Prostate cancer is the most common cancer in older men in the United Kingdom (UK), United States (USA) and Western Europe [1]. Despite its high incidence, the disease is often responsive to treatment even when metastatic and may be cured when localized. In patients with locally advanced tumors, recurrent or metastatic, the goals of therapy are to prolong survival, slow the progression of disease and preserve the quality of life [2].

Androgen deprivation (AD) constitutes, in most cases, the first-line of treatment for these cases. However, the deleterious effects of continuous androgen deprivation (CAD) are widely known and are related to some degree of deterioration in the quality of life. The most frequent symptoms resulting from AD include sexual dysfunction, fatigue, anemia, reduced muscle and bone mass, depression, abnormal lipid metabolism, cognitive dysfunction and development or worsening of metabolic syndrome [3, 4]. The negative impact of CAD in quality of life, secondary to the adverse events of sustained hormone deprivation, plus the costs of this therapy, motivated the intermittent treatment approach.

In recent years, non-randomized studies (most of them with heterogeneous criteria for selection and clinical assessment) were performed to confirm the effectiveness of intermittent androgen deprivation (IAD) in patients with prostate cancer. Two systematic reviews [5, 6] previously published analyzed the results of these non-randomized studies and the authors suggested that the best candidates for intermittent androgen deprivation are patients with biochemical progression after prostatectomy or radiation, with no evidence of metastases and with mildly aggressive tumors. On the other hand, patients with large tumor volumes, positive lymph nodes and bone metastases, PSA >100 ng/ml or short PSA doubling time, would be best treated with continuous deprivation.

Irrespective of official guideline recommendations, IAD is a treatment option used worldwide by both urologists and oncologists even outside of clinical trials [5].

The 2008 UK National Institute for Health and Clinical Excellence (NICE) recommends that IAD may be offered to men with metastatic prostate cancer providing they are informed that there is no long-term evidence of its effectiveness [7].

The results of some randomized controlled trials (RCT) were statistically inconclusive [8] or controversial. Crook et al. [9, 10] analyzed IAD versus CAD for prostate-specific antigen (PSA) elevation after radiotherapy, assessing overall survival (OS) in a non-inferiority randomized trial with 1,386. The results demonstrated that IAD was non-inferior to CAD in regard to OS (8.8 years versus 9.1 years respectively - hazard ratio for death, 1.02; CI 95% 0.86 to 1.21, p for non-inferiority = 0.009), besides providing potential benefits in aspects such as physical function, fatigue, urinary problems, hot flashes, libido, and erectile function. Furthermore, the authors pointed that time to hormone resistance was statistically significantly improved on the IAD arm (HR 0.80, 95% CI 0.67-0.98; p = 0.024).

Regarding time-to-progression or castration-resistant disease, however, Crook et al. [9, 10] showed better results in favor of CAD, while the results of Salonen et al. [11, 12] were favorable to IAD. Such contradictory results make it difficult to emit a strong scientific-based recommendation for or against IAD.

The objective of this study is to analyze all published randomized controlled trials (RCTs) that compared the efficacy and adverse events profile of IAD versus CAD for locally advanced, recurrent or metastatic hormone-sensitive prostate cancer.

The diagram represents the flow of identification and inclusion of trials, as recommended by the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) statement [27] (Figure 1).

Overall, 73 references were identified and screened.

Meta-analysis

Overall, TTP was similar in patients who received IAD or CAD (fixed effect: HR = 1.04; CI 95% = 0.96 to 1.14; p = 0.3), with high moderate heterogeneity (Chi² = 13.59, df = 8 [P = 0.09]; I² = 41%) (Figure 2).

OS and CSS were also similar in patients treated with IAD or CAD (OS: fixed effect: HR = 1.02; CI 95% = 0.95 to 1.09; p = 0.56 with moderate heterogeneity Chi² = 9.57, df = 7, P = 0.21, I² = 27% and CSS: fixed effect: HR = 1.06; CI 95% = 0.96 to 1.18; p = 0.26 also with moderate heterogeneity Chi² = 9.75, df = 6, P = 0.14, I² = 38% (Figures 3 and 4, respectively).

In order to explore this heterogeneity, the study by Salonen et al. [11, 12] was removed from the survival analysis, since patients treated in the IAD arm had lower levels of baseline PSA than patients on CAD group (IAD: mean PSA 116.0 ± 173.4 ng/ml; CAD: mean PSA 186.3 ± 454.4 ng/ml). Regarding OS, results remain similar between the groups (fixed effect: HR = 1.04; CI 95% = 0.96 to 1.12; p = 0.32) while there was a decrease in heterogeneity (Chi² = 6.87, df = 5, P = 0.23, I² = 27%). Furthermore, CSS was favorable to CAD (fixed effect: HR = 1.16; CI 95% = 1.02 to 1.31; p = 0.02; NNT = 6) with no heterogeneity (Chi² = 3.51, df = 5, P = 0.62, I² = 0%).

Four studies [8, 48–50, 54, 55] included only patients with metastatic disease (or ≥90% metastatic). In this subgroup of patients, only 1 study [50] reported TTP data and another [54] reported cancer-specific survival data, so a meta-analysis was not feasible. Two studies [8, 50, 55] reported OS data, which permitted meta-analysis. OS was also similar in patients treated with IAD or CAD (fixed effect: HR = 1.10; CI 95% = 0.98 to 1.24; p = 0.11) with no heterogeneity (Chi² = 0.02, df = 1, P = 0.88, I² = 0%).

