The mode of action of the AAs results in the blockade of the androgen receptors of the prostate cells. There are two types of AAs: steroidal AAs and nonsteroidal AAs (NSAAs). Steroidal AAs induce a decrease in plasma levels of testosterone by slowing the release of pituitary LH and by partial inhibition of 5-alpha-reductase. Steroidal AAs include cyproterone acetate and megestrol acetate, which also block the cellular androgen receptors.
The NSAAs are more interesting from a clinical point of view because they are purely AAs acting mainly by inhibiting competition with the fixation of DHT on the androgen receptors. They do not reduce, and may even increase, the plasma levels of testosterone and this may have an impact on the libido of the patients. The NSAAs include flutamide, nilutamide, and bicalutamide.
Total Androgen Blockade
The association of AAs with an LHRH agonist such as leuprolide allows total androgen blockade (TAB) at both testicular and adrenal levels. Results of the first randomized National Cancer Institute study that took place in 1989 were very encouraging. In this study, 603 stage 2 patients were randomized between chemical castration with leuprolide and placebo and AA with flutamide. The results showed an improvement in the rate of progression (13.6 versus 16.5 months) and a marked improvement in global survival (28.3 versus 35.6 months), a gain of 7.3 months (p = 0.035) in the TAB group. These results, reported by Crawford and colleagues were later confirmed in 1993 by a European Organization for Research and Treatment of Cancer (EORTC) study. At the same time, Denis and co-workers reported a similar improvement in survival time of 7.3 months (p = 0.02), in favor of a combination of flutamide with LHRH agonist compared to orchiectomy alone.
In 1995, Crawford, in a second study with 1,387 D2 patients treated with orchiectomy and flutamide or placebo, did not find such a clear-cut difference in the decrease of PSA or in progression-free survival (33 versus 30 months). In the same year, a meta-analysis of 25 trials comparing castration alone to TAB found no significant difference between the two treatments (five-year survival: 22.8% versus 26.2%; p = 0.0512).
The different means of achieving TAB do not appear to be equivalent. The long-term effects of using estrogens and LHRH agonists compared to bilateral orchiectomy do not seem to be the same. The trials that show a significant benefit with TAB in terms of survival are those where castration is medical and nonsurgical. It has been shown that estrogens and the LHRH agonists have a direct cytotoxic effect on prostate cancer cells. Moreover, the association between LHRH agonists and AAs seems to have an additive if not synergistic effect. Indeed, investigations of receptors to LHRH on immortal lines of prostate cancer cells (LNCaP and ALVA-31) have taken place. Results revealed that the combination of LHRH agonists with AAs has greater powers of inhibition than each one of them alone acting on androgen sensitive (LNCaP) or resistant lines (ALVA-31).
Caubet and colleagues in a recent meta-analysis used rigid inclusion criteria that excluded nonrandomized studies and those studies where there is no NSAA. This meta-analysis included nine studies and established the benefits of TAB in terms of objective response as well as progression-free survival and overall survival (but without significant statistical difference). In the context of TAB, the use of LHRH agonists with NSAAs appears to be the better option.
Flutamide is the reference AA. A recent randomized study of 813 patients compared flutamide with bicalutamide associated with an LHRH agonist. The results show progression-free survival and an identical survival at 95 weeks but with a better tolerance to bicalutamide, especially gastrointestinal (lower incidence of diarrhea)