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ORIGINAL ARTICLE

Association between statins and clinical outcomes among menwith prostate cancer: a systematic review and meta-analysisAD Raval1,2, D Thakker3, H Negi4, A Vyas5 and MW Salkini6,7

BACKGROUND: Mixed evidence exists regarding the effects of statins among men with prostate cancer. We aimed to determinethe association between statin use and clinical outcomes in prostate cancer using systematic review and meta-analysis.METHODS: Original articles published until second week of August 2015 were searched in electronic databases (Medline-Ovid,Pubmed, Scopus, The Cochrane Library, Web of Science, ProQuest) for studies on statin use in prostate cancer. The main clinicaloutcomes for the review were: biochemical recurrence (BCR), metastases, and all-cause and prostate cancer-specific mortality.Meta-analysis was performed to calculate the pooled hazard ratio (pHR) and their 95% confidence interval (95% CI). Heterogeneitybetween the studies was examined using I2 statistics. Meta-regression was performed, wherever significant heterogeneity wasfound in the meta-analyses, to find factors associated with poor outcomes, and sensitivity analyses were conducted to assess therobustness of findings. The analyses were conducted using RevMan v5.3, STATA v14, and R v3.1.1.RESULTS: Out of the 1002 retrieved citations, 34 observational cohort studies met the inclusion criteria. Statin use was associatedwith a 21% reduction in the risk of BCR among those treated with radiation therapy (pHR: 0.79, 95% CI: 0.65, 0.95, P-value = 0.01, 10studies, I2 = 54%), whereas it was not associated with the BCR among those treated with radical prostatectomy (pHR: 0.94, 95% CI:0.81, 1.09, P-value = 0.43, 15 studies, I2 = 65%). Statin use was associated with a 22% reduction in the risk of metastases (pHR: 0.78,95% CI: 0.68, 0.87, P-valueo0.001, 6 studies, I2 = 0%), and a 24% reduction in risk of both all-cause mortality (pHR: 0.76, 95% CI: 0.63,0.91, P-value = 0.004, 6 studies, I2 = 71%), and prostate cancer-specific mortality (pHR: 0.76, 95% CI: 0.64, 0.89, P-value = 0.0007, 5studies, I2 = 40%).CONCLUSIONS: Our systematic review found that statin significantly reduced the all-cause and prostate cancer-specific mortalityand improved the BCR in certain subgroup of men with prostate cancer. In future, randomized controlled trials should beconducted to establish efficacy of statins among men with prostate cancer.

Prostate Cancer and Prostatic Diseases advance online publication, 19 January 2016; doi:10.1038/pcan.2015.58

INTRODUCTIONAccording to the recent report of the World Health Organizationof 184 countries, prostate cancer is the most common non-skincancer in men with an estimated incidence of 1.1 million cases ofprostate cancer and accounts for 15% of cancer cases diagnosedin men as of 2012. Prostate cancer is the fifth leading cause ofdeath owing to cancer in men (6.6% of total death in men)worldwide with an estimated death of 307 000 in 2012.1 Men withprostate cancer usually experience a rise in the PSA levels, acondition called biochemical recurrence (BCR).2 BCR is also one ofthe strongest factors associated with development of subsequentmetastasis and death. Although radiation therapy (RT) and radicalprostatectomy (RP) are the key treatment options to reduce therisk of BCR, nearly 20–40% men treated with RP3–5 or 30–50% ofthose treated with RT develop BCR.5 Therefore, there are urgentneeds for effective treatment to improve survival and quality oflife by reducing the risk of recurrence and metastases among menwith prostate cancer.Statins aka 3-hydroxy-3-methylglutaryl coenzyme A reductase

inhibitors are usually prescribed to decrease the serum cholesterollevels and reduce the risk of cardiovascular disease.6 Recently, the

role of statins has been examined for the management of prostatecancer owing to its anticancer properties.7 Cancer cells haveincreased rates of lipid biosynthesis to improve the cellularstructure, angiogenesis and to reduce the rates of apoptosis.8

Statins inhibit lipid biosynthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A, leading to increase the apoptosis ofcancer cells.7–9 In addition, statins have pleiotropic effects, whichhelp in the reduction of inflammation and cellular proliferation byinhibiting Ras proteins,7,10 and inhibit other cellular pathways. Inaddition, certain lipophilic statins in high concentrations inhibitcancer cell's migration in prostate cancer cells, which may preventmetastases.11 Therefore, many clinical studies have been per-formed to investigate the clinical utility of statin among men withprostate cancer.Two prior systematic reviews of epidemiological studies

reported mixed findings on the association between statin useand clinical outcomes among men with prostate cancer.12,13 In thefirst systematic review, Scosyrev et al.13 retrieved eight cohortstudies as of May 2012 and concluded that statin use was notassociated with BCR among men treated with either RP or RT. Inthe subsequent meta-analysis, Park et al.12 retrieved 13 studies as

1Department of Pharmaceutical Systems and Policy, School of Pharmacy, West Virginia University, Morgantown, WV, USA; 2Healthcore, Inc., Wilmington, DE, USA; 3HealthOutcomes Research, Capita India, Mumbai, India; 4Department of Pharmacology, Post-Graduate Medical Education and Research Institute (PGIMER), Chandigarh, India;5Department of Epidemiology, School of Public Health, Rutgers, the State University of New Jersey, Piscataway, NJ, USA; 6Department of Hospital Medicine, Cleveland Clinic,Cleveland, OH, USA and 7Department of Urology, School of Medicine, West Virginia University, Morgantown, WV, USA. Correspondence: Dr AD Raval, HealthCore, Inc., 123Justison Street, Suite 200, Wilmington, DE 19801, USA.E-mail: [email protected] 2 September 2015; revised 11 October 2015; accepted 8 November 2015

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of August 2012 and concluded that statin use was associated witha 32% reduction in the risk of BCR among men treated with RT;however, this study did not find any association between statinuse and BCR among men treated with RP. The investigators of thisstudy also noticed a significant heterogeneity in the pooled studyestimates from the limited number of studies and suggested theneed for further research to provide conclusive evidence.12 Manystudies have been published since the date of search of thosesystematic reviews. Therefore, we have conducted this systematicreview and meta-analysis to examine the association betweenstatin use and clinical outcomes such as BCR, metastases and all-cause and prostate cancer-related mortality among men withprostate cancer.

MATERIALS AND METHODSWe followed the standard guidelines of the Preferred Reporting Itemsfor Systematic Reviews and Meta-Analyses (PRISMA) Statement14 andCochrane Collaboration guidelines15 to carry out this systematic reviewand meta-analysis.

Criteria for study selectionWe included both prospective randomized clinical trials (RCTs) (double-blinded, single-blinded or cross-over) and observational (cohort or case–control) studies examining the clinical outcomes of statins among menwith prostate cancer. We excluded animal studies and in vitro studies, quasior pseudo RCTs and studies with shorter duration (⩽6 months) of follow-up. The primary outcome of interest for our review was BCR. Secondaryoutcomes of interest were: development of metastases, all-cause mortality,and prostate cancer-specific mortality.

