Androgenic suppression combined with radiotherapy for the treatment of prostate adenocarcinoma: a systematic review

Prostate cancer is the second most prevalent neoplasm and the sixth leading cause of cancer mortality, with an estimated incidence of 903,500 new cases and 258,400 deaths in 2008 [1]. Historically, the incidence of this condition had a rapid increase during the early 1990s with later stabilization. This can be largely explained by the introduction of prostate specific antigen (PSA) testing, causing a sudden diagnosis boost worldwide. For the same reason, the distribution of prostate cancer cases was heterogeneous, with higher rates observed in the United States, Australia, Norway, Japan, Italy and others [2]. On the other hand, mortality has been declining in such countries, probably as a consequence of recent advances in treatment and support [3].

The advent of improved curative intent therapy for local disease has been suggested as one of the reasons for the decrease of prostate cancer deaths in the past decade. Current strategies for the management of localized prostate cancer consist of either surgical treatment or radiotherapy. Until the present, there has been no accurate comparison coming from randomized clinical trials evaluating the clinical efficacy of these strategies. Another reason could be related to response to therapy, which is highly dependent on other prognostic factors. For example, patients classified as low-risk (PSA ≤ 10 ng/ml, Gleason ≤ 6, stage T1c or T2a) and treated with radiotherapy have better prognosis, with a reported 10 year mortality of 2%, while higher risk patients face mortality rates ranging from 12% to 30% [4]. On the other hand, a surgical approach for locally advanced prostate cancer had shown cure rates of less than 25% [5]. Therefore, external-beam radiotherapy is usually the preferred treatment in this setting, due to an acceptable survival rate [6] and less morbidity than surgery. Nonetheless, patients with locally advanced disease have the worst prognosis and higher chances of relapse [7].

Since the 1970s, the role of androgen deprivation therapy adjuvant to radiotherapy to treat locally advanced prostate cancer has been investigated [8]. The inhibitory effect of androgen deprivation on the growth and proliferation of prostate cancer cells is well established. Several studies have shown a rapid regression of prostate cancer after total androgen blockade, leading to hypothesize that the marked regression observed at the prostatic level of both malignant and non-malignant tissue may increase radiation efficacy. In decreasing the tumor size by antiandrogen medication, an optimal dose of radiation could treat adequately prostate cancer with less adverse events.

In this context, androgen deprivation therapy has been a matter of discussion and study as a complementary treatment for high-risk patients. Evidence in favour of its use combined with radiotherapy has been described, with benefit in terms of overall survival [9]. However, the optimal time for introduction, duration of hormone therapy, and the type of suppression involved are still unanswered issues.

In this meta-analysis, the authors intended to summarize all the published data to perform appropriate comparisons between the different regimens used for androgen deprivation in patients receiving radiotherapy for localized or locally advanced prostate cancer.

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.

This meta-analysis was able to demonstrate a benefit from the combination of androgen deprivation therapy and external-beam radiotherapy for high-risk prostate cancer patients. The use of goserelin for a period longer than 1 year was associated with more beneficial survival outcomes, and should be considered standard treatment for those with higher risk of relapse. At this time, there is insufficient evidence to support other LHRH analogues or identify possible limiting long-term toxicities.