Controversies Surrounding Androgen Deprivation for Prostate Cancer

Stephen G. Patterson, MD, Lodovico Balducci, MD, Julio M. Pow-Sang, MD


Cancer Control. 2002;9(4) 

In This Article

Present Approach to Hormonal Treatment

Castration, the time-honored frontline treatment for metastatic prostate cancer, was previously defined by induction of a serum testosterone level of <50 ng/mL.[23,24] Recent literature redefines this upper limit to <20 ng/mL.[25] Testosterone is converted into a more potent compound, DHT. Conversion occurs in the cytoplasm of prostatic cells by the enzyme 5-alpha reductase. In addition to testosterone, adrenal androgens may give origin to DHT.[26] According to some studies,[27] as much as 40% of DHT is derived from adrenal precursors. This alternative source of DHT may explain in part the progression of some prostate cancers despite castration. Clinical responses still may be observed with adrenal ablation after failure from androgen withdrawal.[28] The combination of castration and adrenal ablation is the basis for the MAB approach. The hormonal agents available for treatment of prostate cancer are listed in Table 1 .

The first method of permanent castration was bilateral orchiectomy, and the first reversible method was diethylstilbestrol (DES).[29,30,31] Medical castration may be obtained with estrogen agonists, LHRH agonists, LHRH antagonists, and ketoconazole.

The value of the LHRH analogs is supported by several randomized studies that show equivalent effectiveness between these medications and orchiectomy or DES. When compared to 5 mg of DES, LHRH analogs have a more favorable cardiovascular safety profile with a reduced risk of deep vein thrombosis and congestive heart failure.[32,33,34] LHRH analogs are associated with hot flashes and may lead to osteoporosis over several years.[35] Potential benefits of estrogen include hot flashes and osteoporosis, as well as preservation of some libido.[36] Furthermore, it has never been conclusively demonstrated that DES at 1 mg/day is not as effective and as safe as LHRH analogs. In at least two studies,[31,37] this dose of DES appeared equivalent to castration.

Two preparations of LHRH agonists are commercially available in the United States: leuprolide acetate (Lupron) and goserelin acetate (Zoladex). Since both of these agents are LHRH agonists, they cause an initial surge in serum testosterone lasting 1 to 2 weeks, which may stimulate tumor growth.[38,39] For this reason, LHRH analogs are discouraged as initial monotherapy in men with impending spinal cord compression, urinary obstruction, or painful metastatic disease. An antiandrogen (bicalutamide, flutamide, or nilutamide) may be started 2 weeks prior to the administration of an LHRH analog as prophylaxis against these complications.[40] An alternate form of firstline therapy involves castration with ketoconazole. Like orchiectomy, ketoconazole provides rapid castrate levels of testosterone.[41] Therefore, it may be used for initial temporary treatment in patients who need immediate efficacy and are poor surgical candidates.

The equivalence of orchiectomy, estrogen agonists, and LHRH analogs has been well demonstrated in several studies reviewed in a recent meta-analysis by Seidenfeld et al.[42] Inconclusive results were reported in the comparison of castration and single-agent androgen antagonists. Three of the eight studies in the meta-analysis demonstrated longer survival in the group undergoing castration. This is not surprising because the use of antiandrogen without simultaneous blockage of the hypothalamic-pituitary axis may be associated with increased production of LH, ultimately stimulating the production of testosterone and potentially overwhelming the receptor block. Interestingly, the studies showing equivalence between castration and antiandrogen used cyproterone, a steroidal antiandrogen not available in the United States because of a side effect associated with blockade of pituitary gonadotropin production. The conclusion of the meta-analysis was that monotherapy with steroidal antiandrogens was inferior to castration.[42] Similar conclusions to those in the meta-analysis were reported in a 1999 publication prepared for the Agency for Health Care Policy and Human Services.[43]

Boccardo et al[44] reported the equivalence of bicalutamide and goserelin plus flutamide. The benefits of monotherapy with antiandrogen included preservation of libido in a number of patients. It is noted that this was a small study with short follow-up and with doses of bilcalutamide 3-fold as high as those normally used. Until these results are confirmed by larger trials, castration remains the frontline treatment of metastatic prostate cancer.

LHRH antagonists represent a recently developed class of drug used for androgen deprivation. PPI-149 (Abarelix), a peptide antagonist of the LHRH receptor,[45] works by directly inhibiting LHRH so there is no initial stimulation of the LHRH receptor.[46] In contrast, the LHRH analogs leuprolide, buserelin, and goserelin stimulate the LHRH receptor. Thus, there is no initial testosterone flare with administration of Abarelix as occurs with LHRH analogs. Practical shortcomings such as histamine release have limited the use of LHRH antagonists in clinical applications. Several published studies[46,47,48,49] have concluded that Abarelix as monotherapy achieves castrate levels of testosterone, reduces serum PSA, and avoids the testosterone flare that is characteristic of LHRH analogs. Routine use of LHRH antagonists for advanced prostate cancer may depend on a demonstration of a survival advantage derived from avoiding the testosterone flare.[46]


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