Data sources and searchesWe searched Medline (Ovid), Scopus and the Cochrane library (sinceinception to second week of March 2015) to identify RCTs andobservational studies assessing the effects of statins among men withprostate cancer. In addition, we also searched the Web of Science andProQuest Dissertations and Theses Full Text until March 2015 to identifygray literature related to unpublished theses or dissertations on the effectsof statins on prostate cancer. We searched these databases usingkeywords, such as ‘statins’, ‘prostate neoplasm’ and ‘prostate cancer’. Thesearch strategy for each database is reported in Supplementary AppendixS1 with keywords and the number of retrieved citations per string. We alsocreated weekly alerts for new articles for the electronic databases andincluded the new articles available until 15 August 2015. Finally, we alsoskimmed through the reference lists of identified studies to find additionalpertinent studies.

Data extraction and quality assessmentTwo authors (DT, HN) independently assessed the retrieved articlesand gray literature for inclusion of articles in the review. The inter-raterkappa statistic was calculated to assess the agreement between thetwo authors for inclusion or exclusion of the articles. Discrepancies aboutthe inclusion or exclusion were resolved by consensus of the thirdauthor (ADR).From all the eligible studies, all four authors (ADR, AV, DT, and HN)

independently extracted information from the included studies using apredefined data extraction form. In the presence of multiple publicationsof a study, we included the article with latest and comprehensiveinformation available out of those multiple publications. We designed thedata extraction form to capture information about study design, country ofparticipants, year of publication, sample size, inclusion and exclusioncriteria of individual studies, prostate cancer stage and severity relatedvariables, duration of statin use, type and other baseline characteristics. Inaddition, we also extracted data on the reported outcomes from eachstudy on BCR, metastases, all-cause mortality, and prostate cancer-specificmortality with details on statistical parameters, such as unadjusted andadjusted hazard ratios (HRs).We utilized the Newcastle–Ottawa scale (NOS) tool to examine the risk

of bias in included observational studies. The NOS allots up to nine pointsfor the least risk of bias in three domains: (1) selection of study groups(four points); (2) comparability of groups (two points); and (3)

ascertainment of exposure and outcomes (three points) for cohortstudies.16 The risk of bias or poor quality were considered as ‘high’ withone or four score total scores, ‘fair’ with a total score of 4 to 6 and ‘good’with a total score ⩾7.17

Data synthesis and analysisWe computed a pooled hazard ratio (pHR) with 95% confidence interval(CI) for all clinical outcomes reported in the included studies usingrandom-effects models in RevMan version 5.3 (The CochraneCollaboration, Copenhagen, Denmark).18 We used the Cochrane Chi-square χ2 (Cochran Q) statistic and the I2 test to analyze heterogeneityacross the included studies.18 We performed meta-regression analysiswherever we found considerable heterogeneity in the pooled analysis. Weentered parameters such as: age, follow-up duration, publication year, PSAlevel, percentage of patients in tumor stage ⩾ T2, percentage of patientswith Gleason score ⩾ 7, and ethnicity, which could be responsible for thedifferences in the outcomes observed among the studies. We processedmeta-regression analysis in STATA version 14 (STATA, College Station,TX, USA) using the metareg command.19 We also derived the polygramsbased on various predicted values of the factors that were found to besignificantly associated with the outcomes in the meta-regression analysisin R version 3.1.1 (R Foundation for Statistical Computing, Vienna, Austria).We determined the presence of publication bias in observational studiesusing Egger’s method (Kendall’s Tau)20 and using a contour-enhancedfunnel plot to determine other causes of publication bias by examining thesymmetry of the plot.21 Further, we did sensitivity analyses by status ofprimary therapy (RT or RP) for prostate cancer to assess the robustness ofpooled estimates.

RESULTSWe retrieved a total of 1002 citations through electronic databasesand gray literature. Figure 1 depicts the study selection process asper PRISMA framework from the retrieved citations. We excludedthe following studies: studies assessing outcomes followingstatin use in animal models; in vitro studies; reviews; RCTs ofinterventions other than statins; statin use in other population;and assessing risk of prostate cancer with the use of statins.Finally, 34 studies (59 references) met the inclusion criteria for thecurrent review. Multiple references per study was mainly due tothe study published as conference presentations or comments onthe published studies.

Characteristics of included studiesCharacteristics of all the 34 studies are presented in Table 1. All thestudies were observational cohort studies published between2003 and 2015. Twenty-five studies were conducted in theUnited States,22–46 two in France,47,48 two in Korea,49,50 onein Greece,51 one in United Kingdom,52 one in Canada53 and onein Norway54 each while the last one utilized data from six centerslocated in the North America and Europe.55 The study cohort sizeranged from 247 (ref. 50) to 11 772 (ref. 52) among the includedstudies. Overall, the percentage of statin users ranged from 5.3%24

to 71.1%.27 All the included studies had at least 2 years mean ormedian follow-up. Sixteen studies restricted the study cohort tomen with prostate cancer treated with RP25–31,33–35,47–51,55 and notusing adjuvant hormone therapy and RT, whereas 13 studiesincluded men with prostate cancer treated with RT and nottreated with RP.32,36–46 The rest of the five studies included mendiagnosed with prostate cancer without restricting them to anyprimary prostate cancer treatment RP/RT.Furthermore, 12 of the included studies restricted their study

cohort to those diagnosed with localized prostate cancer andexcluded those who have metastatic or node-positive prostatecancer,22,29–32,40,44,46,47,52,53,55, whereas 11 studies excluded thosewith receipt of adjuvant hormone therapy.24,25,28,32,33,35,39,40,47,49,53

Statin use among men with prostate cancerAD Raval et al

2

Prostate Cancer and Prostatic Diseases (2016), 1 – 12 © 2016 Macmillan Publishers Limited

Characteristics of men with prostate cancerThe median or mean age of the study cohort ranged between 55and 76 years, with two studies including predominant elderly menwith the median/mean age 470 years. Among 12 studies thatreported findings by race, African-Americans constituted 1–49%among the statin users.22,25,28–35,40,52 There were no significantdifferences in the statin use by race. Among 15 studies thatreported the presence of chronic conditions,22,23,26,30–32,35,37,38,48–53

1 study reported the score of Charlson comorbidity index53 whilethe other studies reported the proportion of men with diabetes andother chronic conditions. A significantly greater proportions of menwith statin use had diabetes, heart disease, hypertension, hyperli-pidemia, and chronic kidney disease as compared with non-users inthose included studies. Seventeen studies reported body massindex and majority of the study participants were in the overweightor obese categories.22,23,25,26,29–34,37,38,47–50,52 There were no sig-nificant differences in body mass index categories and statin use(For details, see Supplementary Appendix S2.1).

Prostate cancer-specific characteristics by statin useThirty studies reported the status of preoperative PSAlevels.22,25,26,28–40,42,43–52,54,55 Those with statin use had signifi-cantly lower levels of baseline PSA values as compared with

non-users. Thirty studies reported the Gleason score among statinusers and non-users.22,25–40,42–50,52,54–56 A significant proportion ofmen had Gleason scores of 7 or 8, with no difference betweenstatin users and non-users in these studies. Sixteen studiesreported the tumor stages and seven studies reported theNational Comprehensive Cancer Network (NCCN) risk categoriesor D’Amico Risk categories.29,30,35,37,40,42–50,53,54 (For details, seeSupplementary Appendix S2.1)

Quality assessment of the included studiesWe utilized NOS tool to determine the quality of the includedstudies as shown in Supplementary Appendix S3. All the includedstudies had a fair or good quality as per the NOS scale. The detailson each of the three domains for risk of bias selection,ascertainment of exposure and outcomes and comparability areprovided in Supplementary Appendices S2.2–S2.4. All the includedstudies utilized observational cohort design. Out of the 34 studies,27 of the included studies utilized single or multiple hospital-based data,24–30,33–51,55 and 7 studies utilized cancer-registry-linked electronic medical records or administrative claimsdatabases.22,23,31,32,52–54 Except registry-based studies, studiesutilizing hospital-based data did not clearly report the identifica-tion of prostate cancer. Overall, 21 studies reported use of any

