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UROSCAN
Year : 2010  |  Volume : 26  |  Issue : 1  |  Page : 152-153
 

Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: Where is the evidence?


Department of Urology, Christian Medical College, Vellore, India

Date of Web Publication23-Mar-2010

Correspondence Address:
T J Nirmal
Department of Urology, Christian Medical College, Vellore
India
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Source of Support: None, Conflict of Interest: None


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How to cite this article:
Nirmal T J, Kumar S. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: Where is the evidence?. Indian J Urol 2010;26:152-3

How to cite this URL:
Nirmal T J, Kumar S. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: Where is the evidence?. Indian J Urol [serial online] 2010 [cited 2019 Jun 19];26:152-3. Available from: http://www.indianjurol.com/text.asp?2010/26/1/152/60470

Fernando EC Calais da Silva, Aldo V Bono, Peter Whelan, Maurizio Brausi, Anton Marques Queimadelos, Jose A Portillo Martin, Ziya Kirkali, Fernando MV Calais da Silva, Chris Robertson. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: Results from a randomized phase 3 study of the South European Uroncological Group. European Urology 2009; 55: 1269-1277.



   Summary Top


This multicenter, phase III, randomized study compares intermittent hormonal therapy (IHT) with continuous therapy for the treatment of advanced prostate cancer. [1] Men below 80 years of age, with histologically confirmed prostate cancer of stage T3 and above, with or without metastasis; and a prostate specific antigen (PSA) level ≥4 to <100 ng/ ml have been included. A total of 766 patients received induction with cyproterone acetate (CPA) 200 mg for two weeks and then monthly depot injections of a luteinizing hormone-releasing hormone (LHRH) analogue plus 200 mg of CPA daily for three months. The patients (626 in number) whose PSA level decreased to <4 ng/ml or to 80% below the initial value were randomized; 314 were randomized to the intermittent arm and stopped treatment and 312 randomized to the continuous arm received 200 mg of CPA daily plus an LHRH analogue. Therapy was restarted in the intermittent arm if the PSA level rose to ≥10 ng/ml for symptomatic individuals or to ≥20 ng/ ml for those without symptoms. For the patients whose PSA level dropped to <80% of the initial value, therapy was restarted when the PSA level rose to ≥20% above the nadir value. The study was designed to detect a 30% reduction in median time to progression (objective or subjective) in the intermittent arm compared with the continuous arm. Secondary outcomes were survival and quality of life (QoL). While 127 patients in the continuous arm progressed, only 107 from the intermittent arm showed progresssion. The difference, however, was not statistically significant [hazard ratio (HR) of 0.81, P = 0.11]. There was no difference in survival, with a HR of 0.99 (95% CI: 0.80- 1.23). There were 170 deaths in the intermittent arm and 169 in the continuous arm. The greater number of cancer deaths in the intermittent treatment arm (106 Vs 84) was balanced by a greater number of cardiovascular deaths in the continuous arm (52 Vs 41). Side-effects were encountered more often in the continuous arm. Men on intermittent hormonal therapy reported greater sexual activity as recorded by the QLQ C30 questionnaire. Median time off therapy for those in the intermittent arm was 52 weeks (95% CI: 39.4- 65.7). Thus, the authors propose routine use of IHT for patients with locally advanced prostate cancer.


   Comments Top


Androgen deprivation has been the mainstay treatment for metastatic prostate cancer for many years. [2] It helps to palliate, delay or prevent the onset of symptoms related to the disease and its complications but does not improve overall survival. [2] Majority of the patients on continuous therapy become vulnerable to its various side effects and ultimately progress to hormone resistant prostate cancer (HRPC) in two to three years. [3] The concept of IHT for prostate cancer and its beneficial effect on QoL was first clinically described by Klotz et al., in 1986. IHT in murine models (lymph node cancer of the prostate [LNCaP] and Shionogi carcinoma significantly delayed the onset of HRPC [4] and heralded the beginning of various clinical trials. Over the years, >20 phase two trials which have included >2000 patients have evaluated the feasibility, efficacy, and safety of IHT. [5] It is apparent that IHT has a beneficial effect on QoL and has additional advantages in terms of reduced health care costs. However, the two essential questions to be answered are:

