Skip to main content

Advertisement

Log in

Intermittent Versus Continuous Androgen Deprivation Therapy in Advanced Prostate Cancer

  • Prostate Cancer (D Parekh, Section Editor)
  • Published:
Current Urology Reports Aims and scope Submit manuscript

Abstract

Intermittent androgen deprivation is increasingly employed as an alternative to continuous life long androgen deprivation therapy for men with advanced or recurrent prostate cancer. Two recent phase III trials have clarified the benefits of intermittent therapy. In men with non-metastatic disease with PSA recurrence after definitive local therapy, intermittent therapy showed equivalent survival to continuous therapy, with significant improvements in quality of life. Patients on intermittent therapy experience improved bone health, less metabolic and hematologic disturbances, fewer hot flashes, as well as improved sexual function. In men with metastatic disease, the data is less clear. The long-awaited results of SWOG 9324 comparing intermittent to continuous therapy in metastatic disease showed a trend to worse outcome in the patients with ‘minimal’ metastatic disease, and no difference in those with widespread bone mets. The significance of this observation is in dispute. This review also addresses practical issues in the use intermittent therapy, including patient selection, follow-up and cycling of therapy. The recent results of randomized clinical trials now establish that intermittent androgen deprivation therapy is an approach that should be considered the standard of care for most patients with non-metastatic prostate cancer requiring hormonal therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Huggins C, Hodges CV. 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. J Urol. 2002;168(1):9–12.

    Article  PubMed  Google Scholar 

  2. Mottet N, Bellmunt J, Bolla M, Joniau S, Mason M, Matveev V, et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2011;59(4):572–83.

    Article  PubMed  Google Scholar 

  3. Higano CS. Side effects of androgen deprivation therapy: monitoring and minimizing toxicity. Urology. 2003;61(2 Suppl):32–8.

    Article  PubMed  Google Scholar 

  4. • Klotz LH, Herr HW, Morse MJ, Whitmore Jr WF. Intermittent endocrine therapy for advanced prostate cancer. Cancer. 1986;58(11):2546–50. The first report of intermittent androgen deprivation therapy in clinical practice.

    Article  PubMed  CAS  Google Scholar 

  5. Akakura K, Bruchovsky N, Goldenberg SL, Rennie PS, Buckley AR, Sullivan LD. Effects of intermittent androgen suppression on androgen-dependent tumors. Apoptosis and serum prostate-specific antigen. Cancer. 1993;71(9):2782–90.

    Article  PubMed  CAS  Google Scholar 

  6. Bruchovsky N, Rennie PS, Coldman AJ, Goldenberg SL, To M, Lawson D. Effects of androgen withdrawal on the stem cell composition of the Shionogi carcinoma. Cancer Res. 1990;50(8):2275–82.

    PubMed  CAS  Google Scholar 

  7. Sato N, Gleave ME, Bruchovsky N, Rennie PS, Goldenberg SL, Lange PH, et al. Intermittent androgen suppression delays progression to androgen-independent regulation of prostate-specific antigen gene in the LNCaP prostate tumour model. J Steroid Biochem Mol Biol. 1996;58(2):139–46.

    Article  PubMed  CAS  Google Scholar 

  8. Chang SL, Liao JC, Shinghal R. Decreasing use of luteinizing hormone-releasing hormone agonists in the United States is independent of reimbursement changes: a Medicare and Veterans Health Administration claims analysis. J Urol. 2009;182(1):255–60. discussion 261.

    Article  PubMed  Google Scholar 

  9. • Abrahamsson P-A. Potential benefits of intermittent androgen suppression therapy in the treatment of prostate cancer: a systematic review of the literature. Eur Urol. 2010;57(1):49. An excellent overview of intermittent therapy, including a critical review of the data.

    Article  PubMed  CAS  Google Scholar 

  10. Shaw GL, Wilson P, Cuzick J, Prowse DM, Goldenberg SL, Spry NA, et al. International study into the use of intermittent hormone therapy in the treatment of carcinoma of the prostate: a meta-analysis of 1446 patients. BJU Int. 2007;99(5):1056–65.

    Article  PubMed  CAS  Google Scholar 

  11. Bruchovsky N, Klotz L, Crook J, Malone S, Ludgate C, Morris WJ, et al. Final results of the Canadian prospective phase II trial of intermittent androgen suppression for men in biochemical recurrence after radiotherapy for locally advanced prostate cancer. Cancer. 2006;107(2):389–95.

    Article  PubMed  Google Scholar 

  12. Bruchovsky N, Klotz L, Crook J, Goldenberg SL. Locally advanced prostate cancer—biochemical results from a prospective phase II study of intermittent androgen suppression for men with evidence of prostate-specific antigen recurrence after radiotherapy. Cancer. 2007;109(5):858–67.

    Article  PubMed  CAS  Google Scholar 

  13. Bruchovsky N, Klotz L, Crook J, Phillips N, Abersbach J, Goldenberg SL. Quality of life, morbidity, and mortality results of a prospective phase II study of intermittent androgen suppression for men with evidence of prostate-specific antigen relapse after radiation therapy for locally advanced prostate cancer. Clin Genitourin Cancer. 2008;6(1):46–52.

