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      The effect of statins on prostate cancer recurrence and mortality after definitive therapy: a systematic review and meta-analysis

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          Abstract

          In this work, we aim to further analyze the association of statins use with biochemical recurrence (BCR) of prostate cancer (PCa) and PCa-specific mortality after definitive therapy. A systematic literature search of PubMed, MEDLINE, and EMBASE through Jul 2015 was conducted. Pooled Hazard ratio (HR) estimates with corresponding 95% confidence intervals (CIs) were calculated using random-effects model. STATA version 10 (Stata corporation, college station, TX) was employed to conduct all statistical analyses. A total of 22 and 8 studies contributed to the biochemical recurrence analysis and PCa-specific mortality, respectively. 13 trials were included for BCR-free survival analysis. The combined result showed statins users had lowered 12% BCR risk of PCa compared with non-users (HR = 0.88, 95%CI: 0.765–0.998) (p < 0.05). The association was null among the men who underwent radical prostatectomy as primary therapy (HR = 0.96, 95%CI: 0.83–1.09), while the improved outcomes had be seen among patients who received radiation therapy (HR = 0.67, 95%CI: 0.48–0.86). After excluding the patients undergoing ADT, participants did not benefit from statins use (HR = 0.94, 95%CI: 0.77–1.11). Meanwhile, long-term statins using did not alter recurrence risk. A lower risk of prostate cancer-specific mortality was observed among statins users (HR = 0.68, 95%CI: 0.56–0.80). There was a plausible trend towards increasing the BCR-free survival rate among statins users.

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          Most cited references 29

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          Use of statins and the risk of death in patients with prostate cancer.

          To determine whether the use of statins after prostate cancer diagnosis is associated with a decreased risk of cancer-related mortality and all-cause mortality and to assess whether this association is modified by prediagnostic use of statins. A cohort of 11,772 men newly diagnosed with nonmetastatic prostate cancer between April 1, 1998, and December 31, 2009, followed until October 1, 2012, was identified using a large population-based electronic database from the United Kingdom. Time-dependent Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) with 95% CIs of mortality outcomes associated with postdiagnostic use of statins, lagged by 1 year to account for latency considerations and to minimize reverse causality, and considering effect modification by prediagnostic use of statins. During a mean follow-up time of 4.4 years (standard deviation, 2.9 years), 3,499 deaths occurred, including 1,791 from prostate cancer. Postdiagnostic use of statins was associated with a decreased risk of prostate cancer mortality (HR, 0.76; 95% CI, 0.66 to 0.88) and all-cause mortality (HR, 0.86; 95% CI, 0.78 to 0.95). These decreased risks of prostate cancer mortality and all-cause mortality were more pronounced in patients who also used statins before diagnosis (HR, 0.55; 95% CI, 0.41 to 0.74; and HR, 0.66; 95% CI, 0.53 to 0.81, respectively), with weaker effects in patients who initiated the treatment only after diagnosis (HR, 0.82; 95% CI, 0.71 to 0.96; and HR, 0.91; 95% CI, 0.82 to 1.01, respectively). Overall, the use of statins after diagnosis was associated with a decreased risk in prostate cancer mortality. However, this effect was stronger in patients who also used statins before diagnosis.
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            Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes.

            To evaluate the association between cumulative duration of metformin use after prostate cancer (PC) diagnosis and all-cause and PC-specific mortality among patients with diabetes. We used a population-based retrospective cohort design. Data were obtained from several Ontario health care administrative databases. Within a cohort of men older than age 66 years with incident diabetes who subsequently developed PC, we examined the effect of duration of antidiabetic medication exposure after PC diagnosis on all-cause and PC-specific mortality. Crude and adjusted hazard ratios (HRs) were calculated by using a time-varying Cox proportional hazard model to estimate effects. The cohort consisted of 3,837 patients. Median age at diagnosis of PC was 75 years (interquartile range [IQR], 72 to 79 years). During a median follow-up of 4.64 years (IQR, 2.7 to 7.1 years), 1,343 (35%) died, and 291 patients (7.6%) died as a result of PC. Cumulative duration of metformin treatment after PC diagnosis was associated with a significant decreased risk of PC-specific and all-cause mortality in a dose-dependent fashion. Adjusted HR for PC-specific mortality was 0.76 (95% CI, 0.64 to 0.89) for each additional 6 months of metformin use. The association with all-cause mortality was also significant but declined over time from an HR of 0.76 in the first 6 months to 0.93 between 24 and 30 months. There was no relationship between cumulative use of other antidiabetic drugs and either outcome. Increased cumulative duration of metformin exposure after PC diagnosis was associated with decreases in both all-cause and PC-specific mortality among diabetic men.
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              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.

              We recently reported reduced prostate cancer (PCa)-specific mortality for β-blocker users among patients receiving androgen-deprivation therapy in a health survey cohort including 655 PCa patients. Information on clinical characteristics was limited. To assess the association between β-blockers and PCa-specific mortality in a cohort of 3561 prostate cancer patients with high-risk or metastatic disease, and to address potential confounding from the use of statins or acetylsalicylic acid (ASA). Clinical information from all men reported to the Cancer Registry of Norway with a PCa diagnosis between 2004 and 2009 (n=24 571) was coupled with information on filled prescriptions between 2004 and 2011 from the Norwegian Prescription Database. Exclusion criteria were low- or intermediate-risk disease; planned radiotherapy or radical prostatectomy; initiation of β-blocker, ASA, or statin use after diagnosis where applicable; missing information on baseline Gleason score, prostate-specific antigen level, T stage or performance status; and missing follow-up. Cox proportional hazards modelling and competing risk regression modelling were used to analyse the effects of β-blocker use on all-cause and PCa-specific mortality, respectively. Differences between β-blocker users and nonusers regarding baseline clinical characteristics were assessed by the Wilcoxon-Mann-Whitney U test, Pearson chi-square test, and Student t test. Median follow-up was 39 mo. β-Blocker use was associated with reduced PCa mortality (adjusted subhazard ratio: 0.79; 95% confidence interval [CI], 0.68-0.91; p value: 0.001). The observed reduction in PCa mortality was independent of the use of statins or ASA. We observed no association with all-cause mortality (adjusted hazard ratio: 0.92; 95% CI, 0.83-1.02). The main limitations of the study were the observational study design and short follow-up. β-Blocker use was associated with reduced PCa-specific mortality in patients with high-risk or metastatic disease at the time of diagnosis. Our findings need validation from further observational studies. Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                07 July 2016
                2016
                : 6
                Affiliations
                [1 ]Department of Urology, West China Hospital, Sichuan University , Chengdu, Sichuan, People’s Republic of China
                [2 ]Institute of Urology, West China Hospital, Sichuan University , Chengdu, Sichuan, People’s Republic of China
                [3 ]Department of Cardiovascular and Thoracic Surgery, West China Hospital, Sichuan University , Chengdu, Sichuan, People’s Republic of China
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                srep29106
                10.1038/srep29106
                4935858
                27384548
                9796dd51-e542-456a-b1f5-5b755e31d443
                Copyright © 2016, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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