ORIGINAL ARTICLE
Ahead of print publication  

Association between 5α-reductase inhibitors therapy and incidence, cancer-specific mortality, and progression of prostate cancer: evidence from a meta-analysis


 Department of Urology and Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510230, China

Date of Submission04-Nov-2018
Date of Acceptance18-Aug-2019
Date of Web Publication08-Nov-2019

Correspondence Address:
Zhi-Gang Zhao,
Department of Urology and Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510230
China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aja.aja_112_19

PMID: 31710001

  Abstract 


5α-reductase inhibitors (5-ARI) are widely employed for the treatment of benign prostatic hyperplasia. It has been noted that 5-ARI exhibit the potential to attenuate the risk of prostate cancer, but consistent agreement has not been achieved. Moreover, the effect of 5-ARI on cancer-specific mortality and progression of prostate cancer remains unclear. Therefore, the goal of the current meta-analysis was to elucidate the impact of 5-ARI on the incidence and progression of prostate cancer. We searched for all studies assessing the effect of 5-ARI on risk of prostate cancer in PubMed, Embase, Medline, and Cochrane Library databases. Pooled relative risk (RR) and corresponding 95% confidence intervals (CIs) were accepted to evaluate the association between 5-ARI and the risk of prostate cancer. Synthetic results implied that subjects who accepted 5-ARI compared with the placebo group experienced a distinctly weakened overall incidence of prostate cancer (RR = 0.74; 95% CI: 0.66–0.82; P < 0.001). Subgroup analyses further revealed that 5-ARI reduction of the incidence of prostate cancer was limited to low-grade (Gleason score 2–6; RR = 0.68; 95% CI: 0.57–0.81; P < 0.001) and intermediate-grade tumors (Gleason score 7; RR = 0.81; 95% CI: 0.67–0.97; P = 0.023), but not high-grade tumors (Gleason score >7; RR = 1.19; 95% CI: 0.98–1.43; P = 0.069). The results also showed that 5-ARI treatment did not significantly alter prostate cancer-specific mortality (RR = 1.0; 95% CI: 0.95–1.05; P = 0.916). In addition, it was worth noting that 5-ARI treatment acted in a protective role that presented a dramatic benefit to delay the progression of low-risk tumors (RR = 0.58; 95% CI: 0.43–0.78; P < 0.001).

Keywords: 5α-reductase inhibitor; meta-analysis; prostate cancer


Article in PDF

How to cite this URL:
Luo LM, Yang RD, Wang JM, Zhao SK, Liu YZ, Zhu ZG, Xiang Q, Zhao ZG. Association between 5α-reductase inhibitors therapy and incidence, cancer-specific mortality, and progression of prostate cancer: evidence from a meta-analysis. Asian J Androl [Epub ahead of print] [cited 2020 Mar 28]. Available from: http://www.ajandrology.com/preprintarticle.asp?id=270594

Lian-Min Luo, Re-Dian Yang
These authors contributed equally to this work.





  Introduction Top


5α-reductase inhibitors (5-ARI) are a class of therapeutic agent that can reduce prostate volume via a hormonal regulation mechanism, thus improving the symptoms of the lower urinary tract in patients suffering from benign prostatic hyperplasia (BPH).[1] Dihydrotestosterone (DHT) serves a crucial role regulating the cell proliferation of both normal prostatic epithelial and prostate cancer.[2],[3] 5-ARI are specific inhibitor of intracellular 5α-reductase, which is necessary for the process of testosterone metabolism into DHT.[4],[5] 5α-reductases consist of mainly two types: Type I and Type II. Type I enzymes are mainly distributed in the skin, and Type II enzymes are mainly distributed in the prostate.[6],[7],[8] Type I 5α-reductase can be selectively inhibited by finasteride, while both Type I and Type II 5α-reductase can be blocked simultaneously by dutasteride. Circulating DHT was reduced by 60%–70% and 90% in individuals administered finasteride and dutasteride, respectively.[9],[10],[11]

