Skip to main content
NCBI home page
Journal of Oncology logoLink to Journal of Oncology
. 2022 Nov 15;2022:9275466. doi: 10.1155/2022/9275466

Statin Use Is Associated with Better Prognosis of Patients with Prostate Cancer after Definite Therapies: A Systematic Review and Meta-Analysis of Cohort Studies

Ye An 1, Jian-Xuan Sun 1, Meng-Yao Xu 1, Chen-Qian Liu 1, Jin-Zhou Xu 1, Xing-Yu Zhong 1, Jia Hu 1, Qi-Dong Xia 1,✉, Heng-Long Hu 1,✉, Shao-Gang Wang 1,✉
PMCID: PMC9681552  PMID: 36425939

Abstract

Objective

Although the prognostic effect of statins on patients with prostate cancer (PCa) has been frequently evaluated, a consistent result is still lacking. We aimed to evaluate the association between statin use and mortality among patients with PCa after definite therapies.

Methods

A systematic search of PubMed and other databases for cohort studies about the effect of statins on patients with PCa was performed until April 2022. Meta-analysis was performed using R software version 4.1.2.

Results

24 cohort studies involving 369, 206 participants were finally included. We found statin use significantly reduced the risk of prostate cancer-specific mortality (PCSM) with a pooled hazard ratio (pHR) = 0.76 (95% CI: 0.69–0.84, 18 studies), especially for postdiagnostic statin users: pHR = 0.81 (95% CI: 0.77–0.85) and patients who accepted androgen deprivation therapy (ADT): pHR = 0.69 (95% CI: 0.59–0.81). Statin use was also associated with a 24% reduction in the risk of all-cause mortality (ACM): pHR = 0.76 (95% CI: 0.68–0.85, 17 studies), especially for postdiagnostic statin users: pHR = 0.81 (95% CI: 0.78–0.85) and patients treated with ADT: pHR = 0.72 (95% CI: 0.63–0.82) or radiotherapy (RT): pHR = 0.68 (95% CI: 0.50–0.93).

Conclusion

In conclusion, the use of statins could promote the prognosis of patients with PCa, especially for postdiagnostic users. For patients who received either ADT or radical prostatectomy (RP), statin use could decrease the PCSM. As for those who received either ADT or RT, statin use could decrease the ACM.

1. Introduction

Prostate cancer (PCa) is one of the most common malignant tumors; it has the second highest incidence and is the fifth leading cause of cancer-related death in men worldwide. Approximately 1.4 million incident cases were diagnosed, which led to more than 300 thousand deaths in 2020 [1]. Although localized PCa has a high 5-year survival rate, advanced PCa usually indicates a poor prognosis [2]. Radical prostatectomy (RP) and radiotherapy (RT) are the main treatments for localized PCa, and androgen deprivation therapy (ADT) is backbone of treatment for advanced PCa. Although ADT could slow tumor progression, a clinical state called castration-resistant PCa inevitably appears after treatment for a while. However, with a better understanding of PCa and the approval of multiple new drugs, the management of advanced PCa or castration-resistant PCa will change rapidly over the next decade [3].

Statins are a type of commonly used drug and are usually used to decrease serum cholesterol levels and prevent cardiovascular diseases by inhibiting cholesterol synthesis through suppression of HMG-CoA reductase. Beyond these effects, more and more evidence suggest that statins also play a role in the treatment of cancer, including colon cancer, breast cancer, and PCa [4–6]. Laboratory studies have proved that statins could limit cancer progression by promoting cell apoptosis, inflammation, and inhibition of cancer cell proliferation, adhesion, and angiogenesis [7–10]. Moreover, our previous study revealed that statins played a significant role in decreasing the risk of biomedical recurrence (BCR) in patients with PCa after definite therapies, especially RT [11].

Previous meta-analyses have demonstrated that statin use is associated with a reduced risk of prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) in PCa patients [12, 13]. But the number of cohort studies included in previous meta-analyses is limited, and many novel studies have been conducted since their publications, and the results of these new studies were inconsistent. Therefore, this systematic review and meta-analysis was conducted and aimed to reevaluate the association between statins and outcomes such as PCSM and ACM among men with PCa. Also, we conducted a subgroup analysis to examine the differences in prognosis among patients with different primary treatments or the time of statin initiation.

2. Methods

This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [14]. The protocol was registered on PROSPERO (ID: CRD 42022337522).

