Advertisement

Side Effects and Management of ADT for Prostate Cancer

  • Mun Su Chung
  • Seung Hwan Lee
Chapter

Abstract

Androgen deprivation therapy (ADT) is the main treatment for advanced prostate cancer and is increasingly used in combination with radiotherapy in patients with earlier stages of prostate cancer. For many years, gonadotropin-releasing hormone (GnRH) agonists have been the ADT standard of treatment. There are, however, several drawbacks related to the mechanism of action of GnRH agonists. In particular, the initial testosterone surge associated with these agents delays the achievement of castration levels of testosterone and can produce a flare in clinical symptoms in patients with advanced disease [1, 2]. Furthermore, microsurges in testosterone levels occur with repeated agonist administration [3]. In this context, it is interesting to note that increases in testosterone above 1.1 nmol/L (32 ng/dL) during agonist treatment were associated with a significantly shorter survival free of androgen-independent progression than patients who had increases <32 ng/dL [4]. Despite the proven success of hormonal therapy, most patients showing an initial response will eventually experience disease progression [5]. Cancer that relapses after initial ADT is termed androgen-independent or castration-resistant prostate cancer (CRPC) [6]. The precise definition of CPRC is, however, controversial. Recent European Association of Urology guidelines define CRPC as castration levels of testosterone (<1.7 nmol/L [50 ng/dL]) and three consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with a PSA > 2 ng/mL, despite consecutive hormonal manipulations [7]. However, other definitions of progression have been used. Sharifi et al., for example, defined androgen independence as the first sustained increase in PSA level from the PSA nadir after starting ADT [8]. Based on this definition, they found that the median time to androgen independence was 13–19 months after starting ADT, depending on the disease stage at initiation. In patients with metastatic disease, it is estimated that >90% will progress to androgen independence within 18–24 months [9]. As CRPC carries a much poorer prognosis [10] and might signal the need for chemotherapy [11], any delay in the onset of castration resistance is clearly desirable. GnRH antagonists represent an alternative form of ADT, with a direct and immediate action that allows castration without an initial testosterone surge or subsequent microsurges.

