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

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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Prostate cancer (PCa) is the most commonly diagnosed malignancy among men in the US. Approximately 220,800 American males are estimated to have been diagnosed with prostate cancer in 2015, and 27,540 will die of the disease1. Unfortunately, up to 40% of patients experienced postoperative disease recurrence or progression on long-term follow-up2. Statins are wildly used medications for lowering hypercholesterolemia. Interestingly, some reports declaims that statins have been associated with a reduced incidence of PCa, with evidence being particularly strong for advanced PCa3,4. This eect may be related to both cholesterol and non-cholesterol-mediated mechanisms. While, the impact of statins use on the incidence and natural history of PCa remains controversial5,6. Moreover, there is increasingly considerable interest in the potential ability of statins to improve PCa outcomes and decrease recurrence risk aer denitive therapy.

A recent meta-analysis, including a total of 13 studies, provided the evidence that statins use could not reduce the recurrence risk among men treated with denitive therapy7. While, these studies included in Park et al.7 covered heterogeneous and limited sized cohorts. Moreover, nine more studies were published aer that7 and provided further evidence on this topic. Thus, a further analysis of the association of statins use with recurrence risk aer denitive therapy for PCa is warrant. Furthermore, whether statins have eect on the PCa-specic mortality still remained unknown.

Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, Peoples Republic of China.

Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, Peoples Republic of China.

Department of Cardiovascular and Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, Peoples Republic of China. *These authors contributed equally to this work. Correspondence and requests for

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We performed a literature search without language restrictions using the databases of PubMed (Jan 1967April 2015), MEDLINE (Jan 1967April 2015), EMBASE (Jan 1990April 2015) to include all studies that investigate the association of statins use with prostate cancer outcomes. In addition, a manual search was conducted to identify additional relevant studies. Aer removing duplicate publications, two reviewers (Tan & Wei) independently assessed all remaining results by checking titles and abstracts. All publications, including abstracts, were eligible for retrieval. When studies reported outcomes from similar or overlapping databases or cohorts, only data from the most recent publication were included. The studies included should analyze the BCR, PCa-specic mortality, or BCR-free survival. BCR dened as a post-treatment PSA value of 0.2ng/ml or greater in men who underwent radical prostatectomy; nadir PSA level +2ng/ml (Phoenix criteria), for men treated with radiation therapy; or any PSA increase in men treated with primary androgen deprivation therapy; and not any evidence of clinical and/or radiographically detected disease. We adapted a PRISMA (preferred reporting items for systematic reviews and meta-analyses) ow-chart to depict the study selection.

Data from each study were independently extracted by two reviewers (Tan & Wei) using a standardized data-extraction form. Any disagreements were resolved by consensus or by consultation with a third reviewer (Yang). Adjusted multivariate Hazard ratio (HR) with corresponding 95% condence intervals (CIs) were used to assess potential association between statins use and BCR and mortality of prostate cancer following treatment. In addition, we also tried to contact authors via e-mail to obtain further information that had not been reported in their published articles. We identied heterogeneity between studies using the standard Cochrans Q test with a signicance level of = 0.10. We also examined heterogeneity with the I2 statistic, which quanties inconsistency across studies to assess the impact of meta-analysis heterogeneity. An I2 statistic of 50% or more indicates a considerable level of heterogeneity. When heterogeneity was found, we attempted to determine potential sources of heterogeneity through stratication by various factors, and inference analysis and exclusion sensitivity analyses. Publication bias was detected using both the Beggs and Eggers tests. Statistical signicance was determined using the two-tailed test, where P< 0.05 was considered signicant. STATA version 10 (Stata corporation, college station, TX) was employed to conduct all statistical analyses.

A total of 3229 publications were identied during the initial search (see Additional le 1.), and aer employing exclusion criteria, a total of 22 studies were included for PCa recurrence analysis829 (Table1), 8 trials were available for PCa-specic mortality22,3036 (Table2), and 13 for BCR-free survival analysis8,9,11,14,17,20,25,29,3640 (Table3). Among 22 studies included in meta-analysis for PCa recurrence, 14 included a population primarily treated with radical prostatectomy (RP). Meanwhile, men in seven studies were treated with radiation therapy (RT-either external beam, brachytherapy or a combination of them). And other one study in which included patients were treated with RP, RT with or without ADT (androgen deprivation therapy) or ADT only22. Among 8 trials included for PCa specic mortality, one included a population of diabetic men34. Two abstract were included in BCR-free survival analysis.

