Currently, many oncology guidelines do not recommend the use of IAD for patients with metastatic hormone-sensitive prostate cancer [36, 59]. But it is important to note that these guidelines date back to 2007. Guidelines from the European Association of Urology (EUA) state that IAD is now widely offered to patients with prostate cancer and should no longer be regarded as investigational [60, 61].
Two other meta-analysis published earlier [62, 63] showed that both treatments had similar results regarding OS and CSS. Analysis of OS was performed with 4 studies [8–12, 44, 45, 55] in the Niraula et al. meta-analysis  and 7 studies [8–12, 44, 45, 50, 52, 53, 55, 57] in Tsai et al. . CSS analysis was performed with 3 [9–12, 44, 45] and 6 studies [8–12, 44, 45, 51, 55, 57] respectively.
In this present meta-analysis, we included a larger number of studies. When HRs were not directly reported in the original study, they were estimated indirectly by using the reported number of events and the corresponding P value for the log-rank statistics, or by reading survival curves as suggested by Parmar et al. . To reduce reading errors, original survival curves were digitalized and enlarged, and data extraction was based on reading electronic coordinates for each point of interest, as described by DeLaurentiis in another meta-analysis .
In the final OS and CSS analyses we included 8 and 7 studies respectively. The induction time of androgen deprivation was, in general, 3-6 months. Two studies were available only in abstract form [48, 49, 56]. Overall, goserelin was the most used LHRHa, followed by leuprorelin. Only two studies [48, 49, 53] did not used luteinizing hormone–releasing hormone agonist (LHRHa) or orchiectomy. These studies used cyproterone acetate (CPA).
In this meta-analysis, randomized studies included heterogeneous groups of patients (locally advanced, metastatic or recurrent). It was not possible to perform the proper analysis of subgroups of patients (i.e. by Gleason score, initial PSA levels, minimal or extensive metastatic disease) because results for such sets were not published in the studies. As to overall survival, our results reinforce the equivalent efficacy of CAD and IAD, regardless of previous treatments.
Apropos of CSS, despite the overall analysis demonstrating only a trend towards treatment with CAD, the results must be interpreted with caution. As mentioned before, in one of the studies [11, 12] the baseline PSA levels were lower on the IAD arm, suggesting that these patients had less extensive disease. Once this trial was excluded from the analysis, results favored the group treated with CAD; therefore we cannot exclude the possibility that IAD may carry a higher risk of death by cancer.
Recently, a large prospective Danish study, including over 30,000 patients, investigated the relationship between androgen deprivation therapy (ADT) and cardiovascular diseases such as myocardial infarction (MI) and stroke in men with prostate cancer . The authors found that patients treated with medical endocrine therapy had an increased risk for MI and stroke with adjusted HRs of 1.31 (95% confidence interval [CI], 1.16-1.49) and 1.19 (95% CI, 1.06-1.35), respectively, compared with nonusers of ADT. However, androgen deprivation secondary to orchiectomy did no increase the risks for MI (HR: 0.90; 95% CI, 0.83-1.29) or stroke (HR: 1.11; 95% CI, 0.90-1.36). Nevertheless, the conclusions might have been affected, by the lack of information on prognostic lifestyles.
In this meta-analysis, mortality secondary to cardiovascular diseases, despite the heterogeneity found and the paucity of studies reporting this outcome, was favorable to the group treated with IAD. This aspect might have influenced the similar results achieved in OS.
In the event of biochemical recurrence after prostatectomy, when androgen deprivation is indicated, the best candidates for IAD are patients who reach PSA values <0.5 ng/mL after the induction time, according to a randomized study that was considered pure (i.e which included only patients with recurrence after prostatectomy) [1, 46, 47]. For biochemical recurrences after radiotherapy, the best candidates for IAD are patients who reach PSA levels <4 ng/mL after the induction time [9, 10]. Only in these situations (recurrence after radiotherapy or prostatectomy), TTP seems to be favorable to patients receiving CAD. In locally advanced and/or metastatic tumors, the best candidates for IAD are patients who reach PSA values <4 ng/mL after induction time.
Although TTP analysis was performed in this meta-analysis, the results should be evaluated with caution since criteria for progression were different among the included studies.
Patients with a lower burden of disease (i.e. less extensive diseases) and without co-morbidities may be the ones achieving most benefits with IAD treatment.
The implementation of guidelines to assess, monitor and reduce known risk factors for cardiovascular disease may influence the results of overall survival in patients treated with CAD.
Regarding quality of life, differences were not clinically significant in most studies. But it was observed that sexual activity scores seemed to be higher in patients treated with IAD, and the incidence of hot flushes was lower.
Furthermore, it is important to note that IAD modality offers an economic benefit with reduction of pharmaceutical costs during “off-therapy” . Economic analysis is not the aim of this investigation. The studies included failed to report the costs of both modalities (intermittent and continuous). Niraula et al. , analyzing only drug costs, estimated that the median cost savings with IAD would be 48%. Hering et al. , also based only on the average drug costs, demonstrated that the cost of treatment in IAD arm was approximately 50% lower that in the CAD, over 48 months.