2.1. Literature Search

A systematic search of papers from Medline (PubMed), Embase (Ovid), and Cochrane was performed from inception to April 2022 by two independent reviewers (SJX and AY); conflicts were confirmed by the third reviewer XQD and finally resolved by consensus. All cohort studies evaluating the effect of statins on prognostic outcomes in patients with PCa were available with no language limitations. The literature was searched using the following terms: (“Prostatic Neoplasms” with its free words) and (“Statin” or “Atorvastatin” or “Cerivastatin” or “Compactin” or “Fluvastatin” or “HMG-CoA” or “Lovastatin” or “Mevastatin” or “Pravastatin” or “Rosuvastati'n or “Rosvastatin” or “Simvastatin”). The detailed search strategies of Medline (PubMed), Embase (Ovid), and Cochrane are shown in Supplement 1 Tables S1A–S1C. Also, potentially relevant studies were screened out from reference lists of articles retrieved, meta-analyses, and reviews.

2.2. Inclusion and Exclusion Criteria

Research articles were included if they satisfied the following criteria: (1) the study design was a cohort study; (2) studies examined the effect of statins on clinical outcomes in patients with prostate cancer; (3) the outcomes of interest were ACM or PCSM; and (4) relevant survival data with a hazard ratio (HR) estimate and its 95% confidence intervals (CIs) were reported. Studies satisfying the following criteria were excluded: (1) a case report, review, comment, or news item; (2) animal studies; (3) in vitro studies; and (4) studies with duration of follow-up shorter than 6 months.

2.3. Data Extraction and Quality Assessment

After exporting all retrieved articles to EndNote X9.3.3, duplicated articles were discarded. Two reviewers (SJX and AY) selected studies that met our criteria and then checked the results. Disagreements were resolved via discussion, involving the third reviewer (XQD). The following data were extracted from eligible articles: first author, year of publication, country of origin, study design, data sources, follow-up period, definition of statin use, tumor stage, primary treatment, adjustment variables, outcome, and HRs with corresponding 95% CIs. We extracted the risk estimate adjusted for the greatest number of confounding factors when a study provided more than one risk estimate.

We used the Newcastle–Ottawa scale (NOS) tool to evaluate the quality of studies, and the score of each study is presented in Supplement 2 Table S2. A study with a score of 7 or more was regarded as high quality.

2.4. Data Synthesis and Analysis

Heterogeneity across studies was measured by the I2 statistic and the 'Cochran's Q-test, with I2 > 50% and the Q-testp < 0.1 indicating significant heterogeneity [15]. The pooled hazard ratio (pHR) with corresponding 95% CIs for all included studies was obtained using a random effects model. Besides, the publication bias of included studies was examined using both Begg's [16] and Egger's [17] tests and then visualized as a contour-enhanced funnel plot. Where significant publication bias existed, the trim and fill method was carried out to normalize the publication bias [18], and the normalized combined effects will be used to verify the initial conclusion. We also performed meta-regression analysis to find the possible reasons responsible for heterogeneity, and we used the following parameters: publication year, median follow-up time, age, BMI value, Gleason score, PSA level, race, and tumor stage. Finally, subgroup analyses were performed stratified by primary treatment and the time of statin initiation.

We performed statistical analyses using R software version 4.1.2 and the package “meta.” A P value less than 0.05 indicated statistical significance.

3. Results

3.1. Study Characteristics

A total of 1,203 citations were screened and assessed, and 24 cohort studies [19–42] were finally included in this study. The PRISMA flow diagram presented in Figure 1 shows the study selection process. Supplement 3 Table S3 shows the basic characteristics of the included studies. All the studies were published between 2010 and 2021, with at least 6 score of NOS results. Among these studies, 7 studies were conducted in the USA [20, 23, 24, 28, 37, 41, 42], 4 in Canada [21, 22, 29, 40], 4 in China [25, 26, 31, 36], 4 in Finland [19, 27, 32, 34], 1 in Italy [30], 1 in Denmark [33], 1 in Germany [35], 1 in the UK [38], and 1 in Norway [39]. 18 studies reported the association between statin use and PCMS, whereas 17 studies examined ACM.

Figure 1.

Figure 1

Open in a new tab

PRISMA flowchart for study selection.