Abbreviations: PCa: Prostate Cancer; RCT: Randomized Controlled-Trials

No. Excluded (n = 48) Statin and other outcomes (n = 27); Review statin in Pca (n = 7); Cholesterol and Outcomes (n = 4); Systematic Reviews statin and outcomes (n = 3); Meeting abstracts non-statin (n = 3); Statin and Genetic analysis (n= 2) Drug interaction studies (n= 2)

No. Excluded (n = 554) Non-statins Reviews (n = 216); Animal/In-vitro studies (n = 171); Statin and Risk of Pca(n = 83); Review of statin on other cancers(n = 33); Observational Studies not on statins(n = 20); RCTs not on statin (n = 22); Case studies, economic studies, genetic analysis or incidence other cancer (n = 9)

Studies included in quantitative synthesis (meta-analysis) (n = 34 studies, 59 references)

Studies included in qualitative synthesis (n = 34 studies, 59 references)

Full-text articles assessed for eligibility (n = 107)

Records identified through electronic databases(n = 968) Medline: 305; The Cochrane Library: 11; Scopus : 263; Web of Science: 389

Scre

enin

g In

clud

ed

Elig

ibili

ty

Additional records identified through other sources (n = 34)

Records screened (n = 661)

Number of duplicates removed (n = 341)

Iden

tific

atio

n

Figure 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow chart for study selection for the systematicreview on statins and clinical outcomes in men with prostate cancer.


3

© 2016 Macmillan Publishers Limited Prostate Cancer and Prostatic Diseases (2016), 1 – 12

Table1.

Characteristicsofincluded

studiesin

thesystem

atic

review

andmeta-an

alysis

Stud

yna

me

Datasou

rce

N(NOS)

Statin

users

N(%

)Follow-upmedian

(IQR),inyears

Age

(years),mean(s.d.)

ormedian(IQ

R)AA(%

)PSA(in

ngml−

1 )mean

(s.d.)or

median(IQ

R)GS

Tumor

stag

e

Radicalprostatectom

yan

d/or

radiationtherap

yKatzet

al.,2

3US

Can

ceroftheProstateStrategic

Urologic

ResearchEn

deavo

r(CaP

SURE);

7042

1824

(25.9)

4(0–16

)μ:6

4.4(7.8)

——

——

Geybelset

al.,2

2US

Seattle-Pu

get

SountSu

rveillance,E

pidem

iology,

andEn

dResultscancerregistry

1001

289(28.9)

μ:6

.1(1)μ:6

3.1(6.8)

(2)μ:6

0.9(8.1)

—(1)M:5

.7(4.4,8

.5)

(2)M:6

.3(4.7,9

.5)

(1)⩾7:

47%

(2)⩾7:

47%

(1)Lo

cal:72

%(2)Lo

cal:73

%Macleodet

al.,2

4US

University

ofWashingtonSchoolofMed

icine

1734

92(5.3)

3.9

——

——

—Grytliet

al.,5

4Norw

ayCan

cerregistryofNorw

ay;N

orw

egian

Prescriptiondatab

ase

3561

927(26.0)

3.25

(1)μ:7

1.9(7.5)

(2)μ:7

1.1(9.3)

—410

:91%

⩾7:

87.1%

⩽T2

a:15

%;T2b

-2c:

19%;⩾T3

a:67

%Yu

etal.,5

2UK

United

Kingdom

National

Can

cerReg

istry

Linkeddatab

ases

1177

234

07(28.9)

μ:4

.4(2.9)

μ:7

6.3(8.1)

(1)1.3%

(2)1.1%

(1)410

:42.7%

(2)410

:40.0%

(1)⩾7:

34.7%

(2)⩾7:

291%

—

Radicalprostatectom

yHam

iltonet

al.,2

5USa

5Ve

teransAdministrationMed

ical

Cen

ters;

Shared

Equal

AccessReg

ional

Can

cerHospital

(SEA

RCH)Datab

ase

1319

236(17.9)

μ:3

.58

(1)μ:6

2.6(5.6)

(2)μ:6

0.6(6.6)

(1)36

%(2)47

%(1)M:6

.2(4.7,9

.1)

(2)M:6

.9(4.9,1

0.5)

(1)⩾7:

50%

(2)⩾7:

38%

(1)T1

c:67

%;

T2/T3:

33%

(2)T1

c:58

%;

T2/T3:

42%

Kraneet

al.,2

6US

VattikutiUrologyInstitute

data

3828

1031

(26.9)

μ:2

.17

(1)μ:6

1.4(6.6)

(2)μ:5

9.4(7.5)

(1)36

%(2)47

%(1)M:5

.0(4.1,6

.5)

(2)M:5

.2(4.1,7

.2)

(1)⩾7:

69%

(2)⩾7:

64%

(1)T1

c:73

;T2

/T3:

27%

(2)T1

c:73

;T2

/T3:

27%

Rioja

etal.,2

7US

Mem

orial

Sloan

-KetteringCan

cerCen

ter

3748

1093

(29.0)

(1)M:6

2(57,

66)

(2)M:5

9(54,

64)

(1)36

%(2)47

%.

(1)M:5

.1(3.8,7

.0)

(2)M:5

.3(3.9,7

.5)

(1)⩾7:

75%

(2)⩾7:

71%

—

Kuet

al.,4

9Korea

SeoulNational

University

Hospital

687

87(12.7)

3.2(0.3–11

.9)

(1)μ:6

5.3(6.8)

(2)μ:6

5.2(6.7)

(1)36

%(2)47

%(1)μ:9

.6(9.3)

(2)μ:1

3.6(20.5)

(1)⩾7:

79.3%

(2)⩾7:

73%

(1)T1

:60

%;

T2–T3

:40

.2%

(2)T1

:60

%;

T2–T3

:40

.3%

Mondulet

al.,2

9US

JohnHopkinsHospital

2399

386(16.1)

7(1)μ:5

7.7

(2)μ:5

6.0

(1)36

%(2)47

%(1)μ:6

.3(2)μ:7

.1(1)⩾7:

18.9%

(2)⩾7:

18.7%

(1)T1

:73

.7%;

T2–T3

a:26

.3%

(2)T1

:67

.7%;

T2–T3

a:32

.1%

Ritch

etal.,2

8US

Columbia

University

Urologic

Onco

logydata

1261

281(22.3)

3.0

(1)μ:6

2.0

(2)μ:5

9.0

(1)36

%(2)47

%(1)M:6

.4(2)M:7

.1(1)M:7

(2)M:6

(1)T1

:92

.5%;

T2–T3

a:07

.5%

(2)T1

:86

.4%;

T2–T3

a:13

.6%

Masset

al.,3

0US

New

York

University

Med

ical

Records

1446

437(30.2)

μ:4

.75

—(1)36

%(2)47

%(1)M:5

.1(4.0,6

.8)

(2)M:5

.0(4.0,7

.0)

(1)⩾7:

42.1%

(2)⩾7:

34.6%

(1)T1

:82

.0%;

T2–T3

a:18

.0%

(2)T1

:81

.6%;

T2–T3

a:18

.4%

Chao

etal.,3

1,32US

KaiserPe

rman

ente

SouthernCalifo

rnia

(KPS

C);

