600 mg as monotherapy for patients with locally advanced or metastatic prostate cancer, compared with castration , 2006, BJU international.

[34]  A. Dobs,et al.  Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  Jorge Yao,et al.  Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. , 2006, The Lancet. Oncology.

[36]  N. Spry,et al.  Adverse effects to quality of life arising from treatment can recover with intermittent androgen suppression in men with prostate cancer. , 2006, European journal of cancer.

[37]  A. Meyer,et al.  Long-term results of interstitial brachytherapy (LDR-Brachytherapy) in the treatment of patients with prostate cancer , 2006, World Journal of Urology.

[38]  L. Collette,et al.  Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  D. Nathan,et al.  Insulin sensitivity during combined androgen blockade for prostate cancer. , 2006, The Journal of clinical endocrinology and metabolism.

[40]  H. Akaza Trends in primary androgen depletion therapy for patients with localized and locally advanced prostate cancer: Japanese perspective , 2006, Cancer science.

[41]  A. Dobs,et al.  Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen‐deprivation therapy , 2006, Cancer.

[42]  C. Pashos,et al.  Gonadotropin-releasing hormone agonists and fracture risk: a claims-based cohort study of men with nonmetastatic prostate cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  J. Finkelstein,et al.  Changes in bone mineral density and body composition during initial and long‐term gonadotropin‐releasing hormone agonist treatment for prostate carcinoma , 2005, Cancer.

[44]  J. Wolff,et al.  Intermittent Androgen Castration: A Biological Reality during Intermittent Treatment in Metastatic Prostate Cancer? , 2005, Urologia Internationalis.

[45]  Richard Kahn,et al.  The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. , 2005, Diabetes care.

[46]  D. Grignon,et al.  Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31. , 2005, International journal of radiation oncology, biology, physics.

[47]  D. Beyer,et al.  Impact of short course hormonal therapy on overall and cancer specific survival after permanent prostate brachytherapy. , 2005, International journal of radiation oncology, biology, physics.

[48]  J. Goodwin,et al.  Risk of fracture after androgen deprivation for prostate cancer. , 2005, The New England journal of medicine.

[49]  C. Tangen,et al.  Bone mineral density in patients with prostate cancer without bone metastases treated with intermittent androgen suppression. , 2004, Urology.

[50]  R. Portin,et al.  Associations between Serum Testosterone Fall and Cognitive Function in Prostate Cancer Patients , 2004, Clinical Cancer Research.

[51]  M. Wirth,et al.  Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at median followup of 5.4 years. , 2004, The Journal of urology.

[52]  Matthew R. Smith Osteoporosis and obesity in men receiving hormone therapy for prostate cancer. , 2004, The Journal of urology.

[53]  T. Tammela,et al.  Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6. , 2004, The Journal of urology.

[54]  R. Martins,et al.  One year follow-up study of the association between chemical castration, sex hormones, beta-amyloid, memory and depression in men , 2004, Psychoneuroendocrinology.

[55]  J. Manola,et al.  6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. , 2004, JAMA.

[56]  L. Niskanen,et al.  Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. , 2004, Diabetes care.

[57]  Matthew R. Smith Changes in fat and lean body mass during androgen-deprivation therapy for prostate cancer. , 2004, Urology.

[58]  M. Cooperberg,et al.  The contemporary management of prostate cancer in the United States: lessons from the cancer of the prostate strategic urologic research endeavor (CapSURE), a national disease registry. , 2004, The Journal of urology.

[59]  T. Mate,et al.  Long-term outcome by risk factors using conformal high-dose-rate brachytherapy (HDR-BT) boost with or without neoadjuvant androgen suppression for localized prostate cancer. , 2004, International journal of radiation oncology, biology, physics.

[60]  Jose A Gonzalez,et al.  No apparent benefit at 5 years from a course of neoadjuvant/concurrent androgen deprivation for patients with prostate cancer treated with a high total radiation dose. , 2003, The Journal of urology.

[61]  C. Higano,et al.  The effects of combined androgen blockade on cognitive function during the first cycle of intermittent androgen suppression in patients with prostate cancer. , 2003, The Journal of urology.

[62]  M. Cooperberg,et al.  National practice patterns and time trends in androgen ablation for localized prostate cancer. , 2003, Journal of the National Cancer Institute.

[63]  J. Eastham,et al.  Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. , 2003, The Journal of urology.

[64]  K. Wallner,et al.  Permanent interstitial brachytherapy for the management of carcinoma of the prostate gland. , 2003, The Journal of urology.

[65]  C. Bulpitt,et al.  Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia , 2003 .

[66]  W. Lee,et al.  The role of androgen deprivation therapy combined with prostate brachytherapy. , 2002, Urology.

