Is any one hormone therapy (androgen ablation) superior to another when given in the first line setting in terms of survival in metastatic disease?
Choice of androgen deprivation therapy
When commencing ADT for a patient with locally advanced or metastatic disease, one has to be mindful and counsel the patient on the risks and benefits for the specific clinical situation and the variations of therapy that can be employed. This is especially true when commencing ADT for a man with metastatic hormone-sensitive prostate cancer as the therapy clearly has a side-effect profile that can have an impact not only on quality of life but also the ability to cause disease regression, lessen symptoms from cancer and prolong overall survival.
It is not possible to counsel a patient on how much of an improvement there is on overall survival from ADT versus no ADT because the known efficacy of ADT makes a no-treatment control arm unethical in the metastatic setting. Moreover, as discussed elsewhere, the available data do not demonstrate a clear-cut benefit for starting ADT early or immediately to treat metastatic disease versus waiting until evidence of progression (while under close observation).
The question then arises as to whether one form of hormonal therapy may be better than another in terms of survival outcomes for metastatic disease. This has been addressed in a sensitivity analysis for M1 patients of a single meta-analysis of the numerous trials comparing various hormone therapies with orchidectomy. The trials date from the 1970s to the 1990s, a period during which staging with bone scans and PSA levels was evolving, and thus the populations with metastatic disease in these trials may be quite heterogeneous. There has been only one trial published post-2000. Some trials included men with locally advanced disease as well as metastatic cancer and thus subgroup analyses are reported. There are also trials comparing various ADTs with oestrogens. However these were not considered further as oestrogen therapies are associated with increased cardiovascular complications and as a result are not advocated for use as a first-line hormone therapy.
The meta-analysis found that there was no difference in survival between therapies used to induce castrate levels of testosterone (LHRH agonists versus orchidectomy) and that anti-androgens were inferior to orchidectomy with a hazard ratio of 1.13 (95% CI=0.99 to 1.3) for steroidal anti-androgens and 1.25 (95% CI=0.99 to 1.59) for non-steroidal androgens. These data strongly suggest there is a lower overall survival if a patient with metastatic prostate cancer is treated with anti-androgens as monotherapy, be they steroidal or nonsteroidal.
These data therefore inform treating physicians and support current practice that androgen deprivation (medical or surgical castration) can be used interchangeably and that anti-androgens should not be used as monotherapy for patients with metastatic prostate cancer.
In essence, the data indicate that castration-based treatment increases overall survival when compared with less effective therapy and presumably would be better again than no therapy. However, there is at best a minimal survival benefit in commencing ADT early in men with metastatic prostate cancer compared with late commencement of LHRH agonist or bilateral orchidectomy therapy (see Early versus delayed androgen deprivation), and these treatments have significant unwanted effects. Therefore judgment should be exercised in relation to the optimal time to introduce these treatments for individual patients with metastatic disease.
Evidence summary and recommendations
| For men with metastatic disease:
benefit when compared with anti-androgen (steroidal or non non-steroidal) monotherapy.
|I, II||, , , , |
|Patients with metastatic prostate cancer can be treated with either orchidectomy or LHRH agonist based on patient preference. Anti-androgen monotherapy should be avoided as the data indicate this is probably associated with a shorter overall survival.||C|
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- Boccon-Gibod L, Fournier G, Bottet P, Marechal JM, Guiter J, Rischman P, et al. Flutamide versus orchidectomy in the treatment of metastatic prostate carcinoma. Eur Urol 1997;32(4):391-5; discussion 395-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9412794.
- Schröder FH, Kurth KH, Fosså SD, Hoekstra W, Karthaus PP, et al. Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local treatment of the primary tumor: results of European Organisation for the Research and Treatment of Cancer 30846--a phase III study. J Urol 2004 Sep;172(3):923-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15310999.