Most studies demonstrated that statins had a neutral eect on recurrence aer prostate cancer diagnosis. Overall, the combined result showed statins users had lowered the risk of recurrence compared with non-users (HR= 0.88, 95%CI: 0.7650.998, I2=65.6%, p<0.001) (Fig.1). The association was null among the men who underwent RP as primary therapy (HR = 0.96, 95%CI: 0.831.09, I2 = 57.5%, p = 0.004). However, the combined result showed an inverse association between statins use and recurrence aer treatment of RT (HR= 0.67, 95%CI: 0.480.86, I2=60.9%, p< 0.001). It is really important to exclude patients undergoing ADT, in order to reduce the correlation between metabolic syndrome secondary androgen deprivation and BCR, as reported in literature. Aer excluding patients undergoing ADT, 11 studies were included and the combined estimates suggested that no patient had benet from statins use aer local therapy (HR= 0.94, 95%CI: 0.771.11) (Fig.2). Additional le 2 and le 3 shown, long-term statins use still cannot alter recurrence risk (HR= 0.90, 95%CI: 0.721.07). No publication bias was detected among 22 studies when Beggs and Eggers tests were conducted (p=0.81, p= 0.87, respectively) (see Additional le 4).

In the stratied analysis, the pooled HR estimates suggested that reverse relationship between statins use and PCa recurrence was observed in the US (HR= 0.86, 95%CI: 0.730.99). However, we failed to nd a similar relation in the non-US (HR = 1.01, 95%CI: 0.671.35). When stratied analyses were performed on the results with or without adjusted for age, BMI, or PSA, we observed that statins use had a neutral eect on PCa recurrence when adjusted for them. Post-operation and pre-operation statins use both cannot alter PCa recurrence risk. Detailed data are illustrated in Table4.

While there was limited data of the eect of statins on local recurrence and metastasis of PCa aer treatment. For low-, intermediate- and high-risk group, statins use did not aect the recurrence risk14. The Mondual et al. also observed that statins using was not associated with the progression to metastasis or death of PCa aer treatment16.

Eight studies evaluated exposure to statins and the recurrence of PCa. Figure3 graphed the HRs and 95%CIs from individual studies and the pooled results. Among them, six studies showed an inverse association. The combined estimates of eight studies showed a decreased risk (HR= 0.68, 95%CI: 0.560.80) (Table5). Aer excluding Serruys et al.30, due to its large condence interval (HR= 0.98, 95%CI: 0.146.92), the result of seven studies was consistent and stable (HR= 0.68, 95%CI: 0.550.80). There was no publication bias (Beggs test, p= 0.386; Eggers test, p= 0.063). Aer adjusting for age, BMI, or PSA, the same trends were observed in these subgroups (see Table5).

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No. of patients

on statins

Estimate(s)(95%

condence interval, CI)

Moyad et al. (2006)8 US brachytherapy+EBRT 938 191 39 40.7 HR:1.5 (0.336.94) Soto et al. (2009)9 US 3D-RT or IMRT 968 220 NR 28.9 HR:1.1 (0.81.6) Rioja et al. (2010)10 US RP 3748 2664 249 0.0 HR:1.15 (0.891.50) Gutt et al. (2010)11 US brachytherapy+EBRT 691 189 113 41.0 HR:0.43(0.250.73) Hamilton et al. (2010)12 US RP 1319 236 304 18.0 HR:0.70 (0.500.97) Krane et al. (2010)13 US rRP 3828 1031 NR 1.5 HR:0.99 (0.831.18) Kollmeier et al. (2011)14 US 3D-RT or IMRT 1681 382 301 56.0 HR:0.69 (0.500.97) Ku et al. (2011)15 Korean RRP 687 87 145 0.0 HR:1.18 (0.672.10) Mondul et al. (2011)16 US RRP 2399 779 127 0.0 HR:0.99 (0.641.55) Ritch et al. (2011)17 US RP 1261 281 NR 0.0 HR:1.54 (1.002.20) Zaorsky et al. (2012)18 US 3D-CRT+IMRT 2051 691 177 0.0 HR:0.63 (0.490.82) Mass et al. (2012)19 US ORRP 1446 437 166 NR HR:1.15 (0.821.61) Rieken et al. (2013)20 Multicenter RP 6842 2275 778 0.0 HR:0.88 (0.761.03) Kontraros et al. (2013)21 Greece RP 588 107 187 0.0 HR:1.63 (1.192.24) Geybels et al. (2013)22 US RP, RT 1001 289 151 NR HR:1.06 (0.741.54) Chao et al. (2013)24 US EBRT 774 401 145 67.0 HR:0.99 (0.701.39) Chao et al. (2013)24 US RP 1184 446 156 0.0 HR:1.00 (0.721.39) Oh et al. (2014)25 US Brachytherapy+EBRT 247 174 18 25.9 HR:0.29 (0.090.89) ishak-Howard et al. (2014)26 US RRP 539 258 115 NR HR:1.06 (0.681.64) Allott et al. (2014)27 US RP 1146 400 402 0.0 HR:0.64 (0.470.87) Danzig et al. (2015)29 US RP 669 76 147 0.0 HR:1.20 (1.502.60) Song et al. (2015)28 Korea rRP or ORRP 1896 211 466 0.0 HR:0.64 (0.401.05)