3.2. Relationship between Statin Use and PCSM

Eighteen studies with 347, 186 participants were included in the analysis of statin use and PCSM. The forest plot (Figure 2(a)) shows the overall effect of statin use on PCSM. The results suggested that statin use led to a significantly decreased risk of PCSM (pHR = 0.76, 95% CI: 0.69–0.84, I2 = 91%, random effects model). Subgroup analysis stratified by primary treatments is shown in Figure 3(a) and indicates that there is a significant reduction in PCSM among patients accepting ADT (pHR = 0.69, 95% CI: 0.59–0.81, I2 = 89%), RP (pHR = 0.72, 95% CI: 0.54–0.96, I2 = 94%), or RT or RP or ADT (pHR = 0.86, 95% CI: 0.77–0.96, I2 = 79%). Surprisingly, we found there was no statistical significance between PCSM and statin use when patients were treated with RT or RP. In the subgroup analysis stratified by the initiation of statin use (Figure 3(b)), we found there existed a significant reduction in PCSM among people accepting prediagnostic statin use (pHR = 0.86, 95% CI: 0.75–0.99, I2 = 73%) and postdiagnostic statin use (pHR = 0.81, 95% CI: 0.77–0.85, I2 = 0%).

Figure 2.

Figure 2

Open in a new tab

The effect of statins on PCSM or ACM of prostate cancer using a random effects model. (a) The forest plot for the HR of PCSM. (b) The forest plot for the HR of ACM.

Figure 3.

Figure 3

Open in a new tab

(a) The forest plot for the HR of PCSM with subgroup analysis by primary treatments. (b) The forest plot for the HR of PCSM with subgroup analysis by the initiation of statin use.

As the heterogeneity of the main analysis and subgroup analysis was significantly high, we performed meta-regression. We constructed a univariate meta-regression model using the publication year, median follow-up time, age, BMI value, percentage of patients with a Gleason score ≥7, race, PSA level, and percentage of patients with a tumor stage ≥T3. We found tumor stage was significantly associated with PCSM (P=0.0237, see Supplement 4 Figure S1A), whereas other parameters were not significantly associated with PCSM.

Also, sensitivity analysis was performed to evaluate the effect of each study on the pHR. By stepwise excluding each study, we could observe that the overall estimates remained stable (Figure 4(a)). Both Begg's rank correlation test (z = −1.93, P=0.0534) and Egger's linear regression test (t = 0.02, P=0.9847) showed no evidence of significant publication bias. The contour-enhanced funnel plot showed a little asymmetry, as few studies were outside the dashed lines (Figure 4(b)). The trim and fill method estimated one study was missing due to publication bias (Figure 4(c)) and showed little evidence of publication bias. Then, we did a filled forest plot (Figure 4(d)), and the pHR was 0.74 (95% CI: 0.67–0.82, I2 = 91%, random effects model), which was consistent with our original result. The Galbraith plot showed a similar result, showing that most studies stood within the dashed lines (Figure 4(e)).

Figure 4.

Figure 4

Open in a new tab

Sensitivity analysis and the detection of publication bias for included studies on the HR of the PCSM. (a) Sensitivity analysis by stepwise excluding the included studies. (b) The funnel plot. (c) The trim and fill funnel plot. (d) The filled forest plot. (e) The Galbraith plot. Effect sizes as z-scores plotted as a function of the inverse standard error for each study reported in the present study. The middle line is the line of best fit, while the upper and lower dashed lines represent the upper and lower 95% confidence limits.

3.3. Relationship between Statin Use and ACM

Seventeen studies with 246 and 167 participants were included in the analysis of statin use and ACM. As shown in the forest plot (Figure 2(b)), the result revealed a significant reduction in ACM among patients using statins (pHR = 0.76, 95% CI: 0.68–0.85, I2 = 96%, random effects model). In the subgroup analysis by primary treatment (Figure 5(a)), patients accepting ADT (pHR = 0.72, 95% CI: 0.63–0.82, I2 = 89%), RT (pHR = 0.68, 95% CI: 0.50–0.93, I2 = 0%), RT or RP (pHR = 0.84, 95% CI: 0.72–0.99, I2 = 0%), or abiraterone or enzalutamide (pHR = 0.44, 95% CI: 0.35–0.56, I2 = 0%) showed decreased risk of ACM, whereas the RP showed no effect on ACM. This result was not consistent with a previous study [43]. When stratified by the initiation of statin use (Figure 5(b)), only postdiagnostic statin use (pHR = 0.81, 95% CI: 0.78–0.85, I2 = 23%) was connected with a reduced risk of ACM.

Figure 5.

