REVIEW 5α-Reductase Inhibitors Could Prevent the Clinical and Pathological Progression of Prostate Cancer: A Meta-analysis Yue Yang1,2,3, Haifeng Hu1**, Hanchao Zhang1,2,3, Zhengdao Liu2,3, Faliang Zhao2, Jin Yang1, Guobiao Liang2,3* Purpose: To explore the efficacy of 5-ARIs in PCA (Prostate Cancer). Methods: Searching through the major medical databases such as PubMed, Science Citation Index, EMBASE, Medline, Web of Science, Cochrane Library for all published studies in English until 2018. The following search terms were used: “Finasteride”, “dutasteride”, “5α reductase inhibitors”, “5-ARIs”, “prostate cancer”, “prostate neoplasm” and the additional related studies were manually searched. Newcastle-Ottawa Scale (NOS) assessed the qualities of studies, and the outcome measures were observed by RR or OR with 95% CIs. Results: We included 9 eligible studies for analyses from 2011 to 2017. We found that 5-ARIs group may have fewer progression (OR = 0.48 95%CI: 0.37-0.61 P < 0.00001, I2=4% p = 0.39) and lower pathological progression (OR = 0.46; 95%CI: 0.29-0.73; p = 0.001, I2=0% p = 0.45), compared with control groups. However, the OS did not show significant difference between two groups (OR=1.10; 95%CI:0.90-1.35; P = 0.35, I2 = 93% P < .00001 ). Conclusion: The use of 5-ARIs could prevent progression in PCA patients both clinical and pathological. Keywords: 5α-reductase inhibitors, prostate cancer, clinical progression, pathological progression, meta-analysis INTRODUCTION Inhibitors of 5a-reductase(5-ARIs), such as finas-teride and dutasteride, are widely used in the medical treatment of benign prostatic hyperplasia (BPH)(1), and these drugs inhibit the conversion of testosterone to di- hydrotestosterone(DHT) to reduce the prostate size and alleviate the lower urinary obstruction. Blocking DHT leads to a lower level of androgen, which is involved in the development of prostate cancer, thus we may won- der that 5-ARIs may have an effect on prostate cancer or not. The Prostate Cancer Prevention Trial (PCPT)(2), a large, phase III and double-blind placebo-control trial, reported that finasteride may decrease the risk of new prostate cancer through changes in intraprostatic an- drogen. The data was impressive, however, some other studies(3) also pointed out that there were no strong piec- es of evidence that showed the benefit of the finasteride and analogous 5-ARIs. Therefore, researchers have a furious conflict about the efficacy of 5-ARIs in prostate cancer, and we did this meta-analysis to quantify the effect of 5-ARI on PCA patients. METHODS Search Strategy We searched Pubmed, Embase, and the Cochrane Li- brary(until May 6, 2018). In addition, we searched 1Urological Department, The Affiliated Hospital and Clinical Medical College of Chengdu University, Chengdu, Sichuan, China 2Urological Department, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China) 3Medical College of Soochow University, Suzhou, Jiangsu, China *Correspondence: Doctoral Supervisor of Medical College of Soochow University, Suzhou, Jiangsu, China and The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China. Tel: 010-035-88623287 email: yyjakejerry@163.com. ** Contributed equally to this work and should be considered a co-first author. Received September 2018 & Accepted January 2021 potentially relevant trials from the references of select- ed studies by hand. The search strategy was followed by using all possible combinations of medical subject headings(MeSH) or non-MeSH terms: “finasteride”, “dutasteride”, “5α reductase inhibitors”, “5-ARIs”, “prostate cancer”, “prostate neoplasm” and the addi- tional related studies were manually searched. Each search strategy met each database. (Figure 1) Selection Criteria Studies that were published in English were selected if they met the following criteria: (1) All patients should be diagnosed with prostate cancer(PCA) in pathology. (2) All patients’ clinical and pathological parameters were covered (3) All studies should be controlled tri- als which compared 5-ARIs with placebo (4) The ob- servations should report at least one of our outcomes: progression of cancer and overall survival(OS). (5) The same trial that was reported by different articles should be excluded. (6) Case reports, letters, systematic re- views, comments, and animals trial should be excluded. Data