2532 Original Article Association of 5-alpha-reductase inhibitor and prostate cancer incidence and mortality: a meta-analysis Xu Hu1#, Yao-Hui Wang1#, Zhi-Qiang Yang1#, Yan-Xiang Shao1, Wei-Xiao Yang1, Xiang Li2 1West China School of Medicine/West China Hospital, Sichuan University, Chengdu, China; 2Department of Urology, West China Hospital, West China Medical School, Sichuan University, Chengdu, China Contributions: (I) Conception and design: X Li, X Hu; (II) Administrative support: None; (III) Provision of study materials: X Li; (IV) Collection and assembly of data: X Hu, ZQ Yang, YH Wang, YX Shao; (V) Data analysis and interpretation: X Hu, YH Wang, WX Yang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. #These authors contributed equally to this work. Correspondence to: Prof. Xiang Li. Department of Urology, West China Hospital, West China Medical School, Sichuan University, 37 Guoxue Street, Chengdu 610041, China. Email: [email protected]. Background: 5-Alpha-reductase inhibitors (5-ARIs) have been suggested as potential chemopreventive agents for prostate cancer (PCa). This study was conducted to evaluate the effect of 5-ARIs on the incidence and mortality of PCa. Methods: The PubMed, Embase and Cochrane Library databases were searched comprehensively from database inception to October 2019. The clinical outcomes included the incidence of overall PCa, high- grade (Gleason8-10) PCa, metastatic PCa, overall survival (OS), and cancer-specific survival (CSS). Results: Overall, 23 studies were included in the present study, representing 11 cohort studies, 5 case- control studies, and 8 randomized controlled trials. The use of 5-ARIs was associated with a decreased risk of overall PCa [relative risk (RR) =0.77; 95% CI: 0.67–0.88; P<0.001] and increased risk of Gleason 8–10 PCa (RR=1.19; 95% CI: 1.01–1.40; P=0.036). In terms of metastatic PCa, there were no significant between- group differences (RR=1.23; 95% CI: 0.69–2.18; P=0.487). Furthermore, we found that prediagnostic 5-ARI usage was not associated with an increased risk of overall or prostate cancer mortality, with HRs of 1.00 (95% CI: 0.92–1.08; P=0.938) and 0.98 (95% CI: 0.80–1.21; P=0.881), respectively. Conclusions: In conclusion, while male 5-ARI users were associated with a decreased risk of overall prostate cancer and increased risk of high-grade prostate cancer (Gleason 8–10), they were not associated with an increased risk of overall or prostate cancer mortality. 5-ARIs should be recommended carefully for use as chemopreventive agents. Keywords: 5-alpha-reductase inhibitor; prostate cancer (PCa); incidence; mortality; meta-analysis Submitted Apr 01, 2020. Accepted for publication Sep 11, 2020. doi: 10.21037/tau-20-843 View this article at: http://dx.doi.org/10.21037/tau-20-843 Introduction would have a powerful impact on public health (2). In addition, PCa could be an ideal target for chemoprevention Prostate cancer (PCa) is the second most commonly diagnosed noncutaneous malignancy and the fifth leading because of its attributes, such as long latency period and cause of cancer mortality in men worldwide (1), and multistep pathogenesis (3). mortality from PCa (359,000 deaths in 2018) is markedly 5-alpha reductase inhibitors (5-ARIs), such as lower than PCa incidence (1.3 million new cases in 2018) (1). finasteride and dutasteride, are commonly used in the Due to the high occurrence of prostate cancer as well as the treatment of benign prostatic hyperplasia (BPH). They human and economic cost of treatment, preventive measures inhibit the conversion of testosterone to the more potent © Translational Andrology and Urology. All rights reserved. Transl Androl Urol 2020;9(6):2519-2532 | http://dx.doi.org/10.21037/tau-20-843 2520 Hu et al. Association between 5-ARI and PCa incidence and mortality dihydrotestosterone, which reduces the prostate volume and placebo or nonusers; (IV) reported clinical outcomes, such improves urinary flow obstruction (4). 5-ARIs have been as prostate cancer incidence, mortality, or recurrence. We suggested as potential chemopreventive agents for prostate removed the following studies: (I) non-English language; (II) cancer. 5-ARIs were used after the diagnosis or treatment of PCa; Two large randomized controlled trials (RCTs), the (III) did not report relevant clinical outcomes; (IV) reviews Prostate Cancer Prevention Trial (PCPT) and Reduction and conference abstracts. For duplicated records, we only by Dutasteride of Prostate Cancer Events (REDUCE), enrolled the study with the largest cases and most applicable showed 24.8% and 22.8% risk reductions in prostate information. cancer incidence with the use of 5-ARIs, respectively (5,6). However, both trials observed that 5-ARI users have an Data extraction and quality assessment unexpected increased risk of high-grade tumors compared with placebo (5,6). Because it remains unknown whether Two investigators independently extracted the following the association was a result