5-ARI are widely recognized as the major route of nonsurgical treatment to relieve symptoms of patients with BPH.[12] Over the past several years, some reports have stated that a history of 5-ARI exposure could affect the risk of prostate cancer. A study by Thompson et al.,[13] who recruited 9060 patients with BPH, reported that the overall incidence of prostate cancer was 18.4% (803/4368) and 24.4% (1147/4692) among the finasteride-exposed group and the placebo group, respectively. They further observed that the incidence of low-grade cancer (Gleason score ≤6) of the finasteride-exposed group was dramatically weakened compared with the placebo group (relative risk [RR] = 0.619; 95% confidence interval [CI]: 0.561–0.684). However, patients in the finasteride-exposed group achieved an increase in the incidence of high-grade cancer (Gleason score 7–10) compared with those in the placebo group (RR = 1.258; 95% CI: 1.064–1.488). Andriole et al.[14] reported that the proportion of prostate cancer in the dutasteride-exposed group was 19.9% (659/3305), whereas it was 25.0% (858/3424) in the placebo group. 5-ARI exposure was not related to the incidence of tumors with Gleason score of 8–10 (RR = 1.581; 95% CI: 0.888–2.814). Zhu et al.[15] reported that the proportion of prostate cancer was 9.8% among the finasteride-exposed group and 18.6% of individuals in the placebo group. They also observed that high-grade cancer (Gleason score 7–10) accounted for 71.4% and 40% of patients with prostate cancer in the finasteride-exposed group and placebo group, respectively. Based on prospective research conducted in the United States in 2014, it was estimated that patients with 5-ARI treatment had 26% and 34% reduction in the incidence of low-grade (Gleason score 2–6) and intermediate-grade tumors (Gleason score 7), respectively, compared with the placebo group. However, the incidence of tumors with Gleason score 8–10 among the 5-ARI group seemed comparable to the placebo group (RR = 0.97; 95% CI: 0.64–1.64).[16]

Likewise, numerous studies were examined to assess 5-ARI exposure in relation to prostate cancer-specific mortality. A cohort study was conducted by Kjellman et al.,[17] who stated that for the incidence of nonlocalized prostate cancer, patients in the finasteride-exposed group compared with those in the placebo group might have more than a 14% increase. Interestingly, the RR of cancer-specific mortality of the finasteride-exposed group was 0.93 (95% CI: 0.76–1.14), indicating no substantial connection. The results were similar to another study, which assessed the connection between 5-ARI exposure and prostate cancer-specific mortality, while failing to identify a close link (RR = 0.85; 95% CI: 0.72–1.01).[18]

Despite several publications addressing the link between 5-ARI and risk of prostate cancer, consistent agreement was not achieved. Thus, the present meta-analysis was performed to investigate the influence of 5-ARI on risk of prostate cancer.


  Materials and Methods Top


This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [Supplementary Table 1 [Additional file 1]].[19]

Search strategy

The eligible documents were sourced from PubMed, Embase, Medline, and the Cochrane Library databases from the inception to July 2018. Only studies published in English involving human participants were considered in the present meta-analysis. For the search, the following terms were used: (5-alpha-reductase inhibitors) OR (finasteride) OR (dutasteride) OR (5-ARI) AND (prostate cancer) OR (prostate tumor) OR (prostate carcinoma) OR (prostatic neoplasms). In addition, the references of relevant studies were reviewed to expand the search.

Selection criteria

Any available studies that described 5-ARI exposure on risk of prostate cancer were included in the present meta-analysis. Studies were included when they provided information about the effect of 5-ARI on prostate cancer risk or cancer-specific mortality or progression of prostate cancer and reported RR estimates or odds ratios (ORs) with 95% CI or sufficient data to calculate them. In addition, reviews, congress reports, letters, abstract, editorials, case reports, and commentaries did not meet the criteria.

Data extraction and quality assessment

Relevant information was extracted according to a specially designed form by two authors. The methodological quality of nonrandomized studies was dependent on the Newcastle–Ottawa Scale (NOS).[20] Cochrane's risk of bias assessment tool was adopted to evaluate the quality of randomized controlled trial (RCT) studies.

Statistical analyses

The pooled RR and its 95% CI were employed to evaluate the connection between 5-ARI exposure and risk of prostate cancer. P < 0.05 indicated statistical significance. Heterogeneity was assessed according to the Cochrane Q statistic and I2 statistics.[21] The fixed effects model was adopted when significant statistical heterogeneity was free (I2 < 50%; P > 0.10). Otherwise, a random effects model was employed.[22] In addition, sensitivity analysis and subgroup analyses were employed to detect the potential source of heterogeneity. STATA 12.0 was applied in the meta-analysis (Stata Corp., College Station, TX, USA).


  Results Top


Literature search

The steps are depicted in [Figure 1]. In the initial screening, 1265 citations were identified. After eliminating studies that did not meet the inclusion criteria, 17 studies were analyzed.
Figure 1: Flow diagram of search strategy.

