Effects of dutasteride on prostate cancer incidence: A systematic review and meta-analysis

5-Alpha-reductase inhibitors (5-ARIs) are used in the treatment of benign prostate hypertrophy (BPH). 5-ARIs, such as inasteride and dutasteride, suppress the biosynthesis of dihydrotestosterone (DHT), a precursor of androgen, which is closely related to the incidence of prostate cancer (PCa). A previous meta-analysis demonstrated a relationship between inasteride use and the incidence of PCA. However, there have been nometa-analyses on the relationship betweenPCa anddutasteride alone. Thismeta-analysiswas performed to examine the prevalence of PCa in adult males taking dutasteride. We searched PubMed for reports regarding PCa risk and dutasteride use. The study was conducted according to the PRISMA guidelines for systematic reviews and meta-analyses. The analytic hierarchy process (AHP) method was used to weight the studies. Odds ratios (ORs), 95% con idence intervals (CIs), and Pvalueswere calculated using ixedand random-effectsmodels. A total of eight articles were included in the meta-analysis. The overall OR for both the ixedand random-effects models was 0.669 and the 95% CI for the random-effects model (0.526–0.851; P =0.006)waswider than that for the ixed effectsmodel (0.548–0.817; P < 0.001). This study con irmed that the incidence of PCa was signi icantly reduced by taking dutasteride.

INTRODUCTION 5-Alpha-reductase inhibitors (5-ARIs), such as inasteride and dutasteride, are used to treat benign prostate hypertrophy (BPH) (Burnett and Wein, 2006;Liang et al., 2012). These drugs prevent the conversion of testosterone to dihydrotestosterone (DHT) and are known to be closely related to the incidence of prostate cancer (PCa) (Wurzel et al., 2007). Previous studies showed that a reduction in the level of DHT, the androgen precursor, decreased the risk of PCa (Roehrborn et al., 2002;Ross et al., 2012). On the other hand, the US Food and Drug Administration (FDA) does not recommend 5-ARIs as a treatment for PCa because of their potential to increase the incidence and recurrence rates of PCa, and PCa-related mortality (Azoulay et al., 2015;USFDA, 2020).
However, some randomized clinical trials reported that 5-ARI drugs reduced PCa risk (Roehrborn et al., 2011;Rompay et al., 2019). A previous metaanalysis demonstrated a link between inasteride  (Wang et al., 2020). However, there have been no meta-analyses regarding the relationship between the incidence of PCa and treatment with dutasteride alone. Therefore, this meta-analysis was performed to examine the prevalence of PCa in adult males taking dutasteride alone.

Literature search
This study was conducted according to the PRISMA guidelines for systematic reviews and metaanalyses (Moher et al., 2009). We performed a literature search using PubMed. The search terms for dutasteride were "dutasteride" and "dutasteride capsules." The search terms for PCa were "prostate cancer," "PCa," "prostate carcinoma," and "prostate malignancy." All types of articles were searched for, and the reference sections of relevant systemic reviews were searched manually.

Selection criteria
Papers providing data about the relationship between dutasteride and PCa were included if they had suf icient data, such as the number of patients in the intervention and control groups, and the numbers of cases and non-cases, to calculate the odds ratio (OR) or relative risk (RR).

Exclusion criteria
Studies were excluded if they were related to PCa recurrence rather than incidence; included patients with current or previous PCa, or were duplicate publications.  To take consideration of the numbers of events and sample sizes of the study groups, logistic regression can be applied for ixed-effect meta-analysis using the Logistic SAS procedure. Besides, we used the GLIMMIX SAS procedure for mixed-effects logistic regression in the random-effects meta-analysis.

Results of the search
A total of 351 articles were identi ied (Figure 1). Duplicate articles, and those without dichotomous data, were excluded during the screening process. We also included papers in the reference sections of systematic reviews studying the relationship between the incidence of PCa and 5-ARI use (Andriole et al., 2010;Roehrborn et al., 2002).
In total, 37 papers passed the screening process, of which a further 29 were excluded according to the exclusion criteria outlined above. Therefore, a total of eight papers were included in the inal meta-analysis.

Characteristics of the included studies
The characteristics of the eight studies included in the meta-analysis are shown in Table 1. We extracted data regarding the numbers of cases and non-cases in the intervention and control groups. The follow-up period ranged from 3 to 14 years, and the average age of participants ranged from 62.8 to 72.6 years (Akaza et al., 2011).

Evaluation of weights
We used the analytic hierarchy process (AHP) method to weight the studies (Benaïm et al., 2010;de F.S.M. Russo and Camanho, 2015). Four weighting factors were used in this study: information regarding medications, impact factor (IF), sample size, and evidence level. We ranked these four factors based on a 4-point pairwise comparison scale.
We calculated the weights of each factor using the AHP method (Table 2).
Relatively high scores were assigned to studies with high independence of dutasteride among the variables. High scores were also given to trials using dutasteride alone, and low scores to those in which dutasteride was used in conjunction with inasteride, which has the same mechanism of action. High weights were given to studies with larger samples and higher IF values and evidence level (more reliable research method). The inal weights were calculated by matrix multiplication of the weight of factors and weight of studies (Table 4).

Meta-analysis
The overall OR for both the ixed-and randomeffects models was 0.669. The 95% CI of the random-effects model (0.526-0.851; P = 0.0056) was wider than that of the ixed-effect model (0.548-0.817; P < 0.0001) (Figure 2). The results suggested that dutasteride reduces the risk of PCa.

CONCLUSIONS
The results of this study showed that the incidence of PCa was signi icantly reduced when taking dutasteride alone. However, further studies exploring the side effects of dutasteride are required. Besides, additional studies are needed to verify the correla-tion between dutasteride and PCa risk.

Con lict of Interest
The authors declare that they have no con lict of interest

Funding Support
Basic Science Research Program supported this research through the National Research Foundation of Korea(NRF) funded by the Ministry of Education(No. NRF-2019R1F1A1057499).