SEER

Reg

istryData

1184

446(37.7)

μ:4

.3(s.d.:1.35

)(1)μ:6

1.0(6.0)

(2)μ:5

9.0(7.0)

(1)36

%(2)47

%(1)μ:6

.7(4.2)

(2)μ:7

.1(6.4)

(1)⩾7:

48%

(2)⩾7:

44%

(1)Stag

eII:

85.0%

(2)Stag

eII:

87.0%

Kontraroset

al.,5

1

Greece

Hospital

Pitie-Salpetriere

588

107(18.0)

μ:3

.4(s.d.:2.6)

(1)μ:6

5.4(5.2)

(2)μ:6

5.2(5.8)

(1)36

%(2)47

%(1)M:7

.2(5.6,9

.7)

(2)M:8

.0(6,1

0.6)

(1)⩾7:

55.1%

(2)⩾7:

46.7%

—

Rieke

net

al.,5

5

multi-countries

Cen

ters

from

US,

Can

ada,

Austriab

6842

2275

(33.3)

M:2

.08(0.67–

3.5)

(1)μ:6

1.7(6.5)

(2)μ:6

1.0(6.7)

(1)36

%(2)47

%(1)μ:7

.7(5.5)

(2)μ:7

.5(6.0)

(1)⩾7:

43.5%

(2)⩾7:

45.8%

(1)T3

:25

.3%;

N1/M1:

10.9%

(2)T3

a:25

.1%;

N1/M1:

11.4%

Allo

ttet

al.,3

3US

5Ve

teransAdministration(VA)Med

ical

Cen

ters;

Shared

Equal

AccessReg

ional

Can

cerHospital

(SEA

RCH)Datab

ase

1146

400(34.9)

6.4(4.2–8.9)

(1)μ:6

0.6(6.3)

(2)μ:6

0.7(6.5)

(1)36

%(2)47

%(1)M:5

.9(4.7,9

.1)

(2)M:7

.1(5.1,1

0.7)

(1)⩾7:

29%

(2)⩾7:

40%

(1)T1

:61

%;

T2/T3:

39%

(2)T1

:64

%;

T2/T3:

36%

Ishak-Howardet

al.,3

4

US

University

ofMichigan

ProstateCan

cerGen

etics

Project

(PCGP)

539

258(47.9)

μ:7

.9(s.d.:4.7)

(1)μ:5

8.0(7.4)

(2)μ:5

5.2(7.6)

(1)36

%(2)47

%(1)μ:1

.4(13.4)

(2)μ:2

.8(23.0)

(1)⩾7:

50.4%

(2)⩾7:

51.3%

(1)T2

:65

.9%;

T3:20

.9%

(2)T2

:70

.4%;

T3:21

.0%

Dan

ziget

al.,3

5US

Columbia

urologic

onco

logydatab

ase

767

76(9.9)

2.25

(1)M:6

5(2)M:6

3(1)36

%(2)47

%(1)M:5

.72

(2)M:6

.05

(1)⩾7:

65%

(2)⩾7:

54%

(1)T1

:74

%;

T2:24

%;T

3:2%

(2)T1

:67

%;

T2:29

%;T

3:3%

Misraiet

al.,4

8Fran

ceUnclear

377

97(25.7)

μ:2

.8(s.d.:0.83

)M:6

4(61,

70)

M:6

4(59,

60)

(1)36

%(2)47

%(1)M:6

.6(4.8,8

.1)

(2)M:6

.4(4.7,8

.6)

(1)⩾7:

72.1%

(2)⩾7:

77.1%

(1)T1

c:67

%;

T2:31

%;T

3:2%

(2)T1

c:71

%;

T2:26

%;T

3:1%

Songet

al.,5

0Koreaa

AsanMed

ical

Cen

ter

2137

241(11.3)

μ:3

.3(1)67

(63,

70)

(2)67

(63,

71)

(1)36

%(2)47

%(1)M:6

.2(4.5,9

.5)

(2)M:6

.9(4.7,1

1.2)

(1)⩾7:

61.4%

(2)⩾7:

53.7%

(1)T2

:74

.8%;T3

:24

%;N+:2

%(2)T2

:64

.5%;T3

a:32

%;N+:3

%


4


Table1.

(Continued

)

Stud

yna

me

Datasou

rce

N(NOS)

Statin

users

N(%

)Follow-upmedian

(IQR),inyears

Age

(years),mean(s.d.)

ormedian(IQ

R)AA(%

)PSA(in

ngml−

1 )mean

(s.d.)or

median(IQ

R)GS

Tumor

stag

e

Cattarinoet

al.,4

7Fran

ceHospital

Pitie-Salpetriere

591

156(26.4)

M:3

.5(2.2–5)

(1)M:6

4(50,

70)

(2)M:6

2(49,

69)

(1)36

%(2)47

%(1)M:7

.9(3.9,1

1.8)

(2)M:8

.4(4.3,1

3.7)

(1)⩾7:

40.5%

(2)⩾7:

40.7%

(1)T1

c:62

%;T

2:28

%;T

3:10

%(2)T1

c:61

%;T

2:28

%;T

3:12

%Ra

diationtherap

yKatzet

al.,3

6US

Mem

orial

Sloan

-KetteringCan

cerCen

ter

905

153(16.9)

M:3

.3(2–7.6.0)

M:6

9(45,

86)

—M:8

.2(0.6–14

2)M:7

(4–10

)T1

c:41

%;T2

:45%

;T3

:14%

Moyadet

al.,3

8US

Schiffler

Can

cerCen

ter

512

65(12.7)

5.7(2.1)

(1)66

.3(6)

(2)65

.6(7.4)

—(1)μ:6

.5(2.9)

(2)μ:7

.9(4.5).

(1)μ:6

.6(s.d.:

0.7)

(2)μ:6

.6(s.d.:

0.8)

(1)T1

b–T2

b:9

2.3%

;T2

c–T3

a:7.7%

(2)T1

b–T2

b:7

7.4%

;T2

c–T3

a:22

.6%

Moyadet

al.,3

7US

Michigen

Med

ical

Cen

tre

938

191(20.4)

5.4

(1)μ:6

6(6.4)

(2)μ:6

6(7.4)

—(1)M:6

.6(2)M:7

.1.

(1)M:7

(2)M:7

(1)T1

b–T2

b:9

4.2%

;T2

c–T3

a:5.8%

(2)T1

b–T2

b:9

0.6%

;T2

c–T3

a:9.4%

Sharmaet

al.,3

9US

FoxChaseCan

cerCen

ter

983

178(18.1)

4.8

M:6

9(43,

84)

—M:7

.4⩾7:31

%T1

–T2

:90

%;T

3–T4

:3.5%

Soto

etal.,4

0US

Michigen

Can

cerCen

tre

968

220(22.7)

3.9(0.2–16

.5)

(1)μ:6

8.0

(2)μ:6

8.2

(1)8.4%

(2)4.1%

(1)410

:23.3%

(2)4

10:4

1.9%

.(1)⩾7:

58.9%

(2)⩾7:

56.5%

(1)T1

:55

%;T

2:42

%;T

3:3%

(2)T1

:37

%;T

2:51

%;T

3:12

%Sh

ippyet

al.,4

1US

Mem

orial

Sloan

-KetteringCan

cerCen

ter

871

168(19.3)

7.1

——

——

—Kollm

eier

etal.,4

2US

Mem

orial

Sloan

-KetteringCan

cerCen

ter

1681

382(22.7)