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Study characteristics

[Table 1] illustrates the relevant detailed information of included publications. Ten studies focused on the incidence of prostate cancer among 605 970 participants.[13],[14],[15],[16],[23],[24],[25],[26],[27],[28] Six studies assessed the cancer-specific mortality of prostate cancer among 236 320 participants.[16],[17],[18],[29],[30],[31] Two studies evaluated the progression of prostate cancer among 590 participants.[32],[33]
Table 1: Characteristics of studies included in the meta-analysis

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Quality assessment

The outcomes of the quality assessment of the cohort and case–control studies are depicted in [Supplementary Table 2 [Additional file 2]], and the outcomes of methodological quality in the RCT are depicted in [Supplementary Figure 1 [Additional file 3]] and [Supplementary Figure 2 [Additional file 4]].

5-ARI and incidence of prostate cancer

As shown in [Figure 2], the pooled RR for incidence of prostate cancer in patients with 5-ARI exposure as compared with the control group was 0.74 (95% CI: 0.66–0.82, P < 0.001; heterogeneity: I2 = 73.8%, P < 0.001), indicating a protective effect of 5-ARI treatment on overall incidence of prostate cancer.
Figure 2: Forest plots of meta-analysis of the included studies on the association between 5α-reductase inhibitor therapy and incidence of prostate cancer. ES: effect size; CI: confidence interval.

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Subgroup analyses

To further evaluate the effect of 5-ARI treatment on the incidence of prostate cancer, subgroup analyses were performed based on tumor grade, study design, intervention drug, ethnicity, and duration of treatment [Table 2]. In the subgroup analysis stratified by tumor grade, the incidence of low-grade (Gleason score 2–6) and intermediate-grade prostate cancer was reduced by 32.0% and 19.1% among the 5-ARI group, respectively. However, no obvious influence was observed in the risk of high-grade tumors (Gleason score 8–10; RR = 1.19; 95% CI: 0.98–1.43; P = 0.069). In terms of study design, the pooled results of the cohort studies (RR = 0.64; 95% CI: 0.47–0.89; P = 0.008) and case–control studies (RR = 0.89; 95% CI: 0.84–0.94; P = 0.001) as well as RCTs (RR = 0.75; 95% CI: 0.71–0.79; P < 0.001) indicated that the incidence of prostate cancer was found to be dramatically decreased among the 5-ARI group. In terms of drug categories, a significant effect was noted in finasteride (RR = 0.75; 95% CI: 0.70–0.81; P < 0.001) as well as dutasteride (RR = 0.75; 95% CI: 0.68–0.81; P < 0.001). In terms of ethnicity, a beneficial effect of 5-ARI was seen in mixed ethnicity (RR = 0.74, 95% CI: 0.69–0.80; P < 0.001) and Asian ethnicity (RR = 0.57; 95% CI: 0.36–0.89; P = 0.013), but not in Caucasians (RR = 0.72; 95% CI: 0.49–1.06; P = 0.093). In terms of 5-ARI treatment duration, a stronger link was obtained in groups with a treatment duration of 5–10 years (RR = 0.54; 95% CI: 0.33–0.89; P = 0.014) and >10 years (RR = 0.49; 95% CI: 0.31–0.77; P = 0.002) when compared with treatment duration <5 years (RR = 0.79; 95% CI: 0.68–0.92; P = 0.003).
Table 2: Subgroup analysis of the association between 5α-reductase inhibitors and incidence of prostate cancer

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Sensitivity analysis

We drew sensitivity analyses to estimate the impact of each study on the pooled RR. Marked changes were absent in the pooled RR, with a range from 0.72 (95% CI: 0.63–0.82; P < 0.001) to 0.76 (95% CI: 0.69–0.84; P < 0.001) [Table 3] and [Supplementary Figure 3 [Additional file 5]]. Sensitivity analyses were also adopted for the studies that included the prostate-specific antigen (PSA) variable. The pooled RR ranged from 0.57 (95% CI: 0.37–0.88; P < 0.001) to 0.73 (95% CI: 0.56–0.95; P = 0.009) [Supplementary Table 3 [Additional file 6]], indicating that the results were not dominated by any one study.
Table 3: Sensitivity analysis after each study was excluded by turns

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Publication bias

Significant publication bias was absent according to Begg's test (P>|z| = 0.474; z-value is a statistic to evaluate the existence of “publication bias” by determining whether the correlation between the standardized effect scale and variance is statistically significant) as shown in [Supplementary Figure 4 [Additional file 7]].

5-ARI and cancer-specific mortality of prostate cancer

Six studies focused on the cancer-specific mortality of prostate cancer.[16],[17],[18],[29],[30],[31] The pooled RR for cancer-specific mortality of prostate cancer in patients with 5-ARI exposure as compared with the control group was 1.0 (95% CI: 0.95–1.05; P = 0.916; [Supplementary Figure 5 [Additional file 8]], revealing that 5-ARI treatment was not closely related to the cancer-specific mortality of prostate cancer.

