Combination of Hormone Therapy and Radiotherapy in Treatment of Locally Advanced Prostate Cancer—Recent Developments and Update

Oncology & Hematology Review, 2014;10(1):48–53

Abstract:

Prostate cancer is the sixth leading cause of cancer death among men worldwide. Risk stratification is used to facilitate the selection of optimal treatment approach; however, there is a lack of consensus in the prostate cancer risk-stratification systems. Furthermore, the term ‘locally advanced’ is often misused with high-risk disease. This poses problems when interpreting clinical trials and evaluating treatment outcomes. As a result the patients studied in clinical trials represent a heterogeneous population. The current standard care for locally advanced prostate cancer is a combination of radiotherapy (RT) and androgen deprivation therapy (ADT) and this is supported by several large randomized clinical trials. Long-term ADT is recommended but the optimal duration remains to be better defined. The use of newer and more potent hormonal agents appears to be promising, at least in the setting of metastatic castration-resistant disease, but their role in locally advanced disease remains undefined. This article will summarize the available literature concerning the recent development of hormone therapy in reference to locally advanced prostate cancer. As for the future, individualization of treatment and personalized cancer care is the trend. The availability and the use of improved cellular and/or molecular markers to better risk stratify prostate cancer patients will allow us to select the most effective therapy to enhance the overall outcome.

Keywords: Prostate cancer, locally advanced, radiotherapy, hormone therapy, androgen deprivation therapy, risk stratification, androgen receptor inhibitors, androgen synthesis inhibitors, degarelix, abiraterone acetate, enzalutamide, orteronel
Disclosure: The authors have no conflicts of interests to declare.
Received: February 03, 2014 Accepted March 10, 2014 Citation Oncology & Hematology Review, 2014;10(1):48–53
Correspondence: Padraig Warde, MB, MRCPI, FRCPC, Radiation Medicine Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario, M5G 2M, Canada. E: padraig.warde@rmp.uhn.on.ca

An erratum to this article can be found below.

Prostate cancer is the second most common cause of cancer and the sixth leading cause of cancer death among men worldwide with an estimated 899,000 new cases and 258,000 new deaths in 2008.1 Risk-stratification systems are used to assist with treatment selection, ensuring prognostic uniformity in clinical trials, and in the evaluation of treatment outcomes. Based on work by D’Amico et al.,2 the Genitourinary Radiation Oncologists of Canada (GUROC) developed a classification system for patients with localized/locally advanced disease based on T category, prostate specific antigen (PSA) level at diagnosis, and Gleason score.3 High-risk disease is defined as the presence of any of these factors: cT3 or cT4 category, PSA >20 ng/ml, or Gleason score >8. The exact definition of high-risk prostate cancer at diagnosis remains controversial and this lack of consensus remains a barrier to comparing clinical outcomes of various institutional series and results of clinical trials. Table 1 provides a summary of definitions of high-risk disease from different consensus groups.2–6 The term ‘high-risk disease’ is often incorrectly used to describe patients with locally advanced disease. As a result, the patients studied in clinical trials of high-risk prostate cancer represents a heterogeneous group, including those with clinically organ-confined disease (cT1/T2) with Gleason score 8–10 and/or PSA >20 ng/ml, and those with locally advanced disease (cT3/T4). The proportion of patients presenting with locally advanced disease at diagnosis has decreased in the past 20 years, largely as a result of widespread PSA screening; however, this presentation remains a common clinical problem and management remains controversial. Since the discovery of hormone dependence of prostate cancer by Dr Huggins in 1941, hormone therapy has become the mainstay of treatment in metastatic prostate cancer.7 Hormone therapy now has an increasingly important role in earlier stages of prostate cancer and is the standard of care in locally advanced disease when used in combination with radiotherapy (RT). Over the past few years multiple new hormonal agents have become available to treat men with metastatic castration-resistant prostate cancer (mCRPC). In this review, we will focus on the possible role of these agents in clinical locally advanced prostate cancer (cT3/T4).

Current Standard of Care for Patients with Locally Advanced Disease
The current standard treatment for men who present with locally advanced prostate cancer is radiotherapy with concurrent and adjuvant androgen deprivation therapy (ADT). This is based on the result from a number of major clinical trials conducted over the last 20 years. Several large randomized clinical trials demonstrated ADT combined with radical RT is associated with significant benefits in local disease control, development of metastasis, disease-free survival (DFS), and overall survival (OS).