References

  1. 1.
    Van Poppel H, Nilsson S. Testosterone surge: rationale for gonadotropin-releasing hormone blockers? Urology. 2008;71(6):1001.CrossRefPubMedGoogle Scholar
  2. 2.
    Thompson IM. Flare associated with LHRH-agonist therapy. Rev Urol. 2001;3(Suppl 3):S10–4.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Tombal B, Berges R. How good do current LHRH agonists control testosterone? Can this be improved with Eligard®? Eur Urol Suppl. 2005;4:30–6.CrossRefGoogle Scholar
  4. 4.
    Morote J, Orsola A, Planas J, et al. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol. 2007;178:1290–5.CrossRefPubMedGoogle Scholar
  5. 5.
    Hotte SJ, Saad F. Current management of castrate-resistant prostate cancer. Curr Oncol. 2010;17(Suppl 2):S72–9.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Chi KN, Bjartell A, Dearnaley D, et al. Castration-resistant prostate cancer: from new pathophysiology to new treatment targets. Eur Urol. 2009;56:594–605.CrossRefPubMedGoogle Scholar
  7. 7.
    Heidenreich A, Bolla M, Joniau S et al.. Guidelines on prostate cancer. 2011. http://www.uroweb.org/gls/pdf/08_Prostate_Cancer.pdf. Accessed 8 Dec 2011.
  8. 8.
    Sharifi N, Dahut WL, Steinberg SM, et al. A retrospective study of the time to clinical endpoints for advanced prostate cancer. BJU Int. 2005;96:985–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Petrylak D. Therapeutic options in androgen-independent prostate cancer: building on docetaxel. BJU Int. 2005;96(Suppl 2):41–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Walczak JR, Carducci MA. Prostate cancer: a practical approach to current management of recurrent disease. Mayo Clin Proc. 2007;82:243–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Mahon KL, Henshall SM, Sutherland RL, et al. Pathways of chemotherapy resistance in castration-resistant prostate cancer. Endocr Relat Cancer. 2011;18:R103–23.CrossRefPubMedGoogle Scholar
  12. 12.
    Wei JT, Gross M, Jaffe CA, Gravlin K, Lahaie M, Faerber GJ, al w. Androgen deprivation therapy for prostate cancer results in significant loss of bone density. Urology. 1999;54:607–11.CrossRefPubMedGoogle Scholar
  13. 13.
    Michaelson MD, Cotter SE, Gargollo PC, Zietman AL, Dahl DM, Smith MR. Management of complications of prostate cancer treatment. CA Cancer J Clin. 2008;58:196–213.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Moyad MA. Complementary/alternative therapies for reducing hot flashes in prostate cancer patients: reevaluating the existing indirect data from studies of breast cancer and postmenopausal women. Urology. 2002;59:20–33.CrossRefPubMedGoogle Scholar
  15. 15.
    Rousseau L, Dupont A, Labrie F, Couture M. Sexuality changes in prostate cancer patients receiving antihormonal therapy combining the antiandrogen flutamide with medical (LHRH agonist) or surgical castration. Arch Sex Behav. 1988;17:87–98.CrossRefPubMedGoogle Scholar
  16. 16.
    Potosky AL, Knopf K, Clegg LX, Albertsen PC, Stanford JL, Hamilton AS, et al. Quality-of-life outcomes after primary androgen deprivation therapy: results from the Prostate Cancer Outcomes Study. J Clin Oncol. 2001;19:3750–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Alibhai SM, Breunis H, Timilshina N, Marzouk S, Stewart D, Tannock I, Naglie G, Tomlinson G, Fleshner N, Krahn M, et al. Impact of androgen-deprivation therapy on cognitive function in men with nonmetastatic prostate cancer. J Clin Oncol. 2010;28:5030–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Joly F, Alibhai SM, Galica J, Park A, Yi QL, Wagner L, Tannock IF. Impact of androgen deprivation therapy on physical and cognitive function, as well as quality of life of patients with nonmetastatic prostate cancer. J Urol. 2006;176:2443–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Nelson CJ, Lee JS, Gamboa MC, Roth AJ. Cognitive effects of hormone therapy in men with prostate cancer: a review. Cancer. 2008;113:1097–106.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Smith MR, Finkelstein JS, McGovern FJ, Zietman AL, Fallon MA, Schoenfeld DA, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab. 2002;87:599–603.CrossRefPubMedGoogle Scholar
  21. 21.
    Traish AM, Zitzmann M. The complex and multifactorial relationship between testosterone deficiency (TD), obesity and vascular disease. Rev Endocr Metab Disord. 2015;16:249–68.CrossRefPubMedGoogle Scholar
  22. 22.
    Ullah MI, Washington T, Kazi M, Tamanna S, Koch CA. Testosterone deficiency as a risk factor for cardiovascular disease. Horm Metab Res. 2011;43:153–64.CrossRefPubMedGoogle Scholar
  23. 23.
    Zamboni M, Mazzali G, Fantin F, Rossi A, Di Francesco V. Sarcopenic obesity: a new category of obesity in the elderly. Nutr Metab Cardiovasc Dis. 2000;18:388–95.CrossRefGoogle Scholar
  24. 24.
    Smith JC, Bennett S, Evans LM, et al. The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer. J Clin Endocrinol Metab. 2001;86:4261–7.CrossRefPubMedGoogle Scholar
  25. 25.
    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 hyperinsulinemia. Clin Sci (London). 2003;104:195–201.CrossRefGoogle Scholar
  26. 26.
    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.CrossRefPubMedGoogle Scholar
  27. 27.
    Hotamisligil GS, Spiegelman BM. Tumor necrosis factor α: a key component of the obesity-diabetes link. Diabetes. 1994;43:1271–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Cutolo M, Sulli A, Capellino S, et al. Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus. 2004;13:635–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Smith RM. Androgen deprivation therapy and risk for diabetes and cardiovascular disease in prostate cancer survivors. Curr Urol Rep. 2008;9:197–202.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Alibhai SM, Duong-Hua M, Sutradhar R, et al. Impact of androgen deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol. 2009;27:3452–8.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Keating NL, O’Malley J, Stephen J, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst. 2010;102:39–46.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Tsai HT, Keating NL, Stephen K, et al. Risk of diabetes among patients receiving primary androgen deprivation therapy for clinically localized prostate cancer. J Urol. 2015;193:1956–62.CrossRefPubMedGoogle Scholar