  1. Does IHT delay the onset of hormone resistance?
  2. Can IHT improve overall survival?
IHT seems to fall short of expectations in the randomized phase III study by Calais da silva et al. It is known that patients with bulky disease, bone metastasis and PSA levels >100 ng/ ml have a poor response to IHT. [6] Hence, majority of the patients included in this study had asymptomatic, non-metastatic T3 disease and a Gleason score of ≤7. A later amendment restricted entry to PSA <100 ng/ ml. As expected, patients showed an excellent initial response in terms of median reduction in PSA of 96% following induction. However, the necessity for early institution of androgen deprivation in this subgroup is debatable. These patients could delay hormone therapy by several years without affecting survival [7] or take antiandrogens to avoid side-effects of castration.

The highlight of the SEUG trial is the fact that it used a three- month induction period without any demonstrable impact on survival unlike previous trials advocating six to nine months. [8] At three months of induction, 81% of the patients were able to achieve a PSA nadir of <4 ng/ml. The SEUG trial was also able to demonstrate that nadir PSA and metastatic status were independent predictors of progression, with M1 and PSA ≥4 ng/ml associated with greater risk of progression.

There was no statistically significant difference between continuous and IHT in terms of overall survival, number of progressions and time to progression. The only consolation came from the fact that hot flushes and sexual activity improved in patients on IHT. Surprisingly, this was not reflected in the European Organization for Research and Treatment of Cancer (EORTC) QoL questionnaire.

IHT boasts of reduction in treatment costs [5] relative to continuous therapy but is still not comparable to the cost effectiveness of orchiectomy.

Results of the SEUG trial only fuel the debate as to whether the "average improvement in QoL" offered by IHT stands up to the "average improvement in quantity of life" promised by the conventional continuous therapy.

To conclude, the SEUG trial doesn't give us sufficient evidence to recommend its routine clinical use and we must await the results of other phase III trials to define a patient population most likely to benefit from IHT.

 
   References Top

1.Calais da Silva FE, Bono AV, Whelan P, Brausi M, Marques Queimadelos A, Martin JA, 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;55:1269-77.  Back to cited text no. 1      
2.Heidenreich A, Aus G, Bolla M, oniau S, Matveev VB, Schmid HP, et al. EAU guidelines on prostate cancer. Eur Urol 2008;53:68-80.  Back to cited text no. 2      
3.Robinson MR, Smith PH, Richards B, Newling DW, de Pauw M, Sylvester R. The final analysis of the EORTC Genito-Urinary Tract Cancer Co-operative Group Phase III clinical trial (Protocol 30805) comparing orchidectomy, orchidectomy plus cyproterone acetate, and low dose stilboestrol in the management of metastatic carcinoma of the prostate. Eur Urol 1995;28:273-83.  Back to cited text no. 3  [PUBMED]    
4.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;71:2782-90.  Back to cited text no. 4  [PUBMED]    
5.Tunn U. The current status of intermittent androgen deprivation (IAD) therapy for prostate cancer: Putting IAD under the spotlight. BJU Int 2007;99:19-22.  Back to cited text no. 5  [PUBMED]    
6.Salonen AJ, Viitanen J, Lundstedt S, Ala-Opas M, Taari K, Tammela TL. 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;180:915-9.  Back to cited text no. 6      
7.Hussain M, Tangen CM, Higano C, Schelhammer PF, Faulkner J, Crawford ED, et al. Absolute prostatespecific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: Data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol 2006;24:3984-90.  Back to cited text no. 7      
8.Studer UE, Whelan P, Albrecht W, Casselman J, de Reijke T, Hauri D, et al. Immediate or tdeferred androgen deprivation for patients with prostate cancer not suitable for local treatmentwithcurative intent: European Organization for Research and Treatment of Cancer (EORTC) Trial 30891. J Clin Oncol 2006;24:1868-76.  Back to cited text no. 8      




 

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