extraction Two reviewers independently assessed all eligible pub- lications, and disagreements were resolved by discus- sion with a third reviewer. Data from all full-text studies that accorded with selection criteria were independent- ly extracted by each reviewer using a standardized ex- Urology Journal/Vol 18 No. 3/May-June 2021/ pp. 247-251. [DOI: 10.22037/uj.v18i.4831] traction form. All the data extracted from the studies included details on the first author name, publication year, country, study design, study period, number of pa- tients, duration of follow-up (Table 1). Outcome Measures The primary outcome measures were a progression of cancer, defined as the number of the patients who got disease progressing including clinical and pathological progression. Secondary outcome measures in this me- ta-analysis were overall survival (OS), defined as the time from observation to death during the research. Statistical Analysis Differences were expressed as RR with 95% CIs for the primary outcome and OR for the secondary outcome. The RR below 1 meant an advantage of 5-ARIs better than the placebo such as none of the analogy. I2 sta- tistics were used to quantify the heterogeneity across trials, which is a standardized measure of inconsistency and chi-square(Cochrane Q statistic) test. If I2 statistics < 50% and as a p-value > 0.05 for chi-square test, it indicted to have a low level of heterogeneity. A fix-ef- fects model was used to pool estimates in a low level of heterogeneity. A random-effects model was used to pool estimates in a high level of heterogeneity. Patient characteristics and other confounding factors in all the studies didn’t have significant heterogeneity. Mean- while, Subgroup analyses were planned to assess the effect of different progression of the tumor. A P value <.05 was affirmed as statistically significant. Quality Assessment The methodological quality of each controlled trial was evaluated by using the Newcastle-Ottawa Scale (NOS) [4] which was recommended for assessing the qualities of studies and a study with >= 7 awarded stars was con- sidered as a high-quality study. RESULTS After removing 122 duplicates, 209 potential studies were identified through reviewing abstracts and articles, 42 studies were excluded due to no combination thera- py, incomplete outcome data, no comparison group, or not in English. The final set of eligible studies included 9 studies(5-13), published from 2011 to 2017. The selec- tion strategy is shown in Figure 1. The characteristics of 9 included studies are summarized in Table 1. A to- 5-ARIs prevent progression of prostate cancer-Yang et al. Review 248 Table 1. Demographic and clinical data of DM and non-DM patients in different studies. Reference Country Center Design Period Sample Age Follow-up Event Quanity 5-ARI Placebo 5-ARI Placebo ( years) Aners Kjellman 2013 Denmark M T 1989-2001 199 2806 73.9+8.3 73.6+8.5 3 1,2 ********* Antonio Finalli 2011 Canada S T 1995-2010 70 218 65.6+6.4 63.8+7.8 4 3,4 ******* Ashley E.Ross 2011 USA M T 1994-2010 47 540 66 65 4 3,4 ****** Charles Dai 2017 Egypt S T 2002-2015 70 301 66+7 64+7 3 1,3 ******* Fritz Schroder 2013 USA S R N 147 146 69.7 68.6 2 3 ****** Laurent Azoulay 2015 Canada M T 1999-2009 574 13318 76.2+8.2 71.9+9.2 5 3,5 ******** Neil E Fleshner 2012 Canada S R 2006-2007 147 155 N N 3 3,4 ***** Rodolfo Monotironi 2013 Italy S R N 41 42 64+4 63+7 2 3,4 ****** Teemu J.Murtola 2013 Finland S T 1995-2009 24 901 N N 4 1,3,4 ***** Center: M: multiple centers, S: single center ;Event: 1:Overall survival,2:Prostate-cancer specific surviva, 3:Progression, 4:Pathologic progression, 5:All cause mortality;T:Retropective, R:Rondomized;N: not mentioned Figure 1. Selecting flowchat for included studies in the meta-analysis tal of 19764 patients were included in this meta-analy- sis. 1319 patients were treated with 5-ARIs. Effect of interventions on the primary outcome measure Progression (both clinical and pathological progres- sion) was the primary outcome measure in this me- ta-analysis. Using a random-effects model, the pooled OR was 0.48(95%CI: 0.37-0.61; p < 0.00001, Figure 2). This represented significantly fewer progression in patients with 5-ARIs, and no heterogeneity was ob- served (I2=4%, p = 0.39). Furthermore, the subgroup analyses were conducted and shown in Figure 3. The pathological progression