[67]  L. Klotz,et al.  Critical evaluation of hormonal therapy for carcinoma of the prostate. , 2002, Urology.

[68]  Jacques Bernier,et al.  Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial , 2002, The Lancet.

[69]  S. Cerutti,et al.  Changes in bone mineral density, lean body mass and fat content as measured by dual energy x-ray absorptiometry in patients with prostate cancer without apparent bone metastases given androgen deprivation therapy. , 2002, The Journal of urology.

[70]  Anthony L Zietman,et al.  Changes in body composition during androgen deprivation therapy for prostate cancer. , 2002, The Journal of clinical endocrinology and metabolism.

[71]  P. Kantoff,et al.  Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. , 2001, The New England journal of medicine.

[72]  P. de Souza,et al.  The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade , 2001, Cancer.

[73]  M. Parmar,et al.  The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer. , 2001, The Journal of clinical endocrinology and metabolism.

[74]  M Bolla,et al.  EAU guidelines on prostate cancer. , 2001, European urology.

[75]  L. Fried,et al.  Frailty in older adults: evidence for a phenotype. , 2001, The journals of gerontology. Series A, Biological sciences and medical sciences.

[76]  C. Tso,et al.  Androgen deprivation induces selective outgrowth of aggressive hormone-refractory prostate cancer clones expressing distinct cellular and molecular properties not present in parental androgen-dependent cancer cells. , 2000, Cancer journal.

[77]  J. Mckinlay,et al.  Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. , 2000, Diabetes care.

[78]  J. Manola,et al.  Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. , 1999, The New England journal of medicine.

[79]  A W Partin,et al.  Natural history of progression after PSA elevation following radical prostatectomy. , 1999, JAMA.

[80]  J. Sibilia,et al.  Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma. , 1999, The Journal of urology.

[81]  T. Diamond,et al.  The effect of combined androgen blockade on bone turnover and bone mineral densities in men treated for prostate carcinoma , 1998, Cancer.

[82]  M. Laakso,et al.  Hyperinsulinemia predicts coronary heart disease risk in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. , 1998, Circulation.

[83]  T. Tammela,et al.  A Randomised Comparison of ‘Casodex’TM (Bicalutamide) 150 mg Monotherapy versus Castration in the Treatment of Metastatic and Locally Advanced Prostate Cancer , 1998, European Urology.

[84]  R. A. Jones,et al.  Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. The Medical Research Council Prostate Cancer Working Party Investigators Group. , 1997, British journal of urology.

[85]  G. Dagenais,et al.  Hyperinsulinemia as an independent risk factor for ischemic heart disease. , 1996, The New England journal of medicine.

[86]  P. Urdal,et al.  Effects of the luteinizing hormone-releasing hormone agonist leuprolide on lipoproteins, fibrinogen and plasminogen activator inhibitor in patients with benign prostatic hyperplasia. , 1995, The Journal of urology.

[87]  W. Catalona,et al.  Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. , 1993, JAMA.

[88]  D. Heber,et al.  Nutritional and metabolic effects of gonadotropin-releasing hormone agonist treatment for prostate cancer. , 1990, Metabolism: clinical and experimental.

[89]  C. Huggins Endocrine-induced regression of cancers. , 1967, American journal of surgery.

[90]  C. Huggins,et al.  STUDIES ON PROSTATIC CANCER: II. THE EFFECTS OF CASTRATION ON ADVANCED CARCINOMA OF THE PROSTATE GLAND , 1941 .

[91]  C. Huggins,et al.  Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate , 1941, CA: a cancer journal for clinicians.

[92]  N. Unwin,et al.  Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Detection, Evaluation, and Treatment of High Blood Cholesterol Education Program (NCEP) Expert Panel on Executive Summary of the Third Report of the National , 2009 .

[93]  B. Wilson,et al.  Androgen induces adaptation to oxidative stress in prostate cancer: implications for treatment with radiation therapy. , 2007, Neoplasia.

[94]  M. Duh,et al.  Risk of clinical fractures after gonadotropin-releasing hormone agonist therapy for prostate cancer. , 2006, The Journal of urology.

[95]  D. Kirk Timing and choice of androgen ablation , 2004, Prostate Cancer and Prostatic Diseases.

[96]  D. Ferguson,et al.  Progressive osteoporosis during androgen deprivation therapy for prostate cancer. , 2000, The Journal of urology.

[97]  O. Johnell,et al.  Long-Term Risk of Osteoporotic Fracture in Malmö , 2000, Osteoporosis International.

[98]  J. Kaufman,et al.  Testosterone, body composition and aging. , 1999, Journal of endocrinological investigation.

[99]  E. Seeman,et al.  Osteoporosis in Men , 1999, Osteoporosis International.