Table 1. Study characteristics of 22 included studies of the association between statins use and biochemical recurrence risk of PCa aer denitive therapy. Note: XRT, external beam radiotherapy (XRT); RRP, radical retropubic prostatectomy; 3D-CRT, 3-dimensional conformal radiation therapy; IMRT, intensity modulated radiation therapy; ORRP, open radical retropubic prostatectomy; rRP, robotic radical prostatectomy.

Table3 showed 13 retrospective studies were included to evaluate the eect of statins on biochemical recurrence-free survival. The 5-year BCR-free survival rate of statins users ranged from 63.7 to 97.2% and that was 5789.6% for non-users. The statins users had much higher 10-year BCR-free survival rate compared with non-users.

Sensitivity analyses were conducted to evaluate the eect of each study on the overall estimates by sequentially excluding each study in turn. In our meta-analysis, we found that probably no study could aect the summary of risk estimates, means that the results remained stable (data not shown).

In this meta-analysis among men following denitive treatment of localized prostate cancer, approximately 12% reduction risk of recurrence in statins users was found (p< 0.001). In cumulative meta-analysis, a reduction risk was found for the rst time in 2010, when Hamilton et al.12 joined the analysis. When analyzed by treatment modality, statins use had a neutral eect on BCR risk among men who underwent radical prostatectomy. On the contrary, there was almost 33% lower risk of recurrence among statins users who received RT as primary treatment modality. These are consistent with the results from subgroup patients who did not receive adjuvant ADT. The benets were null when estimates controlled for age, BMI or PSA. Overall, there was 32% lower risk of prostate cancer-specic mortality among statins users. To our knowledge, this is the rst meta-analysis to address the relationship between PCa-specic mortality and statins use.

Whether the improved outcomes seen among patients who underwent RT reecting that statins directly inhibit PCa progression, act as a radiosensitizer, or are the result of either residual confounding or type I error of studies is unknown. One postulated possible explanation was statin-induced radiosensitizing eects. Prostate cancer cell death was increased in both in vitro and in vivo models when combined the statins and ionizing radiation, which might attributed to the MYC oncogene, as statins decreasing cellular MYC levels11,41. Statins

also play a synergistic role with radiation by promoting autophagy pathway, causing prostate cancer cell death42.

Moreover, Gutt et al.11 proved that a larger benet was seen in men treated with lower radiation doses. Clinically, RT combined with ADT were oen used to treat PCa. In our work, seven studies analyzed men who treated by RT, but six of them included patients who received ADT. As ADT could reduce PCa recurrence risk, the eect of statins could not be conrmed there.