Figure 5

Open in a new tab

(a) The forest plot for the HR of ACM with subgroup analysis by primary treatments. (b) The forest plot for the HR of ACM with subgroup analysis by the initiation of statin use.

A univariate meta-regression model was constructed using the parameters we mentioned above. We found the percentage of white people was associated with ACM (P=0.0021, see Supplement 4 Figure S1B), and other parameters were not associated with ACM.

Sensitivity analysis was presented in Supplement 4, Figure S2A, and the overall estimates remained stable after excluding each study. The contour-enhanced funnel plot (Supplement 4, Figure S2B) did not show good symmety, where some studies stood outside the dashed lines. However, both Begg's test (z = 0.25, P=0.8048) and Egger's test (t = −0.75, P=0.4647) showed no evidence of statistically significant publication bias. The trim and fill method was carried out, and it was estimated that two studies were missing due to publication bias (Supplement 4 Figure S2C). The filled forest plot (Supplement 4 Figure S2D) was carried out with pHR = 0.81 (95% CI: 0.70–0.93, I2 = 95%, random effects model), which indicated the reliability of our meta-analysis. The Galbraith plot also showed a similar result, showing that a few studies stood outside the dashed lines (Supplement 4 Figure S2E).

4. Discussion

This meta-analysis involving 24 studies with 369, 206 individuals reinvestigated the relationship between statin use and outcomes in patients with PCa and evaluated whether statin use contributed to different clinical outcomes when patients accepted different primary treatments. Our previous study has provided evidence that statins could reduce the risk of BCR in patients with PCa. However, the previous study focused on BCR and ignored other clinical outcomes; also, the study did not distinguish prediagnostic statin users from postdiagnostic users. Therefore, we conducted this meta-analysis to further evaluate the relationship between statins and clinical outcomes and instruct clinical medication. Our results revealed that statin use was associated with a significant reduction of PCSM and ACM. Subgroup analyses by primary treatment and initiation of statins were conducted. For PCSM, patients accepting ADT, RP, or RT or ADT, RP could benefit from statins. However, subgroups including ADT showed significant heterogeneity, which indicated individuals may not always benefit from statins when accepting ADT. Consistent with previous studies [13], our results demonstrated both postdiagnostic and prediagnostic statin users could obtain a reduced risk of PCSM. However, the prediagnostic statin use group showed high heterogeneity (I2 = 73%), indicating this result may not be suitable for all patients. As for ACM, patients accepting ADT, RT or RP, RT, abiraterone or enzalutamide showed potential benefits from statin use, where the ADT subgroup also had high heterogeneity. Although our study showed statin use did not reduce ACM for patients treated with RP, the number of studies in this subgroup was too limited, and further investigation was needed. In the subgroup analysis of ACM, we included two studies that used abiraterone or enzalutamide as the primary treatment. The result revealed statin use may reduce the risk of ACM when accepting abiraterone or enzalutamide, which was consistent with previous meta-analyses [44]. As the selection of primary treatment depends on certain subtypes of PCa, the patients involved in these two studies were all diagnosed with metastatic castration-resistant prostate cancer (mCRPC). Therefore, our study suggested that patients with mCRPC might benefit from statins when treated with abiraterone or enzalutamide. In 2016, an in vitro study discovered that statins could promote the therapeutic effect of enzalutamide in androgen-sensitive LNCaP and VCaP cells [45]. More randomized controlled trials and further studies are needed to clarify the effect of statins on enzalutamide use.

Additionally, we found only postdiagnostic statin use was associated with decreased risk of ACM but not prediagnosis. Alexandre et al. have pointed out [46] that prediagnostic statin users are more likely to be smokers, overweight, older, and have associated cardiovascular diseases or other diseases that might lead to a poor prognosis. Anyway, we observed a decreased risk of PCSM and ACM among patients accepting postdiagnostic statin use. Our findings could help to instruct clinical medication in patients with PCa.

Despite the fact that the antitumor effect of statins has been reported for years, many unknowns remain about their antitumor mechanisms, especially for PCa. It is known that statins can decrease cholesterol synthesis by suppressing HMG-CoA reductase. The presence of PCa was reported to be tightly related to cholesterol accumulation in prostatic tissues [47]. PCa could abnormally accumulate cholesterol by affecting the ABCA1 promoter [48] and activating the PI3K-AKT-mTOR signaling pathway [49]. Statins could suppress tumor growth by breaking the cholesterol balance in prostatic tissues. Cholesterol is a precursor for androgen synthesis, and androgen is essential for the initiation and progression of PCa. Therefore, it is not difficult to understand that statins could suppress androgen synthesis and improve the effect of ADT. This is in accordance with our results that statins could improve prognosis of patients with PCa when treated with ADT. Additionally, it was reported that statins competitively reduced the uptake of dehydroepiandrosterone sulfate, thus inhibiting the tumor's androgen synthesis [50].