Addition of Androgen Deprivation Therapy to Radiotherapy is Beneficial
In the landmark European Organization for Research and Treatment of Cancer (EORTC) 22863 trial, 415 patients were randomized to RT alone (50 Gy to the whole pelvis with an additional 20 Gy to the prostate and seminal vesicle), or RT with androgen suppression (3 years of goserelin). Most patients (91 %) had locally advanced disease (cT3/T4).8,9 With a median follow up of 9.1 years, the 10-year OS rate was 39.8 % in patients treated with RT alone and 58.1 % in those receiving combined modality therapy (hazard ratio [HR] 0.60; p=0.0004). The 10-year DFS was 22.7 % and 47.7 %, respectively (HR 0.42; p<0.0001). The 10-year prostate cancer mortality rate was significantly reduced from 30.4 % to 10.3 % with the addition of ADT to RT (HR 0.38; p<0.0001).10 Similar results were seen in the Radiation Therapy Oncology Group (RTOG) 85- 31 trial in which patients were randomized to either RT and lifelong ADT or RT alone. With median follow up of 7.6 years, the 10-year OS, disease specific survival (DSS), local failure, distant metastases, all favored the combination therapy arm.11

The Optimal Duration of Androgen Deprivation Therapy
Long-term ADT of 2–3 years is the current standard of care in patients with locally advanced disease; however, the optimal duration of ADT remains to be defined. The EORTC 22961 trial, using a non-inferiority design, compared RT with either short- (6 months) or long-term (3 years) ADT in patients with locally advanced disease. With median follow up of 6.4 years, this trial showed an inferior OS with the use of short-term ADT.12 The RTOG 9202 trial randomized patients with locally advanced prostate to either long-term (28 months) or shortterm (4 months) ADT with radiation therapy. Long-term ADT led to improvement in DFS and on subgroup analysis an OS benefit was observed in men with Gleason score of 8–10 (31.9 % versus 45.1 %; p=0.0061).13,14 A recent American Society of Clinical Oncology (ASCO) abstract from Nabid et al., presented the results of a randomized trial that compared intermediate-term ADT (18 months) to long-term ADT (36 months), and found no difference in 5-year OS and DSS between the two approaches.15 The authors suggested that long-term ADT could be ‘safely’ reduced to intermediate-term ADT without compromise of outcome. However, the result of this study should be interpreted with caution as this study was designed as a superiority trial and not powered sufficiently as a non-inferiority trial. A current phase III randomized trial by the Tran-Tasman Radiation Oncology Group TROG 03-04 (RADAR) trial investigating short-term ADT of 6 months versus intermediate term ADT of 18 months. This trial has closed to accrual and results are awaited.16

Radiotherapy is an Essential Part in Management of Locally Advanced Prostate Cancer
Three large phase III trials have shown that RT treatment in addition to ADT improves outcome, including OS, in locally advanced prostate cancer (see Table 2). In the National Cancer Institute of Canada (NCIC) PR3/Canadian Urologic Oncology Group (CUOG)/Medical Research Council (MRC) UK PR07 study, 1,205 patients with locally advanced prostate cancer patients were randomized to ADT treatment alone or ADT in combination with RT. Eightyseven percent of the patients had locally advanced (T3/4) disease. With a median follow up of 6 years, the combined modality treatment resulted in a 23 % reduction in overall mortality (HR 0.77; p=0.03) and a 46 % reduction in disease-specific mortality (HR 0.54; p=0.0001)17 (see Figure 1). A recent update presented at the ASCO annual meeting, with median follow up of 8 years showed sustained and significant OS and DSS benefit for the combined ADT and RT group.18

Similar results were seen in the Scandinavian Prostate Cancer Group (SPCG)-7 study in which 875 patients with locally advanced prostate cancer were randomized to hormonal therapy alone (3 months ADT and then anti-androgen therapy until progression or death) or combination of hormonal therapy and RT. Approximately 80 % of patients in this study had locally advanced disease. With a median follow up of 7.6 years, prostate cancer-specific mortality and overall mortality were significantly reduced by the addition of RT to hormonal management. Overall mortality at 10 years was reduced from 39.4 % in the endocrine alone group to 29.6 % in the combined ADT and RT group (relative risk [RR] 0.68; p=0.004).19 A French study by Mottet et al. reported the results of a randomized phase III trial in which 264 patients with locally advanced prostate cancer were randomly assigned to ADT alone for 3 years or ADT combined with RT. With a median follow up of 67 months, a significant difference was found in favor of the combined approach with regards to loco-regional progression (p<0.0001), metastatic progression (p=0.018), and progression-free survival (PFS) (p<0.001). While there was no improvement demonstrated in OS, this is likely due to the fact that follow up was short (median OS was not reached in either group at the time of analysis). In addition the power of the trial to detect a survival difference was limited due to the small sample size.20

