Cancer Treatment Reviews xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv

Systematic or Meta-analysis Studies

Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies Shanliang Zhong a,1, Xiaohui Zhang a,1, Lin Chen b, Tengfei Ma a, Jinhai Tang c, Jianhua Zhao a,⇑ a

Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing 210009, China Departments of Oncology, Xuzhou Medical College, Xuzhou 221004, China c Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing 210009, China b

a r t i c l e

i n f o

Article history: Received 24 January 2015 Received in revised form 5 April 2015 Accepted 7 April 2015 Available online xxxx Keywords: Prognosis Survival Outcome Tumor Neoplasm

a b s t r a c t Background: Previous studies have examined the effect of statin use on the mortality in cancer patients, but the results are inconsistent. A meta-analysis was performed to assess the association with all available studies. Methods: Relevant studies were identified by searching PubMed and EMBASE to April 2015. We calculated the summary hazard ratios (HRs) and 95% confidence intervals (CIs) using random-effects models. We estimated combined HRs associated with defined increments of statin use, using random-effects meta-analysis and dose–response meta-regression models. Results: Thirty-nine cohort studies and two case-control studies involving 990,649 participants were included. The results showed that patients who used statins after diagnosis had a HR of 0.81 (95% CI: 0.72–0.91) for all-cause mortality compared to non-users. Those who used statin after diagnosis (vs. non-users) had a HR of 0.77 (95% CI: 0.66–0.88) for cancer-specific mortality. Prediagnostic exposure to statin was associated with both all-cause mortality (HR = 0.79, 95% CI: 0.74–0.85) and cancer-specific mortality (HR = 0.69, 95% CI: 0.60–0.79). Stratifying by cancer type, the three largest cancer-type subgroups were colorectal, prostate and breast cancer and all showed a benefit from statin use. HRs per 365 defined daily doses increment were 0.80 (95% CI: 0.69–0.92) for all-cause mortality and 0.77 (95% CI: 0.67–0.89) for cancer-specific mortality. A 1 year increment in duration only conferred a borderline decreased risk of death. Conclusions: In conclusion, the average effect of statin use, both postdiagnosis and prediagnosis, is beneficial for overall survival and cancer-specific survival. Ó 2015 Elsevier Ltd. All rights reserved.

Introduction Cancer is a very serious health problem worldwide, and is the leading cause of death in economically developed countries and the second leading cause of death in developing countries [1]. Considering the different causes, the different tissues affected, and the different symptoms, cancer is a very complex and still incurable disease. Although much effort has been directed at comprehending carcinogenesis and a lot of progress has been achieved, there is still no effective treatment for most cancers. Recently, the potential anticancer properties of statins have attracted more interest. Statins, among the most frequently ⇑ Corresponding author at: Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing 210009, China. Tel.: +86 25 83283334; fax: +86 25 83351406. E-mail addresses: [email protected], [email protected] (J. Zhao). 1 Equal contributors.

prescribed drugs worldwide, reduce serum cholesterol and prevent cardiovascular diseases [2]. They block 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which inhibits the conversion of HMG-CoA to the cholesterol precursor mevalonate, the rate limiting step in cholesterol synthesis [3]. Statins may exert their anticancer effect via lowering protein prenylation [4], reducing tumor cell proliferation and migration [5,6], inhibiting of rat sarcoma (Ras) signaling [7], inducing apoptosis through phosphorylation of Akt and down-regulation of mammalian target of rapamycin (mTOR) [8], and other pleiotropic effects on the cellular level. In the last decade, a number of observational studies have tried to examine the effect of statin use on outcome in patients with several cancer types including breast [5,9–12], prostate [13–18], ovarian[19–21], lymphoma [22,23], renal cell carcinoma [8,24,25] and colorectal cancer [4,26–32] et al.; some have suggested that statin use was associated with longer survival, while others report no benefit. To date, no meta-analysis has been conducted concerning

http://dx.doi.org/10.1016/j.ctrv.2015.04.005 0305-7372/Ó 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Zhong S et al. Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.04.005

2

S. Zhong et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

the therapeutic value of statins on the survival of cancer patients. Therefore, we performed a meta-analysis with all available studies to explore the association between pre- and post-diagnosis statin use and the survival of cancer patients, for both cancer-specific mortality and all-cause mortality. Besides, we also performed a dose–response analysis to further evaluate the potential dose–response relation.