However, there are limitations to this study. First, most included studies did not provide the baseline serum cholesterol levels. As statins are prescribed to decrease cholesterol levels, the serum cholesterol level might be a potential confounder in the analysis. Second, the definition of statin use varied among the included studies. The types of statins, doses of statins, initiation time of statin use, and duration of statin use were various or not complete in the included studies. The differences among these factors may lead to heterogeneity. Third, some patients received more than one kind of treatment, which could influence the result of subgroup analysis when stratified by primary treatment. Fourth, although most results of studies have been adjusted for important covariates, those unadjusted factors might have an impact on the results of individual studies.

5. Conclusion

In conclusion, the use of statins is beneficial for ACM and PCSM, especially for postdiagnostic users. For patients who received either ADT or RP, statin use could decrease the PCSM. As for those who accepted either ADT or RT, statin use could decrease ACM. However, for patients accepting ADT, statin use may not always be beneficial for them. In future studies, prospective studies or large-sample randomized controlled trials are needed to further elucidate the effects and specific mechanisms of statins in PCa.

Acknowledgments

The authors thank all the R package developers. This research was supported by the National Natural Science Foundation of China (81772729).

Contributor Information

Qi-Dong Xia, Email: qidongxia_md@163.com.

Heng-Long Hu, Email: huhenglong@hust.edu.cn.

Shao-Gang Wang, Email: sgwangtjm@163.com.

Data Availability

All the data analyzed in this study are included within article/supplementary material and are available from the corresponding authors upon request.

Disclosure

Ye An and Jian-Xuan Sun are the co-first authors.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors' Contributions

HHL, SJX, HJ, and WSG contributed to research question selection; AY, SJX, and XQD searched the literature, selected the studies, and collected the included studies' information. AY performed the meta-analysis and wrote the manuscript. LCQ, ZXY, XMY, and XJZ revised the manuscript. Ye An and Jian-Xuan contributed equally to this work.

Supplementary Materials

Supplementary Materials

Supplement 1: Details of the search strategy to retrieve the studies. Supplement 2: Newcastle–Ottawa scale for assessing the quality of studies in meta-analysis. Supplement 3: Characteristics of included studies in the systematic review and meta-analysis. Supplement 4: Meta-regression and sensitivity analysis.

Click here for additional data file. (611.4KB, zip)