References:
  1. Ferlay J, Shin HR, Bray F, et al., Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008, Int J Cancer, 2010;127:2893–917.
  2. D’Amico AV, Whittington R, Malkowicz SB, et al., Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer, JAMA, 1998;280:969–74.
  3. Lukka H, Warde P, Pickles T, et al., Controversies in prostate cancer radiotherapy: consensus development, Can J Urol, 2001;8:1314–22.
  4. Roach M, Lu J, Pilepich MV, et al., Four prognostic groups predict long-term survival from prostate cancer following radiotherapy alone on Radiation Therapy Oncology Group clinical trials, Int J Radiat Oncol Biol Phys, 2000;47:609–15.
  5. Mohler J, Bahnson RR, Boston B, et al., NCCN clinical practice guidelines in oncology: prostate cancer, J Natl Compr Canc Netw, 2010;8:162–200.
  6. Heidenreich A, Bellmunt J, Bolla M, et al., EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease, Eur Urol, 2011;59:61–71.
  7. Huggins C, Hodges CV, Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate, CA Cancer J Clin, 1972;22:232–40.
  8. Bolla M, Gonzalez D, Warde P, et al., Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin, N Engl J Med, 1997;337:295–300.
  9. Bolla M, Collette L, Blank L, 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, Lancet, 2002;360:103–6.
  10. Bolla M, Van Tienhoven G, Warde P, et al., External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study, Lancet Oncol, 2010;11:1066–73.
  11. Pilepich MV, Winter K, Lawton CA, et al., Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--longterm results of phase III RTOG 85-31, Int J Radiat Oncol Biol Phys, 2005;61:1285–90.
  12. Bolla M, de Reijke TM, Van Tienhoven G, et al., Duration of androgen suppression in the treatment of prostate cancer, N Engl J Med, 2009;360:2516–27.
  13. Hanks GE, Pajak TF, Porter A, et al., Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02, J Clin Oncol, 2003;21:3972–8.
  14. Horwitz EM, Bae K, Hanks GE, 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, J Clin Oncol, 2008;26:2497–504.
  15. Nabid A, Carrier N, Martin A, et al., Duration of androgen deprivation therapy in high-risk prostate cancer: A randomized trial, J Clin Oncol, 2013;31:(Suppl. 18; abstr LBA4510).
  16. Trans-Tasman Radiation Oncology Group (TROG). A randomised trial investigating the effect on biochemical (PSA) control and survival of different durations of adjuvant androgen deprivation in association with definitive radiation treatment for localised carcinoma of the prostate. In: ClinicalTrials.gov [Internet]. Bethesda (MD). National Library of Medicine (US). 2000- [cited 2014 Jan 08], Available at: http://clinicaltrials.gov/ct2/show/NCT00193856 NLM Identifier: NCT00193856.
  17. Warde P, Mason M, Ding K, et al., Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial, Lancet, 2011;378:2104–11.
  18. Mason M, Parulekar W, Sydes M, et al., Final analysis of intergroup randomized phase III study of androgen deprivation therapy (ADT) plus radiation therapy (RT) in locally advanced prostate cancer (CaP) (NCIC-CTG, SWOG, MRC-UK, INT: T94-0110), J Clin Oncol, 2012;30:(Suppl. 15; abstr 4509).
  19. Widmark A, Klepp O, Solberg A, et al., Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/ SFUO-3): an open randomised phase III trial, Lancet, 2009;373:301–8.
  20. Mottet N, Peneau M, Mazeron JJ, et al., Addition of radiotherapy to long-term androgen deprivation in locally advanced prostate cancer: an open randomised phase 3 trial, Eur Urol, 2012;62:213–9.
  21. Roach M, 3rd, DeSilvio M, Lawton C, et al., Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413, J Clin Oncol, 2003;21:1904–11.
  22. Lawton CA, DeSilvio M, Roach M, 3rd, et al., An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions, Int J Radiat Oncol Biol Phys, 2007;69:646–55.
  23. Gittelman M, Pommerville PJ, Persson BE, et al., Degarelix Study G. A 1-year, open label, randomized phase II dose finding study of degarelix for the treatment of prostate cancer in North America, J Urol, 2008;180:1986–92.
  24. Van Poppel H, Tombal B, de la Rosette JJ, et al., Degarelix: a novel gonadotropin-releasing hormone (GnRH) receptor blocker-- results from a 1-yr, multicentre, randomised, phase 2 dosagefinding study in the treatment of prostate cancer, Eur Urol, 2008;54:805–13.