Material and methods Literature search We searched PubMed (from 1981 to present) and Embase (from 1991 to present) using the following terms (‘‘Statin’’ or ‘‘Atorvastatin’’ or ‘‘Cerivastatin’’ or ‘‘Compactin’’ or ‘‘Fluvastatin’’ or ‘‘HMG-CoA’’ or ‘‘Lovastatin’’ or ‘‘Mevastatin’’ or ‘‘Pravastatin’’ or ‘‘Rosuvastatin’’ or ‘‘Rosvastatin’’ or ‘‘Simvastatin’’) and (‘‘mortality’’ or ‘‘survival’’) and ‘‘cancer’’. The latest date of this search was April 2015. All cohort or case-control studies evaluating the association between statin use and mortality in cancer patients were eligible, without language restriction. Reference lists of every article retrieved and relevant reviews were examined manually to further identify potentially relevant studies. All searches were conducted independently by two reviewers; differences were checked by the two and resolved by discussion. When two or more studies presented possible overlap, the one with largest populations was included.

Inclusion criteria All the studies were included in this meta-analysis if they met the following criteria: (a) the exposure of interest was statin use assessed before or after diagnosis; (b) The study design was casecontrol or cohort; (c) the outcomes of interest were all-cause mortality or cancer-specific mortality; (d) the follow-up period was longer than 1 year; and (e) risk estimates of mortality and 95% confidence intervals (CIs) were reported (or information to calculate them).

Data extraction Data were extracted from the eligible articles by two independent investigators. The extracted data included the last name of first author, year of publication, origin of the study, follow-up period, sample size, study design, patient characteristics, statin use, risk estimates and corresponding 95% CIs, and covariates adjusted for in the multivariable analysis. If risk estimate and corresponding 95% CI were not available [10,33,34], the data were calculated using curve method described by Tierney [35]. For studies provided more than one risk estimate, we extracted the one that was adjusted for the greatest number of confounding factors. Discrepancies were resolved by consensus, involving a third investigator. Study quality assessment The methodological quality of the studies included in present meta-analysis was independently assessed using the nine-star Newcastle Ottawa scale (NOS) [36] by two investigators. Each study was evaluated based on eight items, categorized into three broad perspectives including selection, comparability, and outcome for cohort studies or exposure for case-control studies. We considered studies with a score of 7 or greater as high quality.

Discrepancies were resolved by discussion or through consultation with a third investigator. Statistical methods Because outcomes were relatively rare, the odds ratios (ORs) and relative risks (RRs) were considered approximations of hazard ratios (HRs). Summary estimates of HR and 95% CIs were obtained using a random effects model where the restricted maximum likelihood estimator was used to evaluate the inter-study heterogeneity [37,38]. Prediction interval (PI) of summary estimate for the random effects model was calculated to depict the uncertainty around the estimate [39]. If studies did not report a summary risk estimate for statin use, a summary risk estimate was calculated using risk estimates for each of the statin use categories [9]. For a study provided risk estimates for cancer-specific deaths and other-cause deaths, risk estimates for all-cause mortality were calculated firstly [14]. If studies provided separate risk estimates by statin type [11], tumor stage [9] or treatment [16] without a summary risk estimate, we treated them as different studies. Interstudy heterogeneity was estimated using a chisquare-based Q-test [40], with a P value of 0.21) and Egger’s tests (P > 0.44). Association of prediagnosis statin use with mortality

Fig. 1. Flow chart of the selection of publications included in the meta-analysis.