References

  • 1.Sung H., Ferlay J., Siegel R. L., et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians . 2021;71(3):209–249. doi: 10.3322/caac.21660. [DOI] [PubMed] [Google Scholar]
  • 2.Siegel R. L., Miller K. D., Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians . 2018;68(1):7–30. doi: 10.3322/caac.21442. [DOI] [PubMed] [Google Scholar]
  • 3.Swami U., McFarland T. R., Nussenzveig R., Agarwal N. Advanced prostate cancer: treatment advances and future directions. Trends in cancer . 2020;6(8):702–715. doi: 10.1016/j.trecan.2020.04.010. [DOI] [PubMed] [Google Scholar]
  • 4.Graaf M. R., Beiderbeck A. B., Egberts A. C., Richel D. J., Guchelaar H. J. The risk of cancer in users of statins. Journal of Clinical Oncology . 2004;22(12):2388–2394. doi: 10.1200/jco.2004.02.027. [DOI] [PubMed] [Google Scholar]
  • 5.Poynter J. N., Gruber S. B., Higgins P. D., et al. Statins and the risk of colorectal cancer. New England Journal of Medicine . 2005;352(21):2184–2192. doi: 10.1056/nejmoa043792. [DOI] [PubMed] [Google Scholar]
  • 6.Platz E. A., Leitzmann M. F., Visvanathan K., et al. Statin drugs and risk of advanced prostate cancer. Journal of the National Cancer Institute . 2006;98(24):1819–1825. doi: 10.1093/jnci/djj499. [DOI] [PubMed] [Google Scholar]
  • 7.Wang C., Tao W., Wang Y., et al. Rosuvastatin, identified from a zebrafish chemical genetic screen for antiangiogenic compounds, suppresses the growth of prostate cancer. European Urology . 2010;58(3):418–426. doi: 10.1016/j.eururo.2010.05.024. [DOI] [PubMed] [Google Scholar]
  • 8.Bañez L. L., Klink J. C., Jayachandran J., et al. Association between statins and prostate tumor inflammatory infiltrate in men undergoing radical prostatectomy. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention . 2010;19(3):722–728. doi: 10.1158/1055-9965.epi-09-1074. [DOI] [PubMed] [Google Scholar]
  • 9.Wu J., Wong W. W. L., Khosravi F., Minden M. D., Penn L. Z. Blocking the Raf/MEK/ERK pathway sensitizes acute myelogenous leukemia cells to lovastatin-induced apoptosis. Cancer Research . 2004;64(18):6461–6468. doi: 10.1158/0008-5472.can-04-0866. [DOI] [PubMed] [Google Scholar]
  • 10.Nübel T., Dippold W., Kleinert H., Kaina B., Fritz G. Lovastatin inhibits Rho-regulated expression of E-selectin by TNF-α and attenuates tumor cell adhesion. The FASEB Journal . 2004;18(1):140–142. doi: 10.1096/fj.03-0261fje. [DOI] [PubMed] [Google Scholar]
  • 11.Sun J. X., Liu C. Q., Zhong X. Y., et al. Statin use and the risk of prostate cancer biochemical recurrence following definitive therapy: a systematic review and meta-analysis of cohort studies. Frontiers in oncology . 2022;12 doi: 10.3389/fonc.2022.887854.887854 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Mei Z., Liang M., Li L., Zhang Y., Wang Q., Yang W. Effects of statins on cancer mortality and progression: a systematic review and meta-analysis of 95 cohorts including 1, 111, 407 individuals. International Journal of Cancer . 2017;140(5):1068–1081. doi: 10.1002/ijc.30526. [DOI] [PubMed] [Google Scholar]
  • 13.Zhong S., Zhang X., Chen L., Ma T., Tang J., Zhao J. Statin use and mortality in cancer patients: systematic review and meta-analysis of observational studies. Cancer Treatment Reviews . 2015;41(6):554–567. doi: 10.1016/j.ctrv.2015.04.005. [DOI] [PubMed] [Google Scholar]
  • 14.Shamseer L., Moher D., Clarke M., et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ . 2015;349(1):p. g7647. doi: 10.1136/bmj.g7647. [DOI] [PubMed] [Google Scholar]
  • 15.Hedges L. V., Pigott T. D. The power of statistical tests in meta-analysis. Psychological Methods . 2001;6(3):203–217. doi: 10.1037/1082-989x.6.3.203. [DOI] [PubMed] [Google Scholar]
  • 16.Begg C. B., Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics . 1994;50(4):1088–1101. doi: 10.2307/2533446. [DOI] [PubMed] [Google Scholar]
  • 17.Egger M., Smith G. D., Schneider M., Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ . 1997;315(7109):629–634. doi: 10.1136/bmj.315.7109.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Duval S., Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics . 2000;56(2):455–463. doi: 10.1111/j.0006-341x.2000.00455.x. [DOI] [PubMed] [Google Scholar]