  25. Klotz L, Boccon-Gibod L, Shore ND, et al., The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer, BJU Int, 2008;102:1531–8.
  26. Tombal B, Miller K, Boccon-Gibod L, et al., Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics, Eur Urol, 2010;57:836–42.
  27. Mason M, Maldonado Pijoan X, Steidle C, et al., Neoadjuvant androgen deprivation therapy for prostate volume reduction, lower urinary tract symptom relief and quality of life improvement in men with intermediate- to high-risk prostate cancer: a randomised non-inferiority trial of degarelix versus goserelin plus bicalutamide, Clin Oncol (R Coll Radiol), 2013;25:190–6.
  28. Axcrona K, Aaltomaa S, da Silva CM, et al., Androgen deprivation therapy for volume reduction, lower urinary tract symptom relief and quality of life improvement in patients with prostate cancer: degarelix vs goserelin plus bicalutamide, BJU Int, 2012;110:1721–8.
  29. de Bono JS, Logothetis CJ, Molina A, et al., Abiraterone and increased survival in metastatic prostate cancer, N Engl J Med, 2011;364:1995–2005.
  30. Fizazi K, Scher HI, Molina A, et al., Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study, Lancet Oncol, 2012;13:983–92.
  31. Ryan CJ, Smith MR, de Bono JS, et al., Abiraterone in metastatic prostate cancer without previous chemotherapy, N Engl J Med, 2013;368:138–48.
  32. Millennium Pharmaceuticals, Inc. Study comparing orteronel plus prednisone in patients With metastatic castration-resistant prostate cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD). National Library of Medicine (US). 2000- [cited 2014 Jan 08], National Library of Medicine (US). Available from: http:// clinicaltrials.gov/ct2/show/NCT01193257 NLM Identifier: NCT01193257.
  33. Millennium Pharmaceuticals, Inc. Study comparing orteronel plus prednisone in patients With chemotherapy-naive metastatic castration-resistant prostate cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD). National Library of Medicine (US). 2000- [cited 2014 Jan 08], National Library of Medicine (US). Available from: http://clinicaltrials.gov/ct2/show/NCT01193244 NLM Identifier:NCT01193244.
  34. Radiation Therapy Oncology Group Hormone therapy, radiation therapy, and steroid 17alpha-monooxygenase TAK-700 in treating patients with high-risk prostate cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD). National Library of Medicine (US). 2000- [cited 2014 Jan 08], National Library of Medicine (US). Available from: http://clinicaltrials.gov/ct2/show/NCT01546987 NLM Identifier: NCT01546987.
  35. Scher HI, Beer TM, Higano CS, et al., Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study, Lancet, 2010;375:1437–46.
  36. Scher HI, Halabi S, Tannock I, et al., Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group, J Clin Oncol, 2008;26:1148–59.
  37. Scher HI, Fizazi K, Saad F, et al., Increased survival with enzalutamide in prostate cancer after chemotherapy, N Engl J Med, 2012;367:1187–97.
  38. Medivation Inc. A safety and efficacy study of oral MDV3100 in chemotherapy-naive patients with progressive metastatic prostate cancer (PREVAIL). In: ClinicalTrials.gov [Internet]. Bethesda (MD). National Library of Medicine (US). 2000- [cited 2014 Jan 08], National Library of Medicine (US). Available from: http:// clinicaltrials.gov/show/NCT01212991 NLM Identifier: NCT01212991.
  39. Thomas Jefferson University Enzalutamide, radiation therapy and hormone therapy in treating patients with intermediate or highrisk prostate cancer. 2000- [cited 2014 Jan 08], National Library of Medicine (US). Available from: http://clinicaltrials.gov/ct2/show/ NCT02023463 NLM Identifier:NCT02023463.
  40. Isbarn H, Boccon-Gibod L, Carroll PR, et al., Androgen deprivation therapy for the treatment of prostate cancer: consider both benefits and risks, Eur Urol, 2009;55:62–75.
  41. Ahmadi H, Daneshmand S, Androgen deprivation therapy: evidencebased management of side effects, BJU Int, 2013;111:543–8.
  42. Sharifi N, Gulley JL, Dahut WL, Androgen deprivation therapy for prostate cancer, JAMA, 2005;294:238–44.
  43. Smith MR, Boyce SP, Moyneur E, et al., Risk of clinical fractures after gonadotropin-releasing hormone agonist therapy for prostate cancer, J Urol, 2006;175:136–9; discussion 9.