Two studies [1, 9, 10, 46, 47] included only patients with recurrent disease after definitive local therapy (prostatectomy or radiotherapy). In this subgroup, TTP was favorable to patients who received CAD (fixed effect: HR = 1.19; CI 95% = 1.01 to 1.39; p = 0.03), with moderate heterogeneity (Chi² = 1.57, df = 1 [P = 0.21]; I² = 36%). However, when the random-effects model analysis was performed, no significant difference was detected (random effects: HR = 1.16, CI95% = 0.92 to 1.45; p = 0.22). It was not possible to perform a meta-analysis for OS and CSS, since only Crook et al. [9, 10] reported these data.

One study [58], on re-introduction of treatment in IAD group, used a hormone therapy scheme (cyproterone 300 mg/d) that was different from the one used in the CAD group (LHRHa: triptoreline 11.25 mg plus cyproterone 200 mg/d). When OS analysis was performed without this study, the results remained similar between IAD and CAD (fixed effect: HR = 1.04; CI 95% = 0.97 to 1.12; p = 0.25; with no heterogeneity: Chi² = 7.08, df = 6, P = 0.31, I² = 15%).

In most studies [8–10, 44, 48–50, 55] baseline quality-of-life scores were similar in both groups for the majority of items, with no clinically significant differences. Sexual activity scores appeared to be favorable in the IAD group (Table 5).

Study	EORTC quality-of-life core questionnaire (QLQ-C30) and the EORTC Prostate Cancer Module
Crook 2012 [9, 10](CIC-CTG PR.7 Trial)	Intermittent (better): hot flashes, desire for sexual activity, and urinary symptoms
	Continuous: -
Calais da Silva 2009/2011 [44, 45](SEUG Trial)	Intermittent (better): sexual function
	Continuous (better): emotional domain, nausea and vomiting, severity of insomnia
Hussain 2013 [8, 55](SWOG 9346 Trial)	Intermittent (better): erectile function and mental health at 3 months but not thereafter
	Continuous: -
Salonen 2012/2013 [11, 12](FinnProstate Trial VII)	Intermittent (better): sexual function
	Continuous: -
Tunn 2012 [1, 46, 47](EC507 Trial)	Intermittent: NR
	Continuous: NR
De Leval 2002 [51]	Intermittent: NR
	Continuous: NR
Langenhuijsen 2008/2013 [52, 53] (TULP Trial)	Intermittent: NS
	Continuous: NS
Miller 2007 [56]	Intermittent (better): sexual activity appeared to be favorable in the intermittent
	Continuous: -
Mottet 2012 [50](TAP 22 Trial)	Intermittent: NS
	Continuous: NS
Verhagen 2008/2013 [48, 49]	Intermittent (better): symptom and potency scales
	Continuous: -
Hering 2000 [54]	Intermittent (better): erectile function
	Continuous: -
Irani 2008 [57]	Intermittent (better): ability to have and maintain an erection.
	Continuous: -
Silva 2013 [58](SEUG 9901 Trial)	Intermittent (better): sexual activity
	Continuous: -

Abbreviations: EORTC European Organization for Research and Treatment of Cancer, NS not significant, NR not reported.

The prevalence of adverse events of androgen deprivation such as hot flushes (fixed effect: RR = 0.86; CI 95% = 0.82 to 0.90; p < 0.00001), gynecomastia (fixed effect: RR = 0.72; CI 95% = 0.65 to 0.80; p < 0.00001) and headache (fixed effect: RR = 0.81; CI 95% = 0.68 to 0.97; p-0.02) were more frequent in patients treated with CAD, with high heterogeneity levels (Figure 5). As planned, a random-effects model analysis was performed to better explore this heterogeneity. In this analysis, with exception of hot flushes (RR = 0.65; CI 95% = 0.45 to 0.95; p = 0.03; NNH = 10), adverse events were similar in both groups (gynecomastia: RR = 0.66; CI 95% = 0.39 to 1.13; p = 0.13 and headache: RR = 0.68; CI 95% = 0.42 to 1.10; p = 0.11).

Mortality secondary to cardiovascular events was report in only 4 studies [9–12, 44, 45, 58]. Results of this analysis were favorable to the group treated with IAD (fixed effect: RR = 0.80; CI 95% = 0.67 to 0.94; p = 0.007; NNH = 33) however with high heterogeneity levels (Chi² = 6.67, df = 3 [P = 0.08]; I² = 55%).

According to funnel plot analysis [23] the possibility of publication bias was low for all of the outcomes. When funnel plot shows asymmetry, there is a possibility of bias and despite its limmitations, this method is widely used by authors.

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 [62] and 7 studies [8–12, 44, 45, 50, 52, 53, 55, 57] in Tsai et al. [63]. 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. [18]. 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 [64].

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 [65]. 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” [62]. 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. [62], analyzing only drug costs, estimated that the median cost savings with IAD would be 48%. Hering et al. [54], 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.

Overall survival was similar between IAD and CAD in patients with locally advanced, recurrent or metastatic hormone-sensitive prostate cancer. Data on CSS are weak and the benefits of IAD on this outcome remain uncertain. Impact in QoL was similar for both groups, however, sexual activity scores were higher and the incidence of hot flushes was lower in patients treated with IAD.