  • 19.Peltomaa A. I., Raittinen P., Talala K., et al. Prostate cancer prognosis after initiation of androgen deprivation therapy among statin users. A population-based cohort study. Prostate Cancer and Prostatic Diseases . 2021;24(3):917–924. doi: 10.1038/s41391-021-00351-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Lopez D. S., Huang D., Tsilidis K. K., et al. The role of testosterone replacement therapy and statin use, and their combination, in prostate cancer. Cancer Causes & Control . 2021;32(9):965–976. doi: 10.1007/s10552-021-01450-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Hamilton R. J., Ding K., Crook J. M., et al. The association between statin use and outcomes in patients initiating androgen deprivation therapy. European Urology . 2021;79(4):446–452. doi: 10.1016/j.eururo.2020.12.031. [DOI] [PubMed] [Google Scholar]
  • 22.Goldberg H., Mohsin F. K., Saskin R., et al. The suggested unique association between the various statin subgroups and prostate cancer. European Urology Focus . 2021;7(3):537–545. doi: 10.1016/j.euf.2020.06.005. [DOI] [PubMed] [Google Scholar]
  • 23.Tan X. L., Lin Y., Rebbeck T. R., et al. Individual and joint effects of metformin and statins on mortality among patients with high-risk prostate cancer. Cancer Medicine . 2020;9(7):2379–2389. doi: 10.1002/cam4.2862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Kumar A., Riviere P., Luterstein E., et al. Associations among statins, preventive care, and prostate cancer mortality. Prostate Cancer and Prostatic Diseases . 2020;23(3):475–485. doi: 10.1038/s41391-020-0207-5. [DOI] [PubMed] [Google Scholar]
  • 25.Wu S. Y., Fang S. C., Shih H. J., Wen Y. C., Shao Y. H. J. Mortality associated with statins in men with advanced prostate cancer treated with androgen deprivation therapy. European Journal of Cancer . 2019;112:109–117. doi: 10.1016/j.ejca.2018.11.032. [DOI] [PubMed] [Google Scholar]
  • 26.Li K., Si-Tu J., Qiu J., et al. Statin and metformin therapy in prostate cancer patients with hyperlipidemia who underwent radiotherapy: a population-based cohort study. Cancer Management and Research . 2019;11:1189–1197. doi: 10.2147/CMAR.S166638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Joentausta R. M., Rannikko A., Murtola T. J. Prostate cancer survival among statin users after prostatectomy in a Finnish nationwide cohort. The Prostate . 2019;79(6):583–591. doi: 10.1002/pros.23768. [DOI] [PubMed] [Google Scholar]
  • 28.Anderson-Carter I., Posielski N., Liou J. I., et al. The impact of statins in combination with androgen deprivation therapyin patients with advanced prostate cancer: a large observational study. Urologic Oncology: Seminars and Original Investigations . 2019;37(2):130–137. doi: 10.1016/j.urolonc.2018.11.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Gordon J. A., Buonerba C., Pond G., et al. Statin use and survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide after docetaxel failure: the international retrospective observational STABEN study. Oncotarget . 2018;9(28):19861–19873. doi: 10.18632/oncotarget.24888. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Di Lorenzo G., Sonpavde G., Pond G., et al. Statin use and survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate. European Urology Focus . 2018;4(6):874–879. doi: 10.1016/j.euf.2017.03.015. [DOI] [PubMed] [Google Scholar]
  • 31.Chen Y. A., Lin Y. J., Lin C. L., et al. Simvastatin therapy for drug repositioning to reduce the risk of prostate cancer mortality in patients with hyperlipidemia. Frontiers in Pharmacology . 2018;9:p. 225. doi: 10.3389/fphar.2018.00225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Murtola T. J., Peltomaa A. I., Talala K., et al. Statin use and prostate cancer survival in the Finnish randomized study of screening for prostate cancer. European Urology Focus . 2017;3(2-3):212–220. doi: 10.1016/j.euf.2016.05.004. [DOI] [PubMed] [Google Scholar]
  • 33.Larsen S. B., Dehlendorff C., Skriver C., et al. Postdiagnosis statin use and mortality in Danish patients with prostate cancer. Journal of Clinical Oncology . 2017;35(29):3290–3297. doi: 10.1200/jco.2016.71.8981. [DOI] [PubMed] [Google Scholar]
  • 34.Keskivali T., Kujala P., Visakorpi T., Tammela T. L. J., Murtola T. J. Statin use and risk of disease recurrence and death after radical prostatectomy. The Prostate . 2016;76(5):469–478. doi: 10.1002/pros.23138. [DOI] [PubMed] [Google Scholar]
  • 35.Boegemann M., Schlack K., Fischer A. K., et al. Influence of statins on survival outcome in patients with metastatic castration resistant prostate cancer treated with abiraterone acetate. PLoS One . 2016;11(9) doi: 10.1371/journal.pone.0161959.e0161959 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Sun L. M., Lin M. C., Lin C. L., et al. Statin use reduces prostate cancer all-cause mortality: a nationwide population-based cohort study. Medicine (Baltimore) . 2015;94(39) doi: 10.1097/md.0000000000001644.e1644 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Chan J. M., Kenfield S. A., Paciorek A., Platz E. A., Giovannucci E. L., Stampfer M. J. Postdiagnostic statin use and the risk of lethal prostate cancer in the health professionals follow-up study. Cancer Epidemiology, Biomarkers & Prevention . 2015;24(10):1638–1640. doi: 10.1158/1055-9965.epi-15-0671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Yu O., Eberg M., Benayoun S., et al. Use of statins and the risk of death in patients with prostate cancer. Journal of Clinical Oncology . 2014;32(1):5–11. doi: 10.1200/jco.2013.49.4757. [DOI] [PubMed] [Google Scholar]