also decreased in 5-ARIs groups (OR=0.46; 95%CI: 0.29-0.73; p = 0.001, heterogeneity p = 0.45, I2 = 0%), thus PCA patients gained more benefit from 5-ARIs. The second outcome, Overall survival(OS) did not show significant difference between two groups (OR=1.10; 95%CI, 0.90-1.35; p = 0.35, heterogeneity p < 0.00001, I2=93%, Figure 4).No significant publication bias ex- isted in the funnel plots. DISCUSSION We present this meta-analysis to assess the effect of 5-ARIs in treatment with PCA, and the results showed an inspiring outcome that 5-ARIs may prevent the pro- gression of PCA. In our study, less progression was observed in the 5-ARIs groups ( 5-ARIs vs Placebo OR=0.48 95%CI:0.37-0.61; p < 0.00001). Further- more, the subgroup analysis was also undertaken and we identified a positive effect of 5-ARIs in pathologi- cal progression(5-ARIs vs Placebo, OR=0.46, 95%CI: 0.29-0.73, p = 0.001, I2=0%). Moreover, the results were coincident with recent researches, and increasing evidence suggested that there may be a close affinity between PCA and 5-ARIs. In the Prostate Cancer Pre- vention Trial(PCPT), a total of 18882 patients were as- signed to finasteride or placebo for PCA with 7 years follow-up, and the study showed that the finasteride could reduce the risk of prostate cancer by 25%(14). Meanwhile, Fritz Schroder.et(10)also conducted a rand- omized, placebo-controlled Avodart after radical ther- apy for prostate cancer study(ARTS), which included 294 subjects with dutasteride treatment over 2 years and they concluded that dutasteride could delay the progres- sion of PCA, even in patients with biochemical failure after radical therapy for clinically localized disease. In fact, the drugs, such as finasteride, dutasteride, and oth- er 5-ARIs, inhibited testosterone to DHT, which played an important role in the PCA mechanism. The progres- sion of PCA could perform in a clinical or patholog- ical way. The clinical progression may behave as tu- mor metastasis, a higher level of PSA, or biochemical progression after therapies. Studies demonstrated that PCA was an androgen-relative tumor, thus impeding the original substrate of translation to androgen should prevent the progression of PCA somehow. Besides, pathological progression can be defined as an increased 5-ARIs prevent progression of prostate cancer-Yang et al. Vol 18 No 3 May-June 2021 249 grade, increased number of scores to more than three, or any core involvement over 50%. Noticeably, the tri- al[13] reported that those taking 5-ARIs could bring an approximate 50% reduction in the rate of pathological progression. However, many conflicts(15) also point- ed out that the finasteride contributed to the increase in high-grade cancers. Long-term 5-ARIs treatment had been proposed to alter the histologic appearance of prostate cancer tissue, which would falsely lead to high Gleason grades in a low-grade tumor(5), but larger prostates are more likely to be undergraded at initial di- agnostic biopsy, thus patients who took 5-ARIs might theoretically be likely to be detected with a higher grade with subsequent biopsies(16) and it might not be ascribed the higher Gleason score in a low-grade tumor to a pathologic progression. Eventually, as the aspect of the amount of observation(12), 5-ARIs appeared to diminish the progression of PCA patients. Counting for the overall survivals, our study found there was no significant difference between 5-ARIs and placebo (OR=1.10; 95%CI, 0.90-1.35; p = 0.35). A re- cent Finnish Prostate Cancer Screening trial[18] simi- larly implicated that 5-ARIs use didn’t have an impact on survival ( HR=1.51, p = 0.8). Meanwhile, a larger study(18), which included over 3 million patients from Denmark, reported that 5-ARIs were associated with an increased risk of PCA-specific mortality( HR=2.1, 95%CI: 1.97-2.30). However, even more, studies should be needed to definitely prove this in the future. To our knowledge, this is the first meta-analysis to systemically assess the efficiency of 5-ARIs in the pro- gression of the PCA patients. The present meta-analysis carries few limitations that must be taken into account. The main limitation is that our meta-analysis contains few randomized data, most of the studies included were observational. Although the heterogeneity of studies was not obvious, all the patients in different groups