5.9(0–14

)(1)⩾65

:284

(2)⩾65

:951

—(1)410

:27%

(2)410

:39%

(1)⩾7:

52%

(2)⩾7:

55%

(1)T1

:56

%;T

2:37

%;T

3:7%

(2)T1

:48

%;T

2:40

%;T

3:12

%Gutt

etal.,4

3US

University

ofChicag

o69

118

9(27.4)

4.2

(1)M:6

9(42,

83)

(2)M:6

8(44,

83)

(1)49

%(2)53

%(1)410

:34%

(2)410

:43%

(1)⩾7:

54%

(2)⩾7:

37%

(1)T1

–2a

:88%

;T2

b–c:9%

;T3/4:

3%(2)T1

–2a

:79%

;T2

b–c:15

%;T

3–4:

7%Zao

rsky

etal.,4

6US

FoxChaseCan

cerCen

ter,US

2051

691(33.7)

6.3(1.5–19

.9)

M:6

9(36,

86)

—410

:30%

⩾7:

26%

T1:58

%;T

2:39

%;

T3:3%

Chao

etal.,3

1,32USa

KaiserPe

rman

ente

SouthernCalifo

rnia

(KPS

C)-

SEER

Reg

istryData

774

401(51.8)

μ:4

.10(s.d.:1.4)

(1)μ:6

9.3(5.9)

(2)μ:6

7.5(8.0)

(1)19

.0%

(2)19

.0%

(1)μ:6

.2(s.d.:6.7)

(2)μ:6

.7(s.d.:7.8)

(1)⩾7:

52.1%

(2)⩾7:

49.6%

(1)Stag

eII:

97.5%;

Stag

eIII:2.5%

(2)Stag

eII:

98.7%;

Stag

eIII:1.3%

Cao

net

al.,5

3Can

ada

British

Columbia;

3851

914(23.7)

8.0

(1)μ:7

2(2)μ:7

1—

——

—

Ohet

al.,4

5US

Durham

VeteransAffairs

Med

ical

Cen

ter

247

174(70.4)

4.3(0.78–

11.7)

(1)μ:6

2.8

(2)μ:6

1.4

—(1)410

:5.7%

(2)410

:15.0%

(1)⩾7:

8.1%

(2)⩾7:

17.8%

(1)T1

–T2

a:97

%;

T2b–c:3%

;T3

–4:

0.0%

(2)T1

–T2

a:92

%;

T2b–c:7%

;T3

–4:

1%Cuaronet

al.,4

4US

Mem

orial

Sloan

KetteringCan

cerCen

ter

754

273(36.2)

4(0.08–

13)

(1)⩾65

:72%

(2)⩾65

:60%

—(1)410

:18%

(2)410

:29%

(1)⩾7:

84%

(2)⩾7:

85%

1)T1

–T2

a:79

%;

T2b–T2

c:18

%;

T3a+

:3%

(2)T1

–T2

a:75

%;

T2b–T2

c:19

%;

T3a+

:6%

Abbreviations:AA,African

-American

;GS,

Gleasonscore;IQR,interquartile

range;

M,m

ale;

NOS,

New

castle–Ottaw

ascale.

(1)Den

otesstatin

users

and(2)non-statinuser.Allthestudiesutilized

retrospective

cohortdesign.aIn

thestudybyCao

net

al.,5

3thedistributionofstatin

users

were:

atorvastatin:3

.5%;lovastatin:7

7.8%

;sim

vastatin:1

8.4%

;pravastatin:0

.2%.InthestudybyHam

iltonet

al.,2

5thedistributionof

statin

users

was:sim

vastatin

171(72%

);lovastatin

35(15%

);atorvastatin12

(5%);pravastatin

4(2%);fluvastatin

4(2%);rosuvastatin

1(o

1%);unkn

own9(4%).Th

estudybySo

nget

al.50usedthefollo

wing

statins:atorvastatin:57.2%

;sim

vastatin:19.2%

;rosuvastatin:11.4%

;pitavastatin:6.2%;p

ravastatin:3.1%;lovastatin:2.0%;fl

uvastatin:0.9%.InthestudybyIshak-Howardet

al.,3

419

6(36.4%

)werelip

ophilicstatin

users

and51

(9.5%)werehyd

rophilicstatin

users

.bTh

eau

thors

utilized

electronic

med

ical

reco

rdsofthefollo

wingsixcenters:(1)New

York

PresbyterianHospital;(2)University

ofMontreal,Can

ada;

(3)

University

ofTexas,TX

,USA

;(4)Urological

ResearchInstitute,Italy;(5)

Prostatecancercenter,Austria;

and(6)Med

ical

UnivesityofGraz,Austria.


5


statins, whereas rest of 13 studies mentioned the use of specificstatins. Four studies also considered the use of cerivastatin whileidentifying the stain use.23,34,40,52 Statin exposure was measuredafter initial therapy in 17 studies,22,24,26–32,38,44,47,49–52 during orafter initial cancer therapy in 13 studies23,30,33–35,39–41,43–45,48,55

and after initial cancer therapy in 2 studies,25,36 whereas the

measurement of statin exposure was unclear in two studies.37,42

Every included studies performed multivariable regressioncontrolling for the potential confounders. Although there weredifferences in the number of controlled factors amongincluded studies, age, body mass index, comorbid conditions,prostate cancer stage, and grade were the most common

Study or Subgroup

Radiationtherapy

Chao 2013, US

Cuaron 2015, US

Gutt 2010, US

Kollmeier2009, US

Moyad 2006, US

Oh 2015, US

Sharma 2006, US

Shippy2007, US

Soto 2006, US

Zaorsky 2011, USSubtotal (95% CI)

Heterogeneity: Tau² = 0.05; Chi² = 19.47, df = 9 (P = 0.02); I² = 54%

Test for overall effect: Z = 2.45 (P = 0.01)

Radical Prostatectomy

Allott 2014, US

Chao 2013a, US

Danzig 2015,US

Hamilton 2010, US

Ishak-Howard 2014

Kontraros 2013

Krane 2010, US

Ku 2011, Korea

Mass 2012, US

Misrai 2015, France

Mondul 2011, US

Rieken 2013

Ritch 2011, US

Roija 2010, US

Song 2015 KoreaSubtotal (95% CI)



Radiation and/or Radical Prostatectomy

Geybels 2013, US

Macleod 2013,USSubtotal (95% CI)



Total (95% CI)

Heterogeneity: Tau² = 0.05; Chi² = 69.13, df = 26 (P < 0.00001); I² = 62%

Test for overall effect: Z = 1.83 (P = 0.07)Test for subgroup differences: Chi² = 5.21, df= 2 (P = 0.07), I² = 61.6%

log[Hazard Ratio]

-0.0101

0.1133

-0.5621

-0.3711

0.4055

-1.2448

-0.0408

-0.462

0.0953

-0.462

-0.4463

0

0.1823

-0.3567

0.0583

0.4121

-0.0101

0.1655

0.1398

-0.7765

-0.0101

-0.1278

0.4055

0.1398

-0.6931

0.0583

0.1823

SE

0.1769

0.28

0.1936

0.1643

0.7725

0.6167

0.19

0.21

0.1625

0.1282

0.1575

0.1676

0.4467

0.1616

0.2265

0.2103

0.0899

0.2888

0.1726

0.37

0.2226

0.0748

0.2069

0.1308

0.1968

0.1834

0.1807

Weight

4.2%

2.6%

3.9%

4.4%

0.5%

0.8%

3.9%

3.6%

4.5%

5.1%33.5%

4.6%

4.4%

1.3%

4.5%

3.3%

3.6%

5.9%

2.5%

4.3%

1.8%

3.4%

6.2%

3.7%

5.1%

3.8%58.3%

4.1%

4.1%8.2%

100.0%

IV, Random, 95% CI

0.99 [0.70, 1.40]