5-ARI and progression of prostate cancer in men under active surveillance

Two studies assessed the progression of low-risk prostate cancer.[32],[33] The pooled RR for progression of cancer in patients with low-risk prostate cancer receiving 5-ARI as compared with those not receiving 5-ARI was 0.58 (95% CI: 0.43–0.78; P < 0.001; [Supplementary Figure 6 [Additional file 9]], demonstrating that a benefit of 5-ARI treatment to delay progression of low-risk prostate cancer existed.


  Discussion Top


The effect of 5-ARI on the risk of prostate cancer has been widely discussed for a long time, but has not reached a unanimous conclusion. The goal of the present meta-analysis was to generate evidence regarding the effect of 5-ARI on risk of prostate cancer. Our results indicated that the incidence of prostate cancer was decreased frequently among the 5-ARI exposure group (RR = 0.74; 95% CI: 0.66–0.82), implying that 5-ARI treatment has a protective effect on the occurrence of prostate cancer. Subgroup analyses further clarified that 5-ARI treatment could lead to a lower risk of low-grade (Gleason score ≤ 6) and intermediate-grade cancer (Gleason score 7) by 32.0% and 19.1%, respectively, whereas 5-ARI treatment was marginally related to the risk of high-grade cancer (RR = 1.19; 95% CI: 0.98–1.43). Furthermore, we failed to identify a significant link between 5-ARI exposure and prostate cancer-specific mortality (RR = 1.0; 95% CI: 0.95–1.05; P = 0.916). In addition, it was observed that patients with low-risk prostate cancer who accepted 5-ARI compared with the placebo group had remarkably lower progression (RR = 0.58; 95% CI: 0.43–0.78; P < 0.001).

Previous researchers have noted that 5-ARI exposure exhibited a protective role on the incidence of low-grade prostate cancer, but there was no consensus on the impact of the drug on the incidence of high-grade prostate cancer. Based on the two clinical trials, the hazard reduced by 23%–25% after 5-ARI exposure for overall incidence of prostate cancer.[13],[14] In line with these studies, the meta-analysis demonstrated that a protective effect of 5-ARI treatment against overall incidence of prostate cancer was evident. Androgen has the function of maintaining prostate growth and development. In the androgen-free environment, prostate cells will spontaneously undergo apoptosis, while in the normal androgen-level environment, prostate cells can continue to proliferate and differentiate. Androgen has the same effect on hormone-sensitive prostate cancer cells.[34],[35] Individuals who accepted 5-ARI exhibited a dramatically lower level of DHT in their prostate tissue. Imperato-McGinley et al.[36] stated that PSA expression could not be detected among Type II 5α-reductase-free populations. They further observed a significant shrinking in prostate size. It was unexpected that the risk of suffering from prostate cancer was absent among these patients during follow-up. The observation that 5-ARI exhibited advantages in the reduction of prostate cancer incidence may be explained by detection bias. Currently, prostate cancer screening in clinical work is mainly conducted through the serum PSA test. The level of PSA was found to be obviously decreased in subjects who accepted 5-ARI. In theory, patients would experience a significantly weakened probability for biopsy after 5-ARI treatment, and the corresponding result is a lower rate of detection of prostate cancer. Intriguingly, a study by Preston et al.[16] in 2014 reported that the probability of prostate biopsy was 9% in the general population, while it was 24% among individuals after 5-ARI treatment. Similarly, the results were consistent with another study, which indicated that prostate cancer detected by prostate biopsies driven by elevated PSA in the dutasteride group accounted for 28%–29% of cancer, compared with 24% in the placebo group.[28] Therefore, detection bias was not a convincing explanation for the advantages of 5-ARI in the reduction incidence of low-grade and intermediate-grade tumors.