  33. 33.
    Keating N, Liu P, O’Malley A, Freedland S, Smith M. Androgen-deprivation therapy and diabetes control among diabetic men with prostate cancer. Eur Urol. 2014;65:816–24.CrossRefPubMedGoogle Scholar
  34. 34.
    Morote J, Gomez-Caamano A, Alvarez-Ossorio J, et al. The metabolic syndrome and its components in patients with prostate cancer on androgen deprivation therapy. J Urol. 2015;193:1963–9.CrossRefPubMedGoogle Scholar
  35. 35.
    American Diabetes Association. Standards of medical care in diabetes–2008. Diabetes Care. 2008;31(Suppl 1):12–54.CrossRefGoogle Scholar
  36. 36.
    American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2009;32(Suppl 1):62–7.CrossRefGoogle Scholar
  37. 37.
    Berruti A, Dogliotti L, Terrone C, 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. J Urol. 2002;167:2361–7.CrossRefPubMedGoogle Scholar
  38. 38.
    Keating NL, O’Malley AJ, Freedland SJ, Smith MR. Does comorbidity influence the risk of myocardial infarction or diabetes during androgen-deprivation therapy for prostate cancer? Eur Urol. 2013;64:159–66.CrossRefPubMedGoogle Scholar
  39. 39.
    Zareba P, Duivenvoorden W, Leong DP, Pinthus JH. Androgen deprivation therapy and cardiovascular disease: what is the linking mechanism? Ther Adv Urol. 2016;8:118–29.CrossRefPubMedGoogle Scholar
  40. 40.
    Tsai HK, D’Amico AV, Sadetsky N, et al. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst. 2007;99:1516–24.CrossRefPubMedGoogle Scholar
  41. 41.
    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.CrossRefPubMedGoogle Scholar
  42. 42.
    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.CrossRefPubMedGoogle Scholar
  43. 43.
    Piccirillo JF, Tierney RM, Costas I, et al. Prognostic importance of comorbidity in a hospital-based cancer registry. JAMA. 2004;291:2441–7.CrossRefPubMedGoogle Scholar
  44. 44.
    Smith MR, Klotz L, van der Meulen E, et al. Gonadotropin-releasing hormone blockers and cardiovascular disease risk: analysis of prospective clinical trials of degarelix. J Urol. 2011;186:1835–42.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Albertsen PC, Klotz L, Tombal B, et al. Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol. 2014;65:565–73.CrossRefPubMedGoogle Scholar
  46. 46.
    Stamler J, Stamler R, Neaton JD, et al. Low risk-factor profile and long-term cardiovascular and non-cardiovascular mortality and life expectancy: findings for 5 large cohorts of young adult and middle-aged men and women. JAMA. 1999;282:2012–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Lim TH, Orija IB, Pearlman BL. American College of Cardiology; American College of Cardiology. The new cholesterol treatment guidelines from the American College of Cardiology/American Heart Association, 2013: what clinicians need to know. Postgrad Med. 2014;126:35–44.CrossRefPubMedGoogle Scholar
  48. 48.
    Wall BA. Androgen deprivation therapy and cardiovascular disease risk—The role of exercise in prostate cancer treatment. Front Oncol. 2016;6:200.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Galvão DA, Taaffe DR, Spry N. Combined resistance and aerobic exercise program reverses muscle loss in men undergoing androgen suppression therapy for prostate cancer without bone metastases: a randomized controlled trial. J Clin Oncol. 2010;28:340–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Taaffe DR, Newton RU, Spry N. Effects of different exercise modalities on fatigue in prostate cancer patients undergoing androgen deprivation therapy: A year-long randomised controlled trial. Eur Urol. 2017;72(2):293–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Gaskin CJ, Fraser SF, Owen PJ, Craike M, Orellana L, Livingston PM. Fitness outcomes from a randomised controlled trial of exercise training for men with prostate cancer: the ENGAGE study. J Cancer Surviv. 2016;10:972–80.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Teleni L, Chan RJ, Chan A. Exercise improves quality of life in androgen deprivation therapy-treated prostate cancer: systematic review of randomised controlled trials. Endocr Relat Cancer. 2016;23:101–12.CrossRefPubMedGoogle Scholar
  53. 53.
    Serels S, Melman A. Tamoxifen as treatment for gynecomastia and mastodynia resulting from hormonal deprivation. J Urol. 1998;159:1309.CrossRefPubMedGoogle Scholar
  54. 54.
    Strum SB, McDermed JE, Scholz MC, Johnson H, Tisman G. Anaemia associated with androgen deprivation in patients with prostate cancer receiving combined hormone blockade. Br J Urol. 1997;79:933–41.CrossRefPubMedGoogle Scholar
  55. 55.
    Hosseini SA, Rajabi F, Akbari Sari A, Ayati M, Heidari S, Ghamary F. Degarelix for the treatment of advanced prostate cancer compared with GnRh-Agonists: a systematic review and meta-analysis. Med J Islam Repub Iran. 2016;30:317. eCollection 2016.PubMedPubMedCentralGoogle Scholar
  56. 56.
    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.CrossRefPubMedGoogle Scholar
  57. 57.
    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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of UrologyCatholic Kwandong University, International St. Mary’s HospitalIncheonSouth Korea
  2. 2.Department of Urology, Urological Science InstituteYonsei University College of MedicineSeoulKorea

Personalised recommendations