studies reported on the association between postdiagnosis statin use and all-cause and/or cancer-specific mortality and eighteen studies reported on the association between prediagnosis statin use and all-cause and/or cancer-specific mortality, with six studies having data on both postdiagnosis and prediagnosis statin use (Table 1). Table S1 summarizes the methodological quality of all the included studies. The NOS results showed that the average overall score was 6.0 (range 3–9) and there were eighteen studies with a score of 7 or more. Association of postdiagnosis statin use with mortality Postdiagnostic statin use was defined as any use of statins after cancer diagnosis. Risk estimates of the association between postdiagnosis statin use and mortality in cancer patients are shown in Figs. 2 and 3. When the association of statin use on all-cause mortality was analyzed as users vs. non-users, a HR of 0.81 (95% CI: 0.72–0.91, P < 0.01; 95% PI: 0.49–1.32) was found. In stratified by cancer type, statin use was associated with decreased risk of death from any cause for prostate cancer patients (HR = 0.59, 95% CI: 0.35–0.99, P < 0.05; 95% PI: 0.22–1.55) and ovarian cancer patients (HR = 0.39, 95% CI: 0.22–0.71, P < 0.01) (Fig. 2). In the subgroup analysis by gender, postdiagnostic statin use showed a significant benefit for overall survival in both male (HR = 0.66, 95% CI: 0.47–0.95, P = 0.02; 95% PI: 0.31–1.44) and female (HR = 0.78, 95% CI: 0.62–0.98, P = 0.03; 95% PI: 0.98–1.52) patients (Fig. S1). In terms of cancer-specific mortality, statin use was significantly associated with reduced risk of cancer-specific mortality (HR = 0.77, 95% CI: 0.66–0.88, P < 0.01; 95% PI: 0.49–1.21). When stratified by cancer type, a decreased risk of death from cancer was found in breast (HR = 0.60, 95% CI: 0.41–0.88, P < 0.01; 95% PI: 0.30–1.21), and prostate (HR = 0.77, 95% CI: 0.70–0.85, P < 0.01; 95% PI: 0.70–0.85) cancer patients who took statins after cancer diagnosis (Fig. 3). Further analysis by gender indicated that there was no association between postdiagnosis statin use and cancer-specific mortality in females (HR = 0.81, 95% CI: 0.56– 1.18, P = 0.27; 95% PI: 0.33–1.98) but among males there was a significant association (HR = 0.75, 95% CI: 0.69–0.82, P < 0.01; 95% PI: 0.69–0.82) (Fig. S1).