  44. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS, Risk of fracture after androgen deprivation for prostate cancer, N Engl J Med, 2005;352:154–64.
  45. Oefelein MG, Ricchuiti V, Conrad W, et al., Skeletal fracture associated with androgen suppression induced osteoporosis: the clinical incidence and risk factors for patients with prostate cancer, J Urol, 2001;166:1724–8.
  46. Datta M, Schwartz GG, Calcium and vitamin D supplementation during androgen deprivation therapy for prostate cancer: a critical review, Oncologist, 2012;17:1171–9.
  47. Smith MR, McGovern FJ, Zietman AL, et al., Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer, N Engl J Med, 2001;345:948–55.
  48. Smith MR, Eastham J, Gleason DM, et al., Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer, J Urol, 2003;169:2008–12.
  49. Klotz LH, McNeill IY, Kebabdjian M, et al.; Canadian Urology Research C, A phase 3, double-blind, randomised, parallel-group, placebocontrolled study of oral weekly alendronate for the prevention of androgen deprivation bone loss in nonmetastatic prostate cancer: the Cancer and Osteoporosis Research with Alendronate and Leuprolide (CORAL) study, Eur Urol, 2013;63:927–35.
  50. Choo R, Lukka H, Cheung P, et al., Randomized, double-blinded, placebo-controlled, trial of risedronate for the prevention of bone mineral density loss in nonmetastatic prostate cancer patients receiving radiation therapy plus androgen deprivation therapy, Int J Radiat Oncol Biol Phys, 2013;85:1239–45.
  51. Smith MR, Egerdie B, Hernandez Toriz N, et al., Denosumab in men receiving androgen-deprivation therapy for prostate cancer, N Engl J Med, 2009;361:745–55.
  52. Smith MR, Saad F, Egerdie B, et al., Effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer, J Urol, 2009;182:2670–5.
  53. Keating NL, O’Malley AJ, Smith MR, Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer, J Clin Oncol, 2006;24:4448–56.
  54. Saigal CS, Gore JL, Krupski TL, et al., Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer, Cancer, 2007;110:1493–500.
  55. Efstathiou JA, Bae K, Shipley WU, et al., Cardiovascular mortality and duration of androgen deprivation for locally advanced prostate cancer: analysis of RTOG 92-02, Eur Urol, 2008;54:816–23.
  56. Efstathiou JA, Bae K, Shipley WU, et al., Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31, J Clin Oncol, 2009;27:92–9.
  57. Roach M, 3rd, Bae K, Speight J, et al., Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610, J Clin Oncol, 2008;26:585–91.
  58. Studer UE, Whelan P, Albrecht W, 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, J Clin Oncol, 2006;24:1868–76.
  59. Nguyen PL, Je Y, Schutz FA, et al., Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials, JAMA, 2011;306:2359–66.
  60. Braga-Basaria M, Dobs AS, Muller DC, et al., Metabolic syndrome in men with prostate cancer undergoing long-term androgendeprivation therapy, J Clin Oncol, 2006;24:3979–83.
  61. Smith MR, Lee H, McGovern F, et al., Metabolic changes during gonadotropin-releasing hormone agonist therapy for prostate cancer: differences from the classic metabolic syndrome, Cancer, 2008;112:2188–94.
  62. Dockery F, Bulpitt CJ, Agarwal S, Donaldson M, Rajkumar C. Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia, Clin Sci (Lond), 2003;104:195–201.
  63. Smith MR, Finkelstein JS, McGovern FJ, et al., Changes in body composition during androgen deprivation therapy for prostate cancer, J Clin Endocrinol Metab, 2002;87:599–603.
  64. Galvao DA, Spry NA, Taaffe DR, et al., Changes in muscle, fat and bone mass after 36 weeks of maximal androgen blockade for prostate cancer, BJU Int, 2008;102:44–7.
  65. Smith MR, Changes in fat and lean body mass during androgendeprivation therapy for prostate cancer, Urology, 2004;63:742–5.
  66. Gardner JR, Livingston PM, Fraser SF, Effects of exercise on treatment-related adverse effects for patients with prostate cancer receiving androgen-deprivation therapy: a systematic review, J Clin Oncol, 2014;32:335–46.
Keywords: Prostate cancer, locally advanced, radiotherapy, hormone therapy, androgen deprivation therapy, risk stratification, androgen receptor inhibitors, androgen synthesis inhibitors, degarelix, abiraterone acetate, enzalutamide, orteronel