Intermittent Versus Continuous Androgen Deprivation Therapy in Advanced Prostate Cancer
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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.
KeywordsAndrogen deprivation therapy Prostate cancer Quality of life Phase III trials Hormonal therapy
Dr. Laurence Klotz reported receiving consultancy from Ferring, Astra Zeneca, and Sanofi Aventis and a grant from Abbott.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.Google Scholar
- 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.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.PubMedCrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle Scholar