    Article  PubMed  CAS  Google Scholar 

  14. Bruchovsky N, Klotz LH, Sadar M, Crook JM, Hoffart D, Godwin L, et al. Intermittent androgen suppression for prostate cancer: Canadian Prospective Trial and related observations. Mol Urol. 2000;4(3):191–9.

    PubMed  CAS  Google Scholar 

  15. Miller K, Steiner U, Lingnau A, et al. Randomised prospective study of intermittent versus continuous androgen suppression in advanced prostate cancer [abstract 5105]. Presented at: American Society of Clinical Oncology; June 1–5, 2007; Chicago, IL, USA.

  16. Mottet N, Goussard M, Loulidi S, Wolff J. Intermittent versus continuous maximal androgen blockade in metastatic (D2) prostate cancer patients. A randomized trial. Paper presented at: 24th Congress of the European Association of Urology; March 17–21, 2009; Stockholm, Sweden.

  17. Tunn U, Eckhart O, Kienle E, Hillger H. Intermittent androgen deprivation in patients with PSA-relapse after radical prostatectomy – first results of a randomised prospective phase-III clinical trial (AUO study AP06/95). Eur Urol Suppl. 2003;2(1):24.

    Article  Google Scholar 

  18. Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013;368(14):1314–25.

    Google Scholar 

  19. •• Crook JM, O'Callaghan CJ, Duncan G, Dearnaley DP, Higano CS, Horwitz EM, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med. 2012;367(10):895–903. This is the largest and most definitive prospective randomized trial of intermittent vs. continuous ADT in the non-metastatic setting. The findings are described in the article in detail.

    Article  PubMed  CAS  Google Scholar 

  20. da Silva FEC C, Bono AV, Whelan P, Brausi M, Marques Queimadelos A, Martin JAP, et al. Intermittent Androgen Deprivation for Locally Advanced and Metastatic Prostate Cancer: Results from a Randomised Phase 3 Study of the South European Uroncological Group. Eur Urol. 2009;55(6):1269–77.

    Article  Google Scholar 

  21. Langenhuijsen JF, Badhauser D, Schaaf B, Kiemeney LALM, Witjes JA, Mulders PFA. Continuous vs. intermittent androgen deprivation therapy for metastatic prostate cancer. Urol. Oncol. [Internet]. 2011 May 9 [cited 2012 Mar 21]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/21561791.

  22. Gulley JL, Figg WD, Steinberg SM, Carter J, Sartor O, Higano CS, et al. A prospective analysis of the time to normalization of serum androgens following 6 months of androgen deprivation therapy in patients on a randomized phase III clinical trial using limited hormonal therapy. J Urol. 2005;173(5):1567–71.

    Article  PubMed  CAS  Google Scholar 

  23. •• Piaggio G, Elbourne DR, Pocock SJ, Evans SJ, Altman DG and CONSORT Group. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT 2010 statement. JAMA. 2012;308(24):2594–604. This article should be required reading for anyone interested in non-inferiority trials. It outlines how results of these trials should be interpreted, and describes the pitfalls of the non-inferiority design.

    Article  PubMed  CAS  Google Scholar 

  24. de Leval J, Boca P, Yousef E, Nicolas H, Jeukenne M, Seidel L, et al. Intermittent versus continuous total androgen blockade in the treatment of patients with advanced hormone-naive prostate cancer: results of a prospective randomized multicenter trial. Clin Prostate Cancer. 2002;1(3):163–71.

    Article  PubMed  Google Scholar 

  25. Spry NA, Galvão DA, Davies R, La Bianca S, Joseph D, Davidson A, et al. Long-term effects of intermittent androgen suppression on testosterone recovery and bone mineral density: results of a 33-month observational study. BJU Int. 2009;104(6):806–12.

    Article  PubMed  CAS  Google Scholar 

  26. Malcolm JB, Derweesh IH, Kincade MC, DiBlasio CJ, Lamar KD, Wake RW, et al. Osteoporosis and fractures after androgen deprivation initiation for prostate cancer. Can J Urol. 2007;14(3):3551–9.

    PubMed  Google Scholar 

  27. 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(6):933–41.

    Article  PubMed  CAS  Google Scholar 

  28. Choo R, Chander S, Danjoux C, Morton G, Pearce A, Deboer G, et al. How are hemoglobin levels affected by androgen deprivation in non-metastatic prostate cancer patients? Can J Urol. 2005;12(1):2547–52.

    PubMed  Google Scholar 

  29. Malone S, Perry G, Eapen L, Segal R, Gallant V, Dahrouge S, et al. Mature results of the Ottawa phase II study of intermittent androgen-suppression therapy in prostate cancer: clinical predictors of outcome. Int J Radiat Oncol Biol Phys. 2007;68(3):699–706.

    Article  PubMed  Google Scholar 

  30. Saigal CS, Gore JL, Krupski TL, Hanley J, Schonlau M, Litwin MS. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer. 2007;110(7):1493–500.