Intriguingly, our ndings do not support the hypothesis that statins, when taken at low dose for managing hypercholesterolemia, can reduce the risk of PCa recurrence among men treated with RP as primary therapy. Although many studies found the statins had antineoplastic properties, two precious high quality meta-analyses had conrmed that statins use could not reduce the risk of prostate cancer5,43,44. Another plausible explanation

Study (year) Country Primary treatment(s)

No. of

patients

No. of recurrence

patients ADT (%)

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Estimate(s)(95%

condence interval, CI)

Serruys et al. (2002)30 Multicenter 3.9y 1406 (83.8) 4 HR:0.98 (0.146.92) Marcella et al. (2011)31 US NR 760 (100.0) 380 HR:0.45 (0.290.71) Nielsen et al. (2012)32 Denmark 2.6y 27752 (100.0) 10542 HR:0.81 (0.750.88) Grytli et al. (2013)33 Norway 39 M 3699 (100.0) NR HR:0.78 (0.670.90) Geybels et al. (2013)22 US 6.1y 1001 (100.0) 39 HR:0.19 (0.060.56) Margel et al. (2013)34 Canada 4.64y 3837 (100.0) 291 HR:0.78 (0.620.99) Yu et al. (2014)35 UK 4.4y2.9 11772 (100.0) 1791 HR:0.76 (0.660.88) Caon et al. (2014)36 Canada 8.4y 3851 (100.0) NR HR:0.77 (0.551.08)

Table 2. Study characteristics of 8 studies of the association between statins use and prostate cancer-specic mortality. *PCa, prostate cancer.

Biochemical Recurrence-Free Survival Rate

Duration: Statins users (%) vs Non-statin users (%); P-valueKatz et al. (2003)37 RT# 905 5 year: 88.8% vs 71.2%; P=.009Moyad et al. (2006)8 RT 938 9 year: 98.4% vs 95.2%; P=0.062Shippy et al. (2007)38 RT 871 10-year: 76% vs 66%; P=0.01Soto et al. (2009)9 RT 968 5 year: 67% vs 57%; P=0.03Gutt et al. (2010)11 RT 691 4 year: 93% vs 80%; P<0.001

Kollmeier et al. (2011)14 RT 1711 5 year: 89% (95%CI, 8592%) vs 80% (95%CI, 7286%)

8 year: 83% (95%CI, 8185%) vs 74% (95%CI, 7177%)

Ritch et al. (2011)17 RP$ 1261 5 year: 75% vs 84%; P<0.05Misrai et al. (2012)39 RP 377 2 year: 93% vs 88%; P=0.16

Rieken et al. (2013)20

RP

6842

is that statins are associated with a dose-dependent reduction in the risk of biochemical recurrence. The eect of statins on lowering recurrence risk was observed only when taken at doses 1 DE (dose equivalents)12. Many in vitro studies that demonstrated these protective eects also used statins concentrations that were much higher than those seen with standard therapeutic use.

This meta-analysis suggested that regular statins use reduced 32% risk of PCa-related mortality. Meanwhile, Marcella et al.31 evaluated eect of statin type on prostate cancer mortality, which showed that hydrophilic and lipophilic statins both lowered the risk of PCa-specic mortality. However, there was a trend based on potency in which high-potency statins were associated with a 73% risk reduction, whereas this eect was not observed in low-potency statins.

One of 13 trials evaluating the BCR-free survival suggested that statins users had a lower 5-year BCR-free survival rate compared with non-users17, while some reveled reversely9,25,37 or showed there was no dierence between two groups20. Meanwhile, the BCR-free survival rate at 8 or 9-year were still inconsistent8,14,40. However, the BCR-free survival rate at 10 year among statins users was much higher compared with non-users36,38. These

inconsistencies might be attributed to the composition of risk group of patients, as lower-risk group had higher 5-year BCR-free survival rate compared with intermediate-risk and high-risk group9,11,14,17. Meanwhile, treat

ment modality and the radiation doses among men who underwent RT also contributed to this inconsistency12.

Overall, there is a plausible trend towards increasing the BCR-free survival rate among statins users.

Given the known that income, education and health insurance coverage inuence access to appropriate early detection, statins users are more likely to get PSA testing done and treatment, leading percent of low or intermediate-risk patients much higher among statins users than that in non-users. This might cause an illusion that statins have protective eect. The possible confounding eect arising due to the indications for which statins are prescribed also needs to be emphasized. Statins users are more likely to be obese or older as compared to non-users. This could aect PCa outcomes or progression. The subgroup analyses of 6 studies which adjusted for BMI or age reveled a neutral eect on BCR. This eect was also observed in the combined estimates of four studies adjusted for both BMI and age.