of bias, the utilization of 5-ARIs information from each study: first author’s name, published for chemoprevention is not endorsed. year, study design, enrollment data and location, disease, It can be hypothesized that, because 5-ARIs increase the drugs in experimental and control groups, number of cases, risk of high-grade tumors, they should increase the risk of age, clinical outcomes, and the duration of follow-up. We prostate cancer outcomes, such as mortality. To date, several evaluated the quality assessment observation studies and contradictory studies have explored the impact of 5-ARIs RCTs using the Newcastle-Ottawa Quality Assessment on prostate cancer outcomes (7-10). In addition, some Scale (NOS) and the Cochrane Collaboration Risk of Bias studies did not detect an association between the use of Tool, respectively (13). 5-ARIs and increased risk of high-grade tumor (2,11). As a result, we performed the present study and summarized all Statistical analysis relevant studies to evaluate the association between 5-alpha- reductase inhibitors and prostate cancer incidence and For prostate cancer incidence, we used relative risk (RR) mortality. We present the current study in accordance with as the statistic. For the clinical outcomes, such as overall the Preferred Reporting Items for Systematic Reviews and survival (OS) and cancer-specific survival (CSS), the hazard Meta-Analyses (PRISMA) reporting checklist (12) (available ratio (HR) was applied. The heterogeneity among studies at http://dx.doi.org/10.21037/tau-20-843). was evaluated by calculating the Q and I2 statistics. If the I2 statistics showed P<0.10 or I2 >50%, a random-effect model was applied (14). Sensitivity analysis was carried out by Methods repeating the meta-analysis after the removal of each study Literature search strategy and assessing the robustness of the combined estimate. Concerning publication bias, we applied the Egger’s test PubMed, Cochrane Library, and Embase were and Begg’s test. If publication bias was detected, the trim comprehensively searched from inception to October 2019. and fill method was used to estimate the missing studies and We adopted the following search items: 5-alpha reductase recalculate the statistics (15). We also performed subgroup inhibitor (5-a-reductase inhibitor, 5-ARIs, finasteride, analysis and meta-regression to explore the potential source dutasteride, epristeride) and prostate cancer. We also of heterogeneity. Statistical analyses were conducted using reviewed reference lists of eligible studies to identify any STATA version 12 (StataCorp, College Station, TX, USA). additional relevant studies. Two investigators conducted the A two-sided P value <0.05 was regarded as statistically literature search independently, and any disagreement was significant. resolved by consulting a third investigator. Results Inclusion and exclusion criteria Study selection We included studies that met the following criteria: (I) population-based studies; (II) 5-ARIs were used before Our initial search strategy yielded 4,976 records, whose the diagnosis of PCa; (III) compared 5-ARI users with titles and abstracts were screened. After the removal of © Translational Andrology and Urology. All rights reserved. Transl Androl Urol 2020;9(6):2519-2532 | http://dx.doi.org/10.21037/tau-20-843 Translational Andrology and Urology, Vol 9, No 6 December 2020 2521 Identification Identified studies through database search (N=4,976) Excluded duplicates articles (n=1,193) Screening 3,783 articles remained after duplicates removed Excluded based on titles and abstracts (n=3,702) 81 articles were accepted for further review Eligibility Drugs were used after diagnosis (n=32) Did not compare between 5-ARIs with others (n=11) Duplicated records (n=5) Other exclusion (n=10) Included 23 articles were enrolled in the final analysis Figure 1 Flow chart of the study selection. duplicated records and initial screening, 81 studies were quality. The detailed information is summarized in Table 1. further reviewed in the full text. At the end of the process, The quality assessment of RCT is presented in Table S1. 23 studies were confirmed to match the eligibility criteria and enrolled in the final analysis (2,5-10,16-31) Figure( 1). Overall prostate cancer Concerning the incidence of overall PCa, 16 studies Clinical characteristic of the enrolled studies reported relevant information. We found that the use Overall, 23 studies were included in the present study. They of 5-ARIs was associated with decreased risk of overall included men from the United States, France, Sweden, PCa, with an RR of 0.77 (95% CI: 0.67–0.88; P<0.001; Finland, and others. Of the included studies, 11 were Figure 2A). We detected significant heterogeneity cohort studies, 5 were case-control studies, and 8 were (I2=91.5%; P<0.001); thus, we used the random-effect RCTs. One study consisted of a cohort and case-control model. When stratified by study design, we also observed study (8).