Is there any survival advantage for maximum androgen blockade (or combined hormone therapy) compared with single agent androgen blockade when used as first line therapy in metastatic disease?

From Cancer Guidelines Wiki

Is there any survival advantage for maximum androgen blockade (or combined hormone therapy) compared with single agent androgen blockade when used as first line therapy in metastatic disease?

Single agent versus total androgen blockade

Castration therapies are effective but temporary therapies for metastatic disease, but are justifiable in context of preventing potential androgen “flare” to avoid further impingement if there were other areas of metastatic disease that may already be causing significant but not clinical evidence of cord compression. Numerous RCTs have examined whether combined androgen blockade (CAB) might provide a survival benefit when compared with castration monotherapies in the treatment of metastatic (M1) prostate cancer. Most of these trials have been the subject of three meta-analyses[1][2][3], with the largest of these[3] following up all 8275 participants in 27 RCTs.

There is some heterogeneity in study design in this extensive body of literature, It includes some trials using steroidal anti-androgens and others using non-steroidal anti-androgens in combination with orchidectomy or LHRH agonist. Another source of heterogeneity was the inclusion in some studies of patients with locally advanced disease (M0) along with patients with radiographic evidence of disease (M1). However, over 80% of men included in the largest meta-analyses had metastatic disease.

The overall results of the meta-analyses demonstrate either no significant benefit[3] or only a small benefit{{Cite footnote|Citation:Samson DJ, Seidenfeld J, Schmitt B, Hasselblad V, Albertsen PC, Bennett CL, et al 2002} when results for both steroidal and non-steroidal anti-androgens were combined. The inconsistencies could be explained by the heterogeneous nature of the studies. More specifically, however, the use of cyproterone acetate appears to be detrimental (the difference in mortality rates was 2.8%) in the largest meta-analyses[3] whereas non-steroidal anti-androgens were associated with a modest but significant improvement, with a difference in mortality rates of 2.9%[3] and an odds ratio for overall survival of 1.29 at five years[1]

The number of patients who die of metastatic prostate cancer each year (second leading cause of male cancer deaths) and the overall survival benefit indicates that these data are of significant clinical relevance. The modest increase in overall survival, however, is balanced against the increased side effects of adding a non-steroidal anti-androgen to androgen deprivation (castration) therapy and this limits the clinical impact or usability of combined androgen blockade for all patients.

The data can be directly generalised to patients with metastatic prostate cancer as both LHRH agonists and anti-androgens are on the PBS for this indication and orchidectomy is an easily accessible procedure.

Back to top

Evidence summary and recommendations

Evidence summary Level References
There appears to be a small but significant benefit from adding a non-steroidal anti-androgen to androgen deprivation therapy. This is a class effect in favour of non-steroidal anti-androgens. In contrast, there appears to be a detrimental effect with the use of the steroidal anti-androgens.

However, the benefit is modest and it required a large number of clinical trials to come to this finding.

I, II [1], [2], [3], [4], [5], [6], [7], [8], [9]
Evidence-based recommendationQuestion mark transparent.png Grade
Patients with metastatic prostate cancer may be treated with a non-steroidal anti-androgen combined with androgen deprivation therapy as a continuing strategy (beyond the period of LHRH-induced surge [flare] of testosterone) if they are prepared to accept the greater likelihood of unwanted effects from combination therapy.

It is recommended that patients with high–volume disease or disease where urgent tumour debulking is required (eg impending spinal canal compression or urinary outflow obstruction) be commenced on combined androgen blockade to prevent flare reactions. This required period is approximately one month for an LHRH agonist and covers the time it takes for testosterone levels to reach a castrate state. Continuation of combined therapy beyond that period may be considered if the patient is prepared to accept the greater likelihood of unwanted side effects from combination therapy.

B


Back to top

References

  1. 1.0 1.1 1.2 Schmitt B, Bennett C, Seidenfeld J, Samson D, Wilt T. Maximal androgen blockade for advanced prostate cancer. Cochrane Database Syst Rev 2000;(2):CD001526 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10796804.
  2. 2.0 2.1 Samson DJ, Seidenfeld J, Schmitt B, Hasselblad V, Albertsen PC, Bennett CL, et al. Systematic review and meta-analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate carcinoma. Cancer 2002 Jul 15;95(2):361-76 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12124837.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 Prostate Cancer Trialists' Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Lancet 2000 Apr 29;355(9214):1491-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10801170.
  4. Iversen P, Christensen MG, Friis E, Hornbøl P, Hvidt V, Iversen HG, et al. A phase III trial of zoladex and flutamide versus orchiectomy in the treatment of patients with advanced carcinoma of the prostate. Cancer 1990 Sep 1;66(5 Suppl):1058-66 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2144207.
  5. Tyrrell CJ, Altwein JE, Klippel F, Varenhorst E, Lunglmayr G, Boccardo F, et al. A multicenter randomized trial comparing the luteinizing hormone-releasing hormone analogue goserelin acetate alone and with flutamide in the treatment of advanced prostate cancer. The International Prostate Cancer Study Group. J Urol 1991 Nov;146(5):1321-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1834864.
  6. Tyrrell CJ, Altwein JE, Klippel F, Varenhorst E, Lunglmayr G, Boccardo F, et al. Multicenter randomized trial comparing Zoladex with Zoladex plus flutamide in the treatment of advanced prostate cancer. Survival update. International Prostate Cancer Study Group. Cancer 1993 Dec 15;72(12 Suppl):3878-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8252508.
  7. Tyrrell CJ, Altwein JE, Klippel F, Jurincic-Winkler C, Varenhorst E, Lunglmayr G, et al. Comparison of an LH-RH analogue (Goeserelin acetate, 'Zoladex') with combined androgen blockade in advanced prostate cancer: final survival results of an international multicentre randomized-trial. International Prostate Cancer Study Group. Eur Urol 2000 Feb;37(2):205-11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10705200.
  8. Ansari MS, Gupta NP, Hemal AK, Dogra PN, Seth A. Combined androgen blockade in the management of advanced prostate cancer: a sensible or ostensible approach. Int J Urol 2004 Dec;11(12):1092-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15663681.
  9. Kotake T, Usami M, Akaza H, Koiso K, Homma Y, Kawabe K, et al. Goserelin acetate with or without antiandrogen or estrogen in the treatment of patients with advanced prostate cancer: a multicenter, randomized, controlled trial in Japan. Zoladex Study Group. Jpn J Clin Oncol 1999 Nov;29(11):562-70 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10678560.

Back to top

Appendices