Study (year) Country

Duration of follow-

up (MeanSD ) All male subjects (%)

No. of died

from PCa*

Sources (year) Primary treatment(s) No. of patients

2 year: 94 1% vs 920%; P=NR*

5 year: 84 1% vs 821%; P=NR

10 year: 71 3% vs 663%; P=NR

Caon et al. (2014)36 RTADT 3851 10-year: 94.1% vs 91.2%; P=0.031 Oh et al. (2014)25 RT 247 5 year: 97.2% vs 89.6%; P=0.007 Cuaron et al. (2015)40 RT 754 8-year: 84.5% vs 88.2%; P=0.85

Danzig et al. (2015)29 RP 767 2-year: 79.0% vs 79.3%; P=NR

5-year: 63.7% vs 72.4%; P=NR

Table 3. Characteristics of 13 studies evaluating the eect of statins on Biochemical Recurrence-Free Survival. *NR, not report. #RT, radiation therapy. $RP, radical prostatectomy.

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Figure 1. The eect of statins on BCR risk of prostate cancer among men following denitive therapy.

Figure 2. The eect of statins on BCR risk of prostate cancer among men who did not receive ADT pre- or post-local therapy.

A previous meta-analysis, including 8 studies, initially addressed the relationship between statins use and PCa recurrence and showed that there was no association between statins use and recurrence aer prostate cancer diagnosis (HR= 0.91, 95%CI: 0.721.13), this eect was consistent with men received RP or RT45. Aer that, another meta-analysis included 13 studies in the formal meta-analysis was conducted, which showed the same relationship (HR= 0.90, 95%CI: 0.741.08), while a reverse association was initially observed among men accepted RT (HR = 0.68, 95%CI: 0.490.93)7. Compared with Park et al.7, aer including 9 more new studies

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Pooled estimates Tests of heterogeneity Tests of publication bias HR 95%CI I2 (%) p-val. Beggs p-val. Eggers p-val. All studies 22 0.88 0.7650.998 66.8 <0.001 0.809 0.866 Treatment modality

RP 14 0.96 0.831.09 57.5 0.004 0.784 0.518 RT 7 0.67 0.480.86 60.9 0.018 0.881 0.753 Exclude pts received ADT 11 0.94 0.771.11 68.5 <0.001 0.533 0.493 RP 10 0.99 0.811.17 62.9 0.004 0.788 0.500 RT 1 0.63 0.630.79 Include pts received ADT 8 0.74 0.540.95 71.5 0.001 0.712 0.453 RT 6 0.69 0.430.96 67.5 0.009 0.851 0.495 RP 2 0.86 0.571.14 73.4 0.052 Pre- or post-operation 7 0.87 0.691.04 51.9 0.052 1.000 0.760 Post-operation 5 0.83 0.611.05 59.0 0.045 0.806 0.740 Pre-operation 2 1.00 0.751.24 0.0 0.967 Results for long-term statins use 7 0.90 0.721.07 11.8 0.340 0.548 0.529 Park et al. analysis

Before 12 0.89 0.721.06 70.5 <0.001 0.945 0.994 Aer 10 0.88 0.701.05 65.0 0.002 0.929 0.865 Country

US 18 0.86 0.730.99 66.6 <0.001 0.879 0.710 Non-US 4 1.01 0.671.35 71.6 0.014 0.497 0.730 PSA

Adjusted 11 0.95 0.811.09 52.5 0.021 0.697 0.401 Not adjusted 11 0.80 0.600.99 73.3 <0.001 0.697 0.592 BMI

Adjusted 6 0.93 0.711.16 71.9 0.003 0.851 0.943 Not adjusted 16 0.86 0.721.01 66.5 <0.001 0.928 0.948 Age

Adjusted 8 0.96 0.811.12 59.0 0.017 0.621 0.495 Not adjusted 14 0.82 0.650.98 65.5 <0.001 0.913 0.873 BMI & Age

Adjusted 4 1.00 0.681.32 80.1 0.002 0.497 0.954 Not adjusted 18 0.86 0.730.98 63.5 <0.001 1.000 0.967 BMI or PSA or Age

Adjusted 12 0.95 0.831.07 50.3 0.023 0.681 0.490 Not adjusted 10 0.76 0.550.97 68.2 0.001 0.929 0.865

Table 4. Pooled estimates of BCR analyses in subgroups. Note: HR, Hazard ratio; 95%CI, 95% condence intervals; PCa, prostate cancer; PSA, prostate-specic antigen; RT, radiation therapy; RP, radical prostatectomy. BCR, biochemical recurrence.

that provided stronger evidence, we found a reverse association with statins among men following denitive treatment. Besides, Oh et al.25 updated their data in 2014, which may also contribute to this inconsistency. Unexpectedly, the combined result of these 10 studies showed a neutral eect of statins use on recurrence risk (HR= 0.88, 95%CI: 0.701.05).