    Article  PubMed  CAS  Google Scholar 

  31. Prapotnich D, Fizazi K, Escudier B, Mombet A, Cathala N, Vallancien G. A 10-year clinical experience with intermittent hormonal therapy for prostate cancer. Eur Urol. 2003;43(3):233–40.

    Article  PubMed  Google Scholar 

  32. Salonen AJ, Viitanen J, Lundstedt S, Ala-Opas M, Taari K, Tammela TLJ. Finnish multicenter study comparing intermittent to continuous androgen deprivation for advanced prostate cancer: interim analysis of prognostic markers affecting initial response to androgen deprivation. J Urol. 2008;180(3):915–20.

    Article  PubMed  CAS  Google Scholar 

  33. Scholz MC, Lam RY, Strum SB, Labarba DJ, Becker LK, Chang P, et al. Primary intermittent androgen deprivation as initial therapy for men with newly diagnosed prostate cancer. Clin Genitourin Cancer. 2011;9(2):89–94.

    Article  PubMed  Google Scholar 

  34. Studer UE, Hauri D, Hanselmann S, Chollet D, Leisinger H-J, Gasser T, et al. Immediate versus deferred hormonal treatment for patients with prostate cancer who are not suitable for curative local treatment: results of the randomized trial SAKK 08/88. J Clin Oncol. 2004;22(20):4109–18.

    Article  PubMed  Google Scholar 

  35. Studer UE, Whelan P, Albrecht W, Casselman J, de Reijke T, Hauri D, 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(12):1868–76.

    Article  PubMed  Google Scholar 

  36. Verhagen PCMS, Schröder FH, Collette L, Bangma CH. Does local treatment of the prostate in advanced and/or lymph node metastatic disease improve efficacy of androgen-deprivation therapy? a systematic review. Eur Urol. 2010;58(2):261–9.

    Article  PubMed  Google Scholar 

  37. Lukka H, Waldron T, Klotz L, Winquist E, Trachtenberg J. Maximal androgen blockade for the treatment of metastatic prostate cancer–a systematic review. Curr Oncol. 2006;13(3):81–93.

    PubMed  CAS  Google Scholar 

  38. Benaim EA, Pace CM, Lam PM, Roehrborn CG. Nadir prostate-specific antigen as a predictor of progression to androgen-independent prostate cancer. Urology. 2002;59(1):73–8.

    Article  PubMed  Google Scholar 

  39. Sciarra A, Cattarino S, Gentilucci A, Alfarone A, Innocenzi M, Gentile V, et al. Predictors for response to intermittent androgen deprivation (IAD) in prostate cancer cases with biochemical progression after surgery. Urol. Oncol. [Internet]. 2011 Jun 10 [cited 2012 Feb 21]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/21665494.

  40. Yu EY, Gulati R, Telesca D, Jiang P, Tam S, Russell KJ, et al. Duration of first off-treatment interval is prognostic for time to castration resistance and death in men with biochemical relapse of prostate cancer treated on a prospective trial of intermittent androgen deprivation. J Clin Oncol. 2010;28(16):2668–73.

    Article  PubMed  CAS  Google Scholar 

  41. Morote J, Orsola A, Planas J, Trilla E, Raventós CX, Cecchini L, et al. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol. 2007;178(4):1290–5.

    Article  PubMed  CAS  Google Scholar 

  42. Perachino M, Cavalli V, Bravi F. Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone-releasing hormone therapy: prognostic significance? BJU Int. 2010;105(5):648–51.

    Article  PubMed  CAS  Google Scholar 

  43. Figg WD, Hussain MH, Gulley JL, Arlen PM, Aragon-Ching JB, Petrylak DP, et al. A double-blind randomized crossover study of oral thalidomide versus placebo for androgen dependent prostate cancer treated with intermittent androgen ablation. J Urol. 2009;181(3):1104–13. discussion 1113.

    Article  PubMed  CAS  Google Scholar 

  44. Ward JE, Karrison T, Chatta G, Hussain M, Shevrin D, Szmulewitz RZ, et al. A randomized, phase II study of pazopanib in castrate-sensitive prostate cancer: a University of Chicago Phase II Consortium/Department of Defense Prostate Cancer Clinical Trials Consortium study. Prostate Cancer Prostatic Dis. 2012;15(1):87–92.

    Article  PubMed  CAS  Google Scholar 

  45. Di Silverio F, Sciarra A, Gentile V. Etoricoxib and intermittent androgen deprivation therapy in patients with biochemical progression after radical prostatectomy. Urology. 2008;71(5):947–51.

    Article  PubMed  Google Scholar 

  46. Scholz MC, Jennrich RI, Strum SB, Johnson HJ, Guess BW, Lam RY. Intermittent use of testosterone inactivating pharmaceuticals using finasteride prolongs the time off period. J Urol. 2006;175(5):1673–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

Dr. Laurence Klotz reported receiving consultancy from Ferring, Astra Zeneca, and Sanofi Aventis and a grant from Abbott.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Laurence Klotz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Klotz, L. Intermittent Versus Continuous Androgen Deprivation Therapy in Advanced Prostate Cancer. Curr Urol Rep 14, 159–167 (2013). https://doi.org/10.1007/s11934-013-0325-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11934-013-0325-x

Keywords

Navigation