1.12 [0.65, 1.94]

0.57 [0.39, 0.83]

0.69 [0.50, 0.95]

1.50 [0.33, 6.82]

0.29 [0.09, 0.96]

0.96 [0.66, 1.39]

0.63 [0.42, 0.95]

1.10 [0.80, 1.51]

0.63 [0.49, 0.81]0.79 [0.65, 0.95]

0.64 [0.47, 0.87]

1.00 [0.72, 1.39]

1.20 [0.50, 2.88]

0.70 [0.51, 0.96]

1.06 [0.68, 1.65]

1.51 [1.00, 2.28]

0.99 [0.83, 1.18]

1.18 [0.67, 2.08]

1.15 [0.82, 1.61]

0.46 [0.22, 0.95]

0.99 [0.64, 1.53]

0.88 [0.76, 1.02]

1.50 [1.00, 2.25]

1.15 [0.89, 1.49]

0.50 [0.34, 0.74]0.94 [0.81, 1.09]

1.06 [0.74, 1.52]

1.20 [0.84, 1.71]1.13 [0.88, 1.45]

0.90 [0.80, 1.01]

Hazard Ratio Hazard Ratio

IV, Random, 95% CI

0.1 0.2 0.5 1 2 5 10Favors Statin Favors No-statin

Figure 2. Forest plot of comparison: statin vs no statin for biochemical recurrence with subgroup analysis by primary cancer treatment:(a) radiation therapy, (b) radical prostatectomy, and (c) either radiation therapy or/and radical prostatectomy.


6


controlled variables. However, only 10 studies controlled forco-medications.22,26,29,34,35,46,52–54

Statin and BCRThe hazard of BCR was reported in 27studies.22,24–35,37,39–46,48–51,55 Figure 2 depicts the forest plots onthe statin use and BCR among the included studies. Overall, statinuse was marginally associated with reduction in risk of BCR usingrandom-effects model (pHR: 0.90, 95% CI: 0.80, 1.01, P-value = 0.07,27 studies, I2 = 62%). Overall estimates on BCR had a significantheterogeneity. We carried out subgroup analyses by primarycancer therapy to explore the possible reasons for the hetero-geneity. In a pooled analysis of 10 studies,32,37,39–46 statin use was

associated with 21% reduction in the risk of BCR among thosetreated with RT (pHR: 0.79, 95% CI: 0.65, 0.95, P-value = 0.01, 10studies, I2 = 54%). Among those treated with RP, statin use was notassociated with BCR (pHR: 0.94, 95% CI: 0.81, 1.09, P-value = 0.43,15 studies, I2 = 65%) in random-effects model, with significantheterogeneity.

Meta-regression to explore reasons of heterogeneity for BCRAs heterogeneity was significantly higher in the main analysis andsubgroup analyses, we performed meta-regression to find out thecovariates causing this variability (see Table 2). Age, follow-upduration, publication year, percentage of patients with Gleasonscore ⩾ 7, percentage of patients in tumor stage ⩾ T2, ethnicity,and PSA level were entered into the meta-regression model. Afterrunning the model with these parameters for the RP subgroup,100% between-study variance was explained. We found that stageof cancer (⩾ T2) and African-American race were associated withBCR among those who were treated with RP. Whereas GleasonScore and age were associated with BCR among those treatedwith RT (see Figure 3 for details). With respect to publication bias,we did not detect a statistically significant publication bias basedon the Egger's test or contour enhanced funnel plots.

Statin and metastasesSix studies reported statin use and metastases as an out-come29,31,39,42,44,52 (see Figure 4 for details). Statin use significantlyreduced the risk of development of metastases among indivi-duals with prostate cancer (pHR: 0.78; 95% CI: 0.70, 0.88;P-valueo0.0001; I2 = 0%) without any heterogeneity. We didnot find publication bias based on Egger’s test or trim and fillanalysis.

Statin and all-cause mortalityFive studies reported all-cause mortality as an outcome.22,23,39,52,54,

We also found that statin use significantly reduced the risk of

RE Model

0.05 0.25 1.00 4.00 20.00

Song,2015Roija,2010Ritch,2011Rieken,2013Mondul,2011Misrai,2015Mass,2012Ku,2011Krane ,2010Kontraros,2013Ishak-Howard,2014Hamilton ,2010Danzig,2015Chao,2013Allott ,2014

0.50 [ 0.34 , 0.74 ]1.15 [ 0.89 , 1.49 ]1.50 [ 1.00 , 2.25 ]0.88 [ 0.76 , 1.02 ]0.99 [ 0.64 , 1.53 ]0.46 [ 0.22 , 0.95 ]1.15 [ 0.82 , 1.61 ]1.18 [ 0.67 , 2.08 ]0.99 [ 0.83 , 1.18 ]1.51 [ 1.00 , 2.28 ]1.06 [ 0.68 , 1.65 ]0.70 [ 0.51 , 0.96 ]1.20 [ 0.50 , 2.88 ]1.00 [ 0.72 , 1.39 ]0.64 [ 0.47 , 0.87 ]

0.94 [ 0.80 , 1.11 ]

0.98 [ 0.83 , 1.17 ]0.85 [ 0.65 , 1.10 ]0.73 [ 0.46 , 1.15 ]

T2 = 40%T2 = 70%T2 = 100%

1.16 [ 0.96 , 1.39 ]0.88 [ 0.77 , 1.01 ]0.67 [ 0.53 , 0.85 ]

%AA = 5%%AA = 25%%AA = 45%

Author(s) and Year Log Hazard Ratio [95% CI]

RE Model

0.05 0.25 1.00 4.00 20.00

Zaorsky,2011Soto ,2006Shippy ,2007Sharma,2006Oh ,2015Moyad,2006Kollmeier,2009Gutt,2010Cuaron,2015Chao ,2013

0.63 [ 0.49 , 0.81 ]1.10 [ 0.80 , 1.51 ]0.63 [ 0.42 , 0.95 ]0.96 [ 0.66 , 1.39 ]0.29 [ 0.09 , 0.96 ]1.50 [ 0.33 , 6.82 ]0.69 [ 0.50 , 0.95 ]0.57 [ 0.39 , 0.83 ]1.12 [ 0.65 , 1.94 ]0.99 [ 0.70 , 1.40 ]

0.79 [ 0.65 , 0.95 ]

0.51 [ 0.29 , 0.92 ]

0.91 [ 0.67 , 1.24 ]

1.62 [ 0.97 , 2.70 ]

60 Years

65 Years

70 Years

Author(s) and Year Hazard Ratio [95% CI]

0.26 [ 0.10 , 0.68 ]

0.55 [ 0.32 , 0.93 ]

1.15 [ 0.75 , 1.75 ]

GS 7; 15%

GS 7; 50%

GS 7; 85%

Factors Predicting of BCR: Radical Prostatectomy Factors Predicting of BCR: Radiation Therapy

Figure 3. Meta-regression forest plot with polygons for significant predictors of biochemical recurrence (BCR) among men with prostatecancer treated with (a) radical prostatectomy and (b) radiation therapy.