  • 39.Grytli H. H., Fagerland M. W., Fosså S. D., Taskén K. A. Association between use of β-blockers and prostate cancer-specific survival: a cohort study of 3561 prostate cancer patients with high-risk or metastatic disease. European Urology . 2014;65(3):635–641. doi: 10.1016/j.eururo.2013.01.007. [DOI] [PubMed] [Google Scholar]
  • 40.Caon J., Paquette M., Hamm J., Pickles T. Does statin or ASA affect survival when prostate cancer is treated with external beam radiation therapy? Prostate Cancer . 2014;2014:6. doi: 10.1155/2014/184297.184297 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Geybels M. S., Wright J. L., Holt S. K., Kolb S., Feng Z., Stanford J. L. Statin use in relation to prostate cancer outcomes in a population-based patient cohort study. The Prostate . 2013;73(11):1214–1222. doi: 10.1002/pros.22671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Katz M. S., Carroll P. R., Cowan J. E., Chan J. M., D’Amico A. V. Association of statin and nonsteroidal anti-inflammatory drug use with prostate cancer outcomes: results from CaPSURE. BJU International . 2010;106(5):627–632. doi: 10.1111/j.1464-410x.2010.09232.x. [DOI] [PubMed] [Google Scholar]
  • 43.Raval A. D., Thakker D., Negi H., Vyas A., Salkini M. W., Salkini M. W. Association between statins and clinical outcomes among men with prostate cancer: a systematic review and meta-analysis. Prostate Cancer and Prostatic Diseases . 2016;19(2):151–162. doi: 10.1038/pcan.2015.58. [DOI] [PubMed] [Google Scholar]
  • 44.Joshua A. M., Armstrong A., Crumbaker M., et al. Statin and metformin use and outcomes in patients with castration-resistant prostate cancer treated with enzalutamide: A meta-analysis of AFFIRM, PREVAIL and PROSPER. European journal of cancer . 2022;170:285–295. doi: 10.1016/j.ejca.2022.04.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Syvälä H., Pennanen P., Bläuer M., Tammela T. L., Murtola T. J. Additive inhibitory effects of simvastatin and enzalutamide on androgen-sensitive LNCaP and VCaP prostate cancer cells. Biochemical and Biophysical Research Communications . 2016;481(1-2):46–50. doi: 10.1016/j.bbrc.2016.11.021. [DOI] [PubMed] [Google Scholar]
  • 46.Alexandre L., Clark A. B., Bhutta H. Y., Chan S. S., Lewis M. P., Hart A. R. Association between statin use after diagnosis of esophageal cancer and survival: a population-based cohort study. Gastroenterology . 2016;150(4):854–865.e1. doi: 10.1053/j.gastro.2015.12.039. [DOI] [PubMed] [Google Scholar]
  • 47.Schaffner C. P. Prostatic cholesterol metabolism: regulation and alteration. Progress in clinical and biological research . 1981;75a:279–324. [PubMed] [Google Scholar]
  • 48.Lee B. H., Taylor M. G., Robinet P., et al. Dysregulation of cholesterol homeostasis in human prostate cancer through loss of ABCA1. Cancer Research . 2013;73(3):1211–1218. doi: 10.1158/0008-5472.can-12-3128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Yue S., Li J., Lee S. Y., et al. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metabolism . 2014;19(3):393–406. doi: 10.1016/j.cmet.2014.01.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Harshman L. C., Wang X., Nakabayashi M., et al. Statin use at the time of initiation of androgen deprivation therapy and time to progression in patients with hormone-sensitive prostate cancer. JAMA Oncology . 2015;1(4):495–504. doi: 10.1001/jamaoncol.2015.0829. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Materials

Supplement 1: Details of the search strategy to retrieve the studies. Supplement 2: Newcastle–Ottawa scale for assessing the quality of studies in meta-analysis. Supplement 3: Characteristics of included studies in the systematic review and meta-analysis. Supplement 4: Meta-regression and sensitivity analysis.

Click here for additional data file. (611.4KB, zip)

Data Availability Statement

All the data analyzed in this study are included within article/supplementary material and are available from the corresponding authors upon request.

Articles from Journal of Oncology are provided here courtesy of Wiley

RESOURCES