The available evidence from RCTs might support the use of early instead of deferred AST for patients with node-positive prostate cancer following local therapy for overall survival, cancer-specific survival, and clinical progression. However, this therapy is probably associated with an increased frequency of adverse events. The quality of evidence provided by RCTs is hampered by the risk of bias.
We included data from studies assessing early versus deferred AST. The type of AST was, however, varied among the studies included. This could lead to bias because the debate concerning the equivalence of different AST therapies is still ongoing. LHRH agonists were found to be as effective as surgical castration with orchiectomy . Orchiectomy is currently performed less frequently due to its irreversibility and potential negative psychological effects but is an effective therapy with which to achieve castration . Current guidelines recommend that selection between these two therapy options should be made after a discussion that includes both the patients and the physicians . Non-steroidal antiandrogens (high-dose bicalutamide) might be an alternative to castration for patients with locally advanced, non-metastatic disease (M0). The benefit compared with castration has not been determined . However, we included the data related to bicalutamide therapy (EPC program) only for the evaluation of clinical progression at 3 years (Figure 4) and the results remained significant after exclusion of data to bicalutamide from meta-analysis. The risk of potential bias therefore remains low. Unfortunately, our data allowed no identification of outcome differences between the different AST therapy options.
We included studies assessing AST for patients that were treated with either radical prostatectomy or radiotherapy. Therefore, there might be clinical heterogeneities considering the type of local therapy that the patient received. However, we performed subgroup analyses to address potential outcome differences. Both local therapies (radical prostatectomy or radiotherapy) are often used for the treatment of localized prostate cancer. However, it must be considered that the techniques of radiotherapy and radical prostatectomy have advanced considerably since these studies were conducted. We are not able to estimate how this development can alter the outcome of patients that are currently treated. This omission should be addressed when interpreting our data.
We included data from patients with lymph node-positive disease as assessed by lymphadenectomy or imaging. In two studies (RTOG-85-31, EPC program), imaging was used to define nodal involvement associated with malignancy. Bias might occur because staging performed by any method other than lymphadenectomy might be sub-optimal. Pathological staging is much more accurate than clinical staging with computer tomography. The authors of the study conducted by the Early Prostate Cancer Program (EPC program) suggested that most patients with node-positive disease were diagnosed with radical prostatectomy and therefore had histologically confirmed nodal status . However, we were unable to consider data on the extent of lymph-node involvement for all included studies. This factor is, however, known to significantly impact prognosis [19, 20].
We included a total of 3 studies for the evaluation of overall survival, and all reported favorable overall survival for early AST. We were unable to identify subgroup analyses concerning node-positive patients from any of the excluded randomized controlled trials. However, non-randomized studies provide further evidence for those on node-positive prostate cancer reporting controversial results. In contrast to our results, only two observational studies demonstrated a statistically significant benefit of early AST [21, 22]. Although Myers et al. reported small differences between early and deferred AST , results from other observational studies did not favor either of the two adjuvant therapy options [24–28]. No observational study showed a significant difference for either early or deferred AST for cancer-specific survival for patients with node-positive prostate cancer after local therapy [26–31].
Our results suggest that early AST in patients with node-positive prostate cancer after local therapy delays the progression of clinical disease. This conclusion is supported by several observational studies demonstrating an advantage for early AST as compared to deferred therapy in patients with node-positive prostate cancer [24, 27, 31–33]. There is also evidence from RTOG-85-31 that early AST has a beneficial effect on the incidence of metastatic disease (time from randomization to clinical or radiological evidence of disease beyond the pelvis) as compared to deferred treatment (p = 0.026) .
The information available on adverse events is limited, as they were not consistently reported in all studies. However, our data suggest that early AST results in an increased frequency of adverse events; this conclusion is supported by other reports [34–37]. This should be balanced against a potential improved local control  and a reduced occurrence of complications due to tumor progression (i.e. cord compression, ureteric obstruction, and extra-skeletal metastases) .
Studies included in the present review compared the administration of AST either at the time of local therapy or symptoms of clinical progression, but PSA was not routinely used as a marker for disease progression in any of the studies included. However, PSA testing currently plays an important role in the detection of prostate cancer and biochemical disease progression. In modern patient treatment, PSA testing is used to assess the risk for extraprostatic dissemination or lymph-node involvement, for example, by using nomograms . This has substantially decreased the proportion of men who are upstaged with surgery. Current patient cohorts might therefore be different than those enrolled previously. It might be advisable that it is an obligation to follow high-risk patients using PSA measurement in a regular manner [22, 29, 40].
The application of our results is hampered by the fact that the available studies are rather outdated and included patients who might no longer represent the contemporary population. The risk of bias is also notable. However, the present study provides the best evidence on this clinically relevant topic, reporting improved survival, delayed disease progression, but also more adverse events among patients with node-positive prostate cancer after local therapy treated with early AST as compared to deferred AST. AST is challenging to clinicians for two reasons: for one, patients with advanced prostate cancer demand the highest possible quality of life and are intrigued by the thought of therapy-free intervals suggesting successful overall management. Second, the communication of hypotheses regarding the preservation of androgen dependence in earlier years left many urologists uncertain about the best use of AST and how to counsel patients. Thus, the present data offer the best currently available evidence-based guidance for clinicians. Nevertheless, new studies using modern diagnostic evaluation, biochemical testing, and standardized follow-up schedules are warranted.