Table 2. Multivariable meta-regression for biochemical recurrence

Covariates Coefficient (beta) 95% CI P-value

Model 1: Subgroup—radical prostatectomy⩾ T2 stage − 0.006 (−0.012, − 0.004) 0.037African-American − 0014 (−0.023, − 0.004) 0.015Constant 0.22 (0.086, 0.517) 0.147

Tau2= 0; I2 residuals= 57.95%; adjusted R2= 100%

Model 2: Subgroup—radiation therapyYear of publication − 0.0509 0.120PSA level − 0.257 (−0.120, 0.019) 0.118GS⩾7 0.0214 (0.007, 0.354) 0.012Age 0.111 (0.017, 0.204) 0.029Constant 95.426 (−44.17, 235.0) 0.139

Tau2= 0; I2 residuals= 0%; adjusted R2= 100%

Abbreviations: CI, confidence interval; GS, Gleason score. The results arebased on 15 and 10 studies examining the association between statin useand biochemical recurrence among men treated with radical prostatect-omy and radiation therapy, respectively.


7


all-cause mortality in the pooled analysis (pHR: 0.76; 95% CI: 0.63,0.91; P-value = 0.004; I2 = 71%) with significant heterogeneity(See Figure 5). To find the cause of heterogeneity, leave one outsensitivity analysis and found the effect estimate of Katz et al23

following RP (HR: 0.35) was responsible for the heterogeneity, asrest of the studies included patients following radiotherapy.Following removal of this estimate from the analysis, statin usewas still significant in reducing the all-cause mortality (pHR: 0.82;95% CI: 0.72, 0.92; P-value = 0.001; I2 = 42%) without considerableheterogeneity. We did not find publication bias based on Egger’stest or trim and fill analysis.

Statin and prostate cancer-related mortalityFive studies evaluated statin use and prostate cancer-relatedmortality as an outcome.22,39,52–54 Statin use significantly reducedthe hazard of prostate cancer-related mortality (pHR: 0.76; 95% CI:0.64, 0.89; P-value = 0.0007; I2 = 40%) without significant hetero-geneity (see Figure 6). We did not find publication bias based onEgger’s test or trim and fill analysis.

Subgroup analysis by non-metastatic prostate cancerAdditionally, we also performed the subgroup analysis toexamine the association between statin use and BCR, metastases,all-cause mortality, and prostate cancer-related mortality (seeFigure 7 for details) among men with non-metastatic or loca-lized prostate cancer. Statin use was not significantly associatedwith BCR reduction (pHR: 0.98, 95% CI: 0.85, 1.14, P-value = 0.83, 10studies, I2 = 53%), whereas it was significantly associated with areduction in the risk of metastasis (pHR: 0.77, 95% CI: 0.68, 0.87,P-valueo0.001, I2 = 0%), all-cause mortality (pHR: 0.86, 95%

CI: 0.78, 0.95, P-valueo0.01, I2 = 0%) and prostate cancer-relatedmortality (pHR: 0.68, 95% CI: 0.48, 0.97, P-value = 0.04, I2 = 64%)among men with non-metastatic prostate cancer.

DISCUSSIONThis review aimed to generate evidence on the associationbetween statin use and clinical outcomes among men withprostate cancer. We found 34 observational studies and norandomized controlled trials. We found that statin use wasassociated with significant reduction in the risk of metastases,all-cause mortality, and prostate cancer-specific mortality overall.Additionally, we explored whether the association between statinuse and clinical outcomes varied by the types of prostate cancertherapy. As the selection of initial cancer therapy of either RP or RTdepends of certain subtypes of prostate cancer, the subgroupanalyses by types of prostate cancer treatment yield homogenouspopulation of men with prostate cancer. Despite four studieswhich reported the beneficial association of statin on BCR amongthose treated with RP, overall estimates suggested non-significantassociation with an evidence of heterogeneity. Although meta-regression revealed that African-American race was one of the keyfactors for BCR, heterogeneity in the pooled estimates stillremained the same. These findings suggest that there could besignificant differences in the included studies on those treatedwith RP. Furthermore, among those treated with RT, statins wasassociated with significant reduction in the hazard of BCR withevidence of high heterogeneity, which was explained asdifference in characteristics such Gleason score and age in themeta-regression results.

Study or SubgroupRadiation therapy

Chao 2013, US

Cuaron 2015, US

Kollmeier 2009, US

Sharma 2006, USSubtotal (95% CI)




Mondul 2011, USSubtotal (95% CI)

Heterogeneity: Not applicable


Radiation therapy and/or Radical Prostatectomy

Yu 2014, UKSubtotal (95% CI)


Test for overall effect: Z = 4.12 (P < 0.0001)

Total (95% CI)



Test for subgroup differences: Chi² = 0.52, df = 2 (P = 0.77), I² = 0%

log[Hazard Ratio]

-0.462

-0.5192

0.0862

-0.1393

-0.1625

-0.2614

SE

0.3618

0.5009

0.2333

0.523

0.4108

0.0634

Weight

2.6%

1.4%

6.4%

1.3%11.7%

2.1%2.1%

86.3%86.3%

100.0%

IV, Random, 95% CI

0.63 [0.31, 1.28]

0.59 [0.22, 1.59]

1.09 [0.69, 1.72]

0.87 [0.31, 2.42]0.87 [0.62, 1.23]

0.85 [0.38, 1.90]0.85 [0.38, 1.90]

0.77 [0.68, 0.87]0.77 [0.68, 0.87]

0.78 [0.70, 0.88]


IV, Random, 95% CI

0.01 0.1 1 10 100Favors statin Favors no-statin

Figure 4. Forest plot of comparison: statin vs no statin for metastases with subgroup analysis by primary cancer treatment: (a) radiationtherapy, (b) radical prostatectomy, and (c) either radiation therapy or/and radical prostatectomy.


8


Study or SubgroupRadiation therapy

Katz 2010_RT, US





Katz 2010_RP, USSubtotal (95% CI)




Geybels 2013, US

Grytli, 2014, Norway




Total (95% CI)

Heterogeneity: Tau² = 0.03; Chi² = 17.29, df= 5 (P = 0.004); I² = 71%


Test for subgroup differences: Chi² = 10.18, df = 2 (P = 0.006), I² = 80.3%

log[Hazard Ratio]

-0.5276

0.157

-1.0498

-0.1165

-0.2744

-0.1508

SE

0.2381

0.24

0.2606

0.2549

0.0567

0.0498

Weight

10.7%

10.6%21.3%

9.5%9.5%

9.8%

29.4%

30.1%69.2%

100.0%

IV, Random, 95% CI

0.59 [0.37, 0.94]

1.17 [0.73, 1.87]0.83 [0.42, 1.62]

0.35 [0.21, 0.58]0.35 [0.21, 0.58]

0.89 [0.54, 1.47]

0.76 [0.68, 0.85]

0.86 [0.78, 0.95]0.81 [0.74, 0.90]

0.76 [0.63, 0.91]


IV, Random, 95% CI


Figure 5. Forest plot of comparison: statin vs no statin for all-cause mortality with subgroup analysis by primary cancer treatment: (a) radiationtherapy, (b) radical prostatectomy, and (c) either radiation therapy or/and radical prostatectomy.