Some limits in our meta-analysis should be mentioned. First, the available literature was limited to English language, which might be subject to selective bias and confounding. Second, there was signicant heterogeneity among studies that might be attributed to various percent of risk groups. In a study, the benecial eect was limited to high-risk patients, which proved that risk groups could aect the recurrence-free survival14. While, the data in dierent risk groups was limited; thus, the future studies addressing this topic should take the risk groups into account. Another potential factor contributed to this heterogeneity was starting time of statins use, which means some patients started using statins before operation (RT or RP or both), some started using during operation, while others received statins for the rst time aer operation. Third, the overall result showed that statins use lowered the recurrence of PCa, while the upper condence interval close to 1.00. Therefore the result of this part needs to be explained with caution. At last, limited prospective sequential data was available at the moment, lowering the strength of evidence in this meta-analysis.

In summary, our work demonstrated that statins use could not lower PCa recurrence risk among all patients underwent RP. Although the improved outcomes might be seen among statins users who underwent RT, more

Sources No. of studies

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Figure 3. The relationship between statins use and prostate cancer-specic mortality.

Pooled estimates Tests of heterogeneity Tests of publication bias

HR 95%CI I2 (%) p-val. Beggs p-val. Eggers p-val. PCa-specic mortality 8 0.68 0.560.80 77.2 <0.001 0.386 0.063 Exclude Serruys et al. 7 0.68 0.550.80 80.5 <0.001 0.072 0.018 Age

Adjusted 5 0.64 0.480.79 87.0 <0.001 0.086 0.004 Not adjusted 2 0.78 0.600.97 0.0 0.908 BMI

Adjusted 2 0.62 0.320.92 84.8 0.010 Not adjusted 5 0.68 0.500.85 82.0 <0.001 0.806 0.258 PSA

Adjusted 3 0.61 0.350.86 89.4 <0.001 1.000 0.077 Not adjusted 4 0.70 0.510.89 70.9 0.016 0.734 0.445 BMI & Age

Adjusted 2 0.62 0.320.92 84.8 0.010 Not adjusted 5 0.68 0.500.85 82.0 <0.001 0.806 0.258 BMI or PSA or Age

Adjusted 5 0.64 0.480.79 87.0 <0.001 0.086 0.004 Not adjusted 2 0.78 0.600.97 0.0 0.908

Table 5. Pooled estimates of Mortality analyses in subgroups. Note: HR, Hazard ratio; 95%CI, 95% condence intervals; PCa, prostate cancer; PSA, prostate-specic antigen.

future studies excluded men who received ADT pre- or post-radiation therapy should be done. In addition, statins use decreased the prostate cancer-specic mortality risk. A plausible trend towards increasing the BCR-free survival rate among statins users was also observed.

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This study was supported by the National Natural Science Foundation of China (Grant nos 81370855, 81200551 and 81300627), the Prostate Cancer Foundation Young Investigator Award 2013 and Foundation of Science & Technology Department of Sichuan Province (Grant nos 2013SZ0006 and 2015SZ0230). The funders had no role in study selection, data extraction, analysis or interpretation, writing of this article, or the decision to publish. YL and TP had full access to all the data in the study and TP took nal responsibility for the content and the decision to submit for publication.

Q.W., L.Y. and P.T. had the idea for and designed this review. P.T., S.W., J.L. and Z.T. identied reports of trials and extracted data. L.L. provided statistical advice and S.W. did all statistical analyses. Z.T. and J.L. checked for statistical inconsistency and interpreted data. L.Y., D.C., Y.F. and L.G. contributed to data interpretation. P.T. draed the report and all other authors (Q.W., L.Y., S.W., Z.T. and L.G.) critically reviewed the article. Q.W. is guarantor.

Supplementary information accompanies this paper at http://www.nature.com/srep

Competing nancial interests: The authors declare no competing nancial interests.

How to cite this article: Tan, P. et al. The eect of statins on prostate cancer recurrence and mortality aer denitive therapy: a systematic review and meta-analysis. Sci. Rep. 6, 29106; doi: 10.1038/srep29106 (2016).

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