Controversies Surrounding Androgen Deprivation for Prostate Cancer

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

Disclosures

Cancer Control. 2002;9(4) 

In This Article

Monotherapy vs Maximal Androgen Blockade

The basis of MAB is concomitant neutralization of both testicular and adrenal sources of androgen. The question of whether MAB is advantageous over castration has been debated for 15 years. The rationale of MAB is eliminating the influence of adrenal generated androgens by adding one of the antiandrogens to castration. Several large trials have evaluated the efficacy of MAB. Three large trials suggested that MAB conferred an important survival advantage.[59,60,61] More recently, Eisenberger and colleagues[62] published results of 1,387 men with metastatic prostate cancer treated with orchiectomy and either flutamide or placebo. The addition of flutamide was not associated with a meaningful improvement in survival. It should be noted that patients treated with orchiectomy in this study had similar survival to those treated with MAB in previous studies, suggesting either that enrolled patients had less advanced disease or castration might not have been as complete with LHRH analogs as it was with orchiectomy. In the Intergroup study,[59] castration was obtained with daily injection of leuprolide. It is reasonable to assume compliance with daily injections was inconsistent.

The Prostate Cancer Trialists' Collaborative Group[63] performed a meta-analysis of 27 randomized trials involving 8,275 men with metastatic (88% of subjects) or locally advanced (12% of subjects) prostate cancer. Half were over 70 years of age, and follow-up was typically for 5 years. At the time of meta-analysis, 5,932 men (72%) had died; of the deaths for which causes were provided, approximately 80% were attributed to prostate cancer. The 5-year survival rate was 25.4% with MAB vs 23.6% with androgen suppression alone. The difference was not statistically significant (SE = 1.3; log-rank 2p = 0.11). There was no significant heterogeneity in the treatment effect (MAB vs androgen suppression) with respect to age or disease stage. The results for cyproterone acetate, which accounted for only one fifth of the evidence, appeared slightly unfavorable to MAB (SE = 2.4; log-rank 2p = 0.04 adverse); whereas those for nilutamide and flutamide appeared slightly favorable (SE = 1.3; log-rank 2p = 0.005). Non-prostate cancer deaths accounted for some of the apparently adverse effects of cyproterone acetate. The analysis concluded that in advanced prostate cancer, the addition of antiandrogen to androgen suppression improved the 5-year survival rate by approximately 2% to 3% (depending on whether the analysis includes or excludes the cyproterone acetate trials), but the range of uncertainty as to the true size of this benefit is approximately 0% to 5%.[63] It is not clear from these studies whether the small benefits of the antiandrogen might have arisen from offsetting tumor growth stimulation caused by the initial spike of testosterone following LHRH analog initiation.

Another meta-analysis published in 2001 by Schmitt et al[64] concluded that there was a 5% improvement in survival at 5 years (30% vs 25%) with MAB, as well as an improvement in progression-free survival at 1 year. It is noted that only 7 of the 20 randomized studies evaluated would, however, be considered high-quality studies. If the meta-analysis is limited to these 7 studies, there was no improvement from MAB. Also, only 3 of these 7 studies reported a positive survival advantage for MAB, and this may have skewed the results of the meta-analysis. The necessary interpretations of this closer inspection of the recent meta-analysis are that a minor improvement in survival may be seen with MAB and that if 20 trials have not conclusively demonstrated benefit from MAB over monotherapy, it is doubtful further trials will do so.

Quality-of-life (QOL) parameters in patients receiving monotherapy compared with MAB have been evaluated.[65] Data were collected on five primary QOL parameters including treatment-specific symptoms (diarrhea, gas pain, body image), physical functioning, and emotional functioning. Cross-sectional analyses reported statistically significant differences favoring monotherapy in two of the five parameters: increased diarrhea (P=.001) and worse emotional functioning (P<.003). The longitudinal analyses were reported to replicate these findings. The remaining 3 QOL parameters (gas pain, body image, and physical functioning) favored the group receiving monotherapy; however, the results were not statistically significant. The authors also reported that there was a consistent pattern of better QOL outcomes at each follow-up assessment during the first 6 months of treatment for patients receiving monotherapy, and improvement over time was observed in both treatment groups but more so for the monotherapy patients.

In summary, MAB does not appear significantly better than single-agent LHRH analog therapy. At present, it appears reasonable to prescribe an antiandrogen during the first month of treatment with an LHRH analog. Prolonged treatment beyond 1 month with MAB is not superior to monotherapy with an LHRH analog.

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