An overall conclusion of this review and meta-analysis is that androgen deprivation therapy can be significantly beneficial for patients in terms of DFS and OS, when combined with radiotherapy. Nevertheless, many strategies for suppression have been studied so far, with conflicting results regarding efficacy and tolerability.
Estrogen therapy in high doses seems to be linked with higher risks of cardiovascular and thromboembolic events [24
], but more importantly, failed to produce benefit in a small, single trial of 84 patients. The trials evaluating the performance of orchiectomy indicated a possible advantage to its use, though lacking statistical significance. For the reasons stated, we concluded that there is no evidence so far, to support the use of definite deprivation for such patients, nor accurate analyses of possible long-term toxicity. Hence, current studies point toward androgen suppression with LHRH analogues as more advantageous in these cases. Until the present time, goserelin was the most studied compound in this category. Further studies are warranted to demonstrate a similar benefit from other types of analogues. Additionally, combination therapy with peripheral blockade did not offer a major benefit in comparison to goserelin monotherapy.
There is still much discussion about the comparison of LHRH analogues to surgical castration regarding testosterone levels. Chemical androgen deprivation is reported to be similar among the different types of analogues used, although there is fear that sudden elevations in the level of testosterone, according to distinct pharmacodynamic characteristics, could interfere with treatment and ultimately compromise survival [25
]. Authors of a recent systematic review did not provide evidence of such a presumed effect from the analogues used in practice [26
Our study also suggested that longer androgen suppression results in better DFS and OS. Those observations are in accordance to a previous systematic review focusing the duration of deprivation therapy [27
], and a randomized clinical trial comparing 6 months versus 2 years of treatment [28
Some limiting factors in this meta-analysis must be highlighted. There were different schedules of treatment resulting in the high heterogeneity described and the distinct patient selection criteria applied from each investigator. One example is the trial from Bolla and colleagues [16
], presenting the greatest reported benefit in survival with the use of 3 years of goserelin after completion of radiotherapy. Though statistically significant data were favourable for the use of such a protocol, there are still questions concerning the definition of high-risk patients in this study (T1 or T2 with histological grades greater than 3, or T3 and T4 with any grade). Distinct criteria among studies have limited the possibility to identify, with great accuracy, the groups expected to benefit from androgen suppression.
Moreover, there has been some discussion involving the type of radiotherapy performed, with the hypothesis that either conformational or intensity modulated treatments - by delivering higher doses of radiotherapy - could reduce the necessity of androgen deprivation. This idea, however, was not proven in randomised clinical trials for high-risk patients. In low-risk prostate cancer, one prospective randomised study compared conformational versus standard external beam radiotherapy, and described a reduction of biochemical relapse from 32% to 17%, without impact on overall survival [29
Toxicity analyses were impeded by scarce reports of adverse events in the published articles. Results from observational studies have suggested the possibility that long-term androgen suppression might be related to a higher risk of metabolic syndrome [30
] and osteoporosis [31
], despite the lack of such descriptions in prospective work. Taking into account the tendency of higher efficacy with a longer duration of therapy, as shown in our analysis, such knowledge should be important in future trials.