Prediagnosis statin use was defined as having received statins prior to cancer diagnosis. Fig. 4 presents the estimated HRs of cancer patients with prediagnosis statin use. The results revealed that patients who took statins prior to diagnosis had a HR of 0.79 (95% CI: 0.74–0.85, P < 0.01; 95% PI: 0.70–0.90) for all-cause mortality. When stratifying by cancer type, a reduced risk of death from any cause was found in breast (HR = 0.73, 95% CI: 0.62–0.86, P < 0.01; 95% PI: 0.57–0.94) and colorectal (HR = 0.77, 95% CI: 0.66–0.89, P < 0.01; 95% PI: 0.62–0.95) cancer patients (Fig. 4). In the subgroup analysis by gender, prediagnosis statin use showed a significant benefit for overall survival in both male (HR = 0.76, 95% CI: 0.65–0.87, P < 0.01; 95% PI: 0.62–0.92) and female (HR = 0.79, 95% CI: 0.73–0.85, P < 0.01; 95% PI: 0.73–0.85) patients (Fig. S1). Regarding the cancer-specific mortality, prediagnosis statin use was associated with a significant benificial effect on the risk of cancer-specific mortality (HR = 0.69, 95% CI: 0.60–0.79, P < 0.01; 95% PI: 0.45–1.06). In the subgroup analysis by cancer type, a decreased risk of death from cancer was found in breast (HR = 0.73, 95% CI: 0.61–0.89, P < 0.01; 95% PI: 0.56–0.97), colorectal (HR = 0.82, 95% CI: 0.73–0.91, P < 0.01; 95% PI: 0.70–0.95), and prostate (HR = 0.44, 95% CI: 0.20–0.93, P < 0.01; 95% PI: 0.11–1.74) cancer patients (Fig. 4). When stratified by gender, prediagnosis statin use showed a significant benefit for cancer-specific survival in both males (HR = 0.59, 95% CI: 0.40–0.87, P < 0.01; 95% PI: 0.25–1.43) and females (HR = 0.79, 95% CI: 0.72–0.87, P < 0.01; 95% PI: 0.72–0.87) (Fig. S1). There was significant heterogeneity between studies in cancerspecific mortality analysis (I2 = 88.12%, P < 0.01). When stratified by cancer type, the heterogeneity was still significant for prostate cancer (I2 = 86.34%, P < 0.01; Fig. 4). From the results of the leaveone-out sensitivity analysis, all the results above were not materially altered (data not shown). We found some evidence of publication bias in any analyses using Begg’s (P > 0.05) and Egger’s tests (P 6 0.01). After a correction for potential publication bias using the trim-and-fill method, the main findings for all-cause mortality (HR = 0.82, 95% CI: 0.77–0.88, P < 0.01) and cancer-specific mortality (HR = 0.83, 95% CI: 0.69–0.99, P = 0.04) remained significant. Dose–response meta-analysis The dose–response effects of postdiagnosis statin use on mortality were assessed with eight studies [5–7,9,13,26,28,32] including five studies [5,9,13,26,32] for cancer-specific mortality and eight studies [5–7,9,13,26,28,32] for all-cause mortality. Among these studies, exposure to statins was expressed in units of defined daily dose (DDD) [5,9,13,26] or duration of exposure [6,7,9,13,28,32]. An increment of 365 DDDs was associated with a 20% lower all-cause mortality (HR = 0.80, 95% CI: 0.69–0.92, P < 0.01) and a 23% lower cancer-specific mortality (HR = 0.77, 95% CI: 0.67–0.89, P < 0.01) (Fig. 5). A 1 year increment in duration of exposure to statins conferred a HR of 0.93 (95% CI: 0.86–1.01, P = 0.09) for all-cause mortality and 0.90 (95% CI: 0.81–1.00, P < 0.05) for cancer-specific mortality. Significant heterogeneity was found for all of the dose–response meta-analyses (Fig. 5).

Please cite this article in press as: Zhong S et al. Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.04.005

4

First author Year

Country

Follow-up period

Study design

Patient characteristics

Statin use

Cardwell et al. (2015) [5]

UK

1998–2013 Average 5.7 years (Range 1–14)

Cohort

17,880 stage I–IV breast patients

Prediagnosis Non-user User Postdiagnosis Non-user User

Desai et al. (2015) [12]

USA

Hoffmeister et al. (2015) [32]

Germany

Shao et al. (2015) [31]

China

Viers et al. (2015) [25]

USA

Song et al. (2015) [34]

Korea

Yoon et al. (2015) [65]

USA

Caon et al. (2014) [17]

Canada

Cardwell et al. (2014) [26]

UK

1992–2010 Average 11.5 years (Standard deviation = 3.7)

Cohort

2003–2009 Median 3.4 years (IQR 2.3–5.0)

Cohort

2004–2008 Median 4.2 years

Cohort

1995–2009 Median 7.8 years (IQR 5.3–11.2)

Cohort

2007–2013 Median 38.6 months

Cohort

2007–2010

Cohort

2000–2007 Median 8.4 years

Cohort

1998–2012 Mean 5 years (Range 1–14)

Cohort

Cancer-specific mortality

All cause mortality

HR 1.00 0.81 (0.71–0.93)

HR 1.00 0.78 (0.70–0.86)

HR 1.00 0.84 (0.68–1.04)

HR 1.00 0.84 (0.72–0.97)

7883 postmenopausal women with in situ, local, regional and distant-stage breast cancer

Prediagnosis No Yes

HR 1.00 0.59 (0.32–1.06)

2697 Stage I–IV CRC patients older than 30 years

Postdiagnosis No statin use Any statin use

HR 1.00 1.11 (0.82–1.50)

HR 1.00 1.10 (0.85–1.41)

17,115 stage I, II, or III CRC patients who received curative surgery

Prediagnosis Non-user User

HR 1.00 0.77 (0.68–0.88)

HR 1.00 0.82 (0.74–0.92)

2357 patients treated with radical or partial nephrectomy for pNx/0, M0 RCC

Postdiagnosis No Yes

HR 1.00 1.02 (0.74–1.39)

HR 1.00 0.84 (0.69–1.00)

409 patients with de novo DLBCL who received RCHOP therapy

Postdiagnosis Non-user User

HR 1.00 1.23 (0.89–1.72)

2987 stage I–IV endometrial cancer patients aged 65 years or older who received a hysterectomy

Postdiagnosis Non-user User Non-user User

HR 1.00 0.92 (0.70–1.20) HR 1.00 0.92 (0.65–1.29)

3851 prostate cancer patients treated with external beam radiation therapy ± androgen deprivation therapy

Postdiagnosis No Yes

7657 stage I to III CRC patients

Prediagnosis Non-user User Postdiagnosis Non-user User

Covariate adjustment Year of diagnosis, age at diagnosis, surgery within 6 months, radiotherapy within 6 months, chemotherapy within 6 months, hormone therapy use, comorbidities, other medication usage stage and socioeconomic deprivation in women with nonmissing values Race, education, smoking, BMI, waist circumference, mammogram in the past 2 years, Gail 5-year risk, female relative with breast cancer, age at menarche, number of live births, breast biopsy, hysterectomy, hormone use, oral contraceptive, aspirin use and study component Age at diagnosis, sex, Union Internationale Contre le Cancer stage, location of CRC, surgery, neoadjuvant treatment, chemotherapy, radiotherapy, BMI, lifetime pack-years of active smoking, average lifetime physical activity, ever regular use of NSAIDs, ever use of hormone replacement therapy (women), previous large bowel endoscopy, diabetes, hyperlipidemia, myocardial infarction, stroke, heart failure, participation in general health check-ups, and for a time-dependent effect of chemotherapy Age, sex, tumor stage, adjuvant therapy, and the propensity score were adjusted Age at surgery, sex, race, type of surgery, Charlson comorbidity index, primary tumor classification, preoperative estimated glomerular filtration rate, symptoms, and year of surgery Not state

Age, acetylsalicylic acid, year of treatment, radiation dose, androgen deprivation therapy, initial pretreatment PSA, T–stage, Charlson index, Gleason score

HR 1.00 0.769 (0.548– 1.08)

HR 1.00 0.86 (0.79–0.93) HR 1.00 0.71 (0.61–0.84)

Follow-up time, age, race, neighborhood income, cancer stage, tumor grade, hysterectomy type, chemotherapy, radiation, impaired glucose tolerance, obesity, dyslipidemia and diabetes

HR 1.00 0.75 (0.66–0.84)

Year of diagnosis, age at diagnosis, sex, stage, surgery within 6 months, radiotherapy within 6 months, chemotherapy within 6 months, site, comorbidities, other medication use after diagnosis as time-varying covariates, grade, deprivation, and smoking before diagnosis in individuals without missing values

S. Zhong et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

Please cite this article in press as: Zhong S et al. Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.04.005

Table 1 Characteristic of the included studies.

First author Year

Country

Follow-up period

Study design

Patient characteristics

Statin use

Gaist et al. (2014) [58]

Denmark

2000–2011 Median 6.9 months (IQR 3.8–13.4)

Cohort

1562 GBM patients aged between 20 and 85 years

Prediagnosis Unexposed Exposed

Grytli et al. (2014) [18]

Norway

2004–2011Median 39 months

Cohort

3,699 prostate cancer patients with high-risk or metastatic disease

Prediagnosis Non-user User Postdiagnosis Non-user User

Habis et al. (2014) [19]

USA

Hamilton et al. (2014) [24]

USA

Kaffenberger et al. (2014) [8]

USA

Krens et al. (2014) [4]

The Netherlands

Livingstone et al. (2014) [6]

The Netherlands

Lipworth et al. (2014) [61]

USA

Murtola et al. (2014) [9]

Finland

1992–2013

Cohort

1995–2010 Median 3 years

Cohort

2000–2010 Median 42.5 months (IQR 19.1–67.1)

Cohort

2005–

Cohort

1998–2010 3 years

Cohort

2002–2010 Median 5.6 years

Cohort

1995–2003 3.25 years

Cohort

442 stage I–IV epithelial ovarian patients

Postdiagnosis No Yes

2,608 patients with localized RCC who were treated surgically

Postdiagnosis No Yes

916 patients who underwent radical or partial nephrectomy for RCC

Postdiagnosis Non-user User

529 KRAS mutant metastatic CRC patients treated with capecitabine, oxaliplatin bevacizumab ± cetuximab

Postdiagnosis Non-user User

791 cutaneous melanoma patients (Breslow thickness > 1 mm) aged 18 years or older

Prediagnosis Non-user User Postdiagnosis Non-user User

86,000 adult participants aged 40–79 years

Prediagnosis No Yes

31,236 breast cancer patients of all stages

Prediagnosis Localized 0 1–495 DDD P496 DDD Metastatic 0 1–495 DDD P496 DDD Postdiagnosis Localized

Cancer-specific mortality

All cause mortality

HR 1.00 0.79 (0.63–1.00)

Covariate adjustment

Year of diagnosis, age at diagnosis, gender, Charlson Comorbidity Index score, history of diabetes, hospital contact for allergy or asthma, number of years of schooling, and use of anti-asthma drugs, antihistamines, HRT, low-dose aspirin, and nonaspirin NSAIDs Age, prostate-specific antigen level, Gleason score, clinical T stage, presence and type of metastases, performance status, and androgen-deprivation therapy initiated within 6 months after diagnosis

HR 1.00 0.78 (0.67–0.90) HR 1.00 0.78 (0.67–0.90)

Age at diagnosis, race, BMI, ASA class, metformin use, residual tumor > 1 cm, primary cytoreductive surgery, histologic subtype, stage, tumor site and grade

HR 1.00 1.48 (0.68–3.22)

HR 1.00 0.89 (0.71–1.13)

HR 1.00 0.48 (0.28–0.83)

HR 1.00 0.62 (0.43–0.90)

HR 1.00 1.41 (0.95–2.10)

Demographic, clinical, preoperative, age, gender, black race, Charlson score, glomular filtration rate, surgery year, symptom presentation, and T stage Age, ASA score, pT category, Fuhrman grade, node status, metastatic status, ABO blood group, preoperative anemia, and preoperative hypercalcemia Prior adjuvant therapy, number of affected organs, age, and aspirin use

Age and sex HR 1.00 0.88 (0.58–1.34) HR 1.00 0.76 (0.50–1.61)

S. Zhong et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

Age, year of Southern Community Cohort Study enrollment, marital status, education, income, health insurance, BMI, cigarette smoking, alcohol consumption, history of hypertension, myocardial infarction/coronary artery bypass surgery, diabetes, stroke, race and sex

HR 1.00 0.90 (0.72–1.12)

Age, tumor morphology and treatment selection HR 1.00 0.76 (0.58–0.99) 0.44 (0.28–0.67)

HR 1.00 0.69 (0.56–0.84) 0.51 (0.39–0.68)

HR 1.00 0.79 (0.51–1.20) 0.51 (0.30–0.86)

HR 1.00 0.91 (0.63–1.31) 0.58 (0.37–0.92) Age, tumor stage and morphology, treatment selection and pre–diagnostic statin use 5

Please cite this article in press as: Zhong S et al. Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.04.005

Table 1 (continued)

(continued on next page)

6

First author Year

Country

Nam et al. (2014) [7]

Korea

Yu et al. (2014) [13]

UK

Brewer et al. (2013) [11]

USA

Crivelli et al. (2013) [56]

3 institutions

Geybels et al. (2013) [14]

USA

Follow-