Subgroup analyses demonstrated that 5-ARI treatment exhibited no distinct influence on the hazard of incidence of high-grade prostate cancer (Gleason 7–10/8–10; RR = 1.19; 95% CI: 0.98–1.43). However, it was reported that subjects who accepted 5-ARI treatment exhibited a distinctly higher incidence of higher-grade tumors.[13],[15] A possible explanation for this potential link was that 5-ARI treatment was related to a lower level of DHT, and the morphology of prostate cells induced by this lower level of DHT appeared to be similar to that of high-grade tumors. Previous studies have reported that prostate cancer patients undergo a degree of change in the morphology of cancer cells after androgen deprivation treatment, rendering cancer cells similar to the morphology of high-grade prostate cancer.[37],[38] It was also reported that lower levels of testosterone could be linked to the advanced tumor grades and poor clinical outcomes of prostate cancer when compared with patients with normal testosterone levels.[39],[40] It was also possible that 5-ARI treatment could change the microenvironment in which the tumor grows to a certain extent. This microenvironment change is beneficial to the transformation of low-grade tumors into high-grade tumors. In addition, 5-ARI treatment exhibited a greater impact on the incidence of low-grade malignancies and less of an impact on the incidence of high-grade tumors. Subjects who accepted 5-ARI experienced a relatively decreased incidence of low-grade and intermediate-grade tumors. Therefore, the rate of detection of high-grade tumors in the 5-ARI group will increase, although 5-ARI were not related to high-grade tumors, because it has been suggested that this may be caused by the fact that 5-ARI treatment could shrink the prostate gland and lead to the increased detection sensitivity of prostate cancer.[41] Furthermore, another explanation for the increase in the incidence of high-grade cancer in the 5-ARI treatment group was due to detection bias, rather than the biological characteristics of the tumor. Cohen et al.[42] found that the median prostate volume was 25.1 ml in the 5-ARI treatment group and 33.5 ml in the placebo group. At the final biopsy, the median prostate volume of prostate cancer patients in the 5-ARI treatment group was 24.4 ml, and the placebo group was 31.9 ml. It has been shown that PCa detection rates are higher in smaller prostate glands.[43] The increased risk of high-grade tumors in the 5-ARI treatment group occurred in the early stages of 5-ARI treatment rather than increasing over time, but this does not support the theory that 5-ARI induce high-grade cancer. A possible reason for this situation is that 5-ARI improve the sensitivity of the PSA test in detecting high-grade tumors.[44]

The present meta-analysis also stated that 5-ARI treatment was not closely correlated with the cancer-specific mortality of prostate cancer. The findings were in line with some relevant studies, which revealed that neither the hazard of high-grade tumors nor the cancer-specific mortality of prostate cancer were related to 5-ARI treatment.[16],[24],[27]

Meanwhile, the influence of 5-ARI on the progression of low-risk tumors was explored. Based on the combined results of two studies,[32],[33] we identified that 5-ARI exposure serves as the protective factor for the progression of low-risk tumors (RR = 0.58; 95% CI: 0.43–0.78; P < 0.001).

The main discrepancy between our study and other publications was the effect of 5-ARI on the incidence of high-grade prostate cancer. Thompson et al.[13] reported that 5-ARI treatment serves as an inducer for the incidence of high-grade prostate cancer. However, the present meta-analysis revealed that 5-ARI exposure did not influence the incidence of high-grade prostate cancer. In theory, cancer-specific mortality increases with incidence of high-grade cancer. Intriguingly, the present meta-analysis did not identify any connection between 5-ARI exposure and prostate cancer-specific mortality. Overall, these findings support the notion that 5-ARI exposure was not related to the incidence of high-grade prostate cancer.

Some potential limitations should be acknowledged in this meta-analysis. First, although subgroup analyses and sensitivity analysis were adopted to explore the potential origin, substantial heterogeneity still existed. Second, we did not undertake a dose-response analysis for the effect of 5-ARI on the risk of prostate cancer as a result of the limited data available. Third, the number of included studies that focused on the influence of 5-ARI on cancer-specific mortality and progression of low-risk tumors was limited, especially studies focused on the progression of low-risk tumors. As a result, high-quality, prospective, multicenter studies with long follow-up periods are still needed to confirm our results.


  Conclusion Top


Our results indicated that 5-ARI treatment exhibited a protective role on the incidence of low-grade and intermediate-grade prostate cancer, but not high-grade cancer. The results also showed that there was no close link between 5-ARI treatment and prostate cancer-specific mortality. In addition, it is important to note that 5-ARI treatment has a protective role that has a dramatic benefit by delaying the progression of low-risk tumors.


  Author Contributions Top


LML and RDY carried out the study design and drafted the manuscript. JMW and SKZ participated in data collection. YZL, ZG Zhu, and QX performed the data analysis. ZG Zhao conceived of the study and revised the manuscript. All authors read and approved the final manuscript.


  Competing Interests Top


All authors declared no competing interests.


  Acknowledgments Top


This work was supported by the grants from Science and Technology Planning Project of Guangdong Province (No. 2017B030314108).

Supplementary Information is linked to the online version of the paper on the Asian Journal of Andrology website.



 
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