were not possible to match for age, BMI, preopera- tive therapy, and these biases may affect the primary outcome. All these factors may have contributed to a higher heterogeneity between studies. Because of these limitations, larger and randomized control trials were needed to confirm these results. CONCLUSIONS The use of 5-ARIs could prevent progression in PCA patients both in clinical and pathological terms. ACHNOWLEDGEMENTS Funding: This study was funded by The Education Department Fund Project of Guizhou Province,Grant No.KY (2017) 045 and Science and Technology Fund Project of Guizhou Province (grant no. (2015) 31). CONFLICT OF INTEREST None of the authors have a conflict of interest to de- clare. REFERENCES 1. Taghavi A, Mohammadi-Torbati P, Kashi A H, et al. Polyomavirus Hominis 1(BK virus) Infection in Prostatic Tissues: Cancer versus Hyperplasia[J]. Urol J, 2015,12(4):2240-2244. 2. Hoque A, Yao S, Till C, et al. Effect of finasteride on serum androstenedione and risk of prostate cancer within the prostate cancer prevention trial: differential effect on high- and low-grade disease[J]. Urology, 2015,85(3):616-620. 3. Unger J M, Hershman D L, Till C, et al. Using Medicare Claims to Examine Long- term Prostate Cancer Risk of Finasteride in the Prostate Cancer Prevention Trial[J]. J Natl Cancer Inst, 2018. 4. Irish M, Ramanan S. A question of scale[J]. Elife, 2019,8. 5. Murtola T J, Kujala P M, Tammela T L. High-grade prostate cancer and biochemical recurrence after radical prostatectomy among men using 5alpha-reductase inhibitors and alpha-blockers[J]. Prostate, 2013,73(9):923- 931. 6. Montironi R, Bartels P H, DeCensi A, et al. A randomized phase IIb presurgical study of finasteride vs. low-dose flutamide vs. placebo in men with prostate cancer. Efficacy monitored by karyometry[J]. Urol Oncol, 2013,31(5):557-565. 7. Fleshner N E, Lucia M S, Egerdie B, et al. Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial[J]. Lancet, 2012,379(9821):1103-1111. 8. Azoulay L, Eberg M, Benayoun S, et al. 5alpha- Reductase Inhibitors and the Risk of Cancer- Related Mortality in Men With Prostate Review 250 5-ARIs prevent progression of prostate cancer-Yang et al. Vol 18 No 3 May-June 2021 251 Cancer[J]. JAMA Oncol, 2015,1(3):314-320. 9. Dai C, Ganesan V, Zabell J, et al. Impact of 5alpha-Reductase Inhibitors on Disease Reclassification among Men on Active Surveillance for Localized Prostate Cancer with Favorable Features[J]. J Urol, 2018,199(2):445-452. 10. Schroder F, Bangma C, Angulo J C, et al. Dutasteride treatment over 2 years delays prostate-specific antigen progression in patients with biochemical failure after radical therapy for prostate cancer: results from the randomised, placebo-controlled Avodart After Radical Therapy for Prostate Cancer Study (ARTS)[J]. Eur Urol, 2013,63(5):779-787. 11. Ross A E, Feng Z, Pierorazio P M, et al. Effect of treatment with 5-alpha reductase inhibitors on progression in monitored men with favourable-risk prostate cancer[J]. BJU Int, 2012,110(5):651-657. 12. Wong L M, Fleshner N, Finelli A. Impact of 5-alpha reductase inhibitors on men followed by active surveillance for prostate cancer: a time-dependent covariate reanalysis[J]. Eur Urol, 2013,64(2):343. 13. Kjellman A, Friis S, Granath F, et al. Treatment with finasteride and prostate cancer survival[J]. Scand J Urol, 2013,47(4):265- 271. 14. Unger J M, Till C, Thompson I J, et al. Long- term Consequences of Finasteride vs Placebo in the Prostate Cancer Prevention Trial[J]. J Natl Cancer Inst, 2016,108(12). 15. Lucia M S, Epstein J I, Goodman P J, et al. Finasteride and high-grade prostate cancer in the Prostate Cancer Prevention Trial[J]. J Natl Cancer Inst, 2007,99(18):1375-1383. 16. Kulkarni G S, Al-Azab R, Lockwood G, et al. Evidence for a biopsy derived grade artifact among larger prostate glands[J]. J Urol, 2006,175(2):505-509. 17. Murtola T J, Karppa E K, Taari K, et al. 5-Alpha reductase inhibitor use and prostate cancer survival in the Finnish Prostate Cancer Screening Trial[J]. Int J Cancer, 2016,138(12):2820-2828. 18. Orsted D D, Bojesen S E, Nielsen S F, et al. Association of clinical benign prostate hyperplasia with prostate cancer incidence and mortality revisited: a nationwide cohort study of 3,009,258 men[J]. Eur Urol, 2011,60(4):691-698. 5-ARIs prevent progression of prostate cancer-Yang et al.