Study or Subgroup

Radiation therapy

Caon 2014, Canada





Geybels 2013, US

Grytli, 2014, Norway


Heterogeneity: Tau² = 0.02; Chi² = 5.67, df= 2 (P = 0.06); I² = 65%


Total (95% CI)



Test for subgroup differences: Chi² = 0.17, df = 1 (P = 0.68), I² = 0%

log[Hazard Ratio]

-0.2614

0.5068

-1.6607

-0.2485

-0.2744

SE

0.1735

0.78

0.5881

0.0776

0.072

Weight

16.6%

1.1%17.7%

1.9%

39.2%

41.2%82.3%

100.0%

IV, Random, 95% CI

0.77 [0.55, 1.08]

1.66 [0.36, 7.66]0.80 [0.57, 1.11]

0.19 [0.06, 0.60]

0.78 [0.67, 0.91]

0.76 [0.66, 0.88]0.73 [0.59, 0.91]

0.76 [0.64, 0.89]


IV, Random, 95% CI

0.01 0.1 1 10 100

Favors statin Favors no-statin

Figure 6. Forest plot of comparison: statin vs no statin for prostate cancer mortality with subgroup analysis by primary cancer treatment:(a) radiation therapy, (b) radical prostatectomy, and (c) either radiation therapy or/and radical prostatectomy.


9


Collectively, our study findings on statin use and BCR in prostatecancer could be explained by the study population-specificeffect and additive effects of statins. First, the use of RP is thepreferred treatment option for men with localized prostate cancer,which has been considered a slow-progressive stage. Previousmeta-analyses also suspected the similar reasons. Our subgroupanalyses by stage of cancer confirmed that statin use was notassociated with BCR among those with localized prostate cancer.The use of RT alone or along with hormone therapy is thepreferred treatment option for those with locally advanced ormetastatic stage of prostate cancer. In our review, we also

observed that, among those receiving RT, a greater proportion ofmen had high NCCN risk categories or D’Amico Risk score ascompared with those with RP at baseline. Therefore, statins mayhave role in the prevention of BCR in men with aggressive cancer,such as locally advanced cancer as compared with localizedprostate cancer. In addition, statins may augment the effect ofRT on cancer cells owing to its radiation-sensitizing properties.56

Our findings confirm the previous findings and explained theuncertainties remained in the previous two meta-analyses12,30

with additional 21 studies since publications of those meta-analyses.

Study or Subgroup

Biochemical recurrence

Chao 2013, US

Chao 2013a, US

Cuaron 2015, US

Geybels 2013, US

Kontraros 2013

Mass 2012, US

Mondul 2011, US

Rieken 2013

Soto 2006, US

Zaorsky 2011, USSubtotal (95% CI)



Metastasis

Cuaron 2015, US

Mondul 2011, US




All-cause mortality

Geybels 2013, US




Prostate cancer specific mortality

Caon 2014, Canada

Geybels 2013, US




log[Hazard Ratio]

-0.0101

0

0.1133

0.0583

0.4121

0.1398

-0.0101

-0.1278

0.0953

-0.462

-0.5192

-0.1625

-0.2614

-0.1165

-0.1508

-0.2614

-1.6607

-0.2744

SE

0.1769

0.1676

0.28

0.1834

0.2103

0.1726

0.2226

0.0748

0.1625

0.1282

0.5009

0.4108

0.0634

0.2549

0.0498

0.1735

0.5881

0.072

Weight

9.6%

10.2%

5.3%

9.2%

7.9%

9.9%

7.3%

17.2%

10.5%

12.9%100.0%

1.5%

2.3%

96.2%100.0%

3.7%

96.3%100.0%

38.2%

8.2%

53.5%100.0%

IV, Random, 95% CI

0.99 [0.70, 1.40]

1.00 [0.72, 1.39]

1.12 [0.65, 1.94]

1.06 [0.74, 1.52]

1.51 [1.00, 2.28]

1.15 [0.82, 1.61]

0.99 [0.64, 1.53]

0.88 [0.76, 1.02]

1.10 [0.80, 1.51]

0.63 [0.49, 0.81]0.98 [0.85, 1.14]

0.59 [0.22, 1.59]

0.85 [0.38, 1.90]

0.77 [0.68, 0.87]0.77 [0.68, 0.87]

0.89 [0.54, 1.47]

0.86 [0.78, 0.95]0.86 [0.78, 0.95]

0.77 [0.55, 1.08]

0.19 [0.06, 0.60]

0.76 [0.66, 0.88]0.68 [0.48, 0.97]


IV, Random, 95% CI


Figure 7. Forest plot of comparison: statin vs no statin for (a) biochemical recurrence, (b) metastases, (c) all-cause mortality and (d) prostatecancer-specific mortality among those with non-metastatic prostate cancer.


10


Additionally, we found a beneficial association between statinuse and metastases and all-cause and prostate cancer-specificmortality among men with prostate cancer in the pooled analysiswith no heterogeneity among the included studies even amongthose with non-metastatic prostate cancer. Although prostatecancer is the second leading cause of cancer death in the UnitedStates,57 only 16% of men with prostate cancer died owing toprostate cancer, while others died owing to non-cancer-relatedconditions. Cardiovascular disease is one of the major reasons ofdeaths among men with prostate cancer.58 Statins have shownbeneficial effects of reduction in the risk of cardiovascularevents.59 Our systematic review found the potential of statins inthe reduction in prostate cancer-related mortality, thereforestatins could serve as a therapeutic agent among men withprostate cancer.However, the findings should be carefully interpreted in the

light of limitations of meta-analytical techniques. First, there maybe potential bias of statin use by indication, that is, a greaterproportion of men receiving statins had preexisting cardiovasculardiabetes and/or diabetes. Therefore, studies examining the role ofstatins in the prostate cancer outcomes often have a different setof characteristics as compared with those with prostate cancerand not having diabetes and/or cardiovascular diseases. Second,there would be potential misclassification bias as some of thestudies included the use of the banned and potentially harmfulcerivastatin to define statin use. The inclusion of statins may havea negative impact on the clinical outcomes. Third, the timing ofstatin use among included studies varied in the included studies.Additionally, a very few of the included studies examined theduration and dose of statins. The differences in the time, dose andduration of statins among included studies could be a potentialreason for the heterogeneity in the pooled study estimates. Inaddition, none of the studies rationalized the timing of initiatingstatin therapy among those with prostate cancer. Often men withprostate cancer had a change in the adherence to non-cancermedications as evident from the real-world studies.60 Timing andduration of statin use could be considered as potentialconfounders while examining the relationship between statinuse and clinical outcomes in men with prostate cancer.Strengths and limitations of our study findings suggest a scope

for future clinical trials to examine the effects of statins amongmen with advanced stage or grade of prostate cancer treated withRT. As statins are relatively cheaper as compared with newer-generation chemotherapy (ranged from $14 839 to $93 000),61

finding beneficial effects of statins will provide a cost-effectivesolution to manage prostate cancer. In addition, the futureobservational studies should have robust measures to control fortreatment selection bias, such as use of inverse-probabilityweighting, propensity-score matching or instrumental variableanalysis techniques.62

CONCLUSIONSWe believe ours is the most comprehensive systematic review tofind that statin significantly reduced the all-cause and prostatecancer-specific mortality and improved BCR in certain subgroup ofmen with prostate cancer. In future, randomized controlled trialsshould be conducted to establish efficacy of statins among menwith prostate cancer.

CONFLICT OF INTERESTThe authors declare no conflict of interest.

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11


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Supplementary Information accompanies the paper on the Prostate Cancer and Prostatic Diseases website (http://www.nature.com/pcan)


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Association between statins and clinical outcomes … between statins and clinical outcomes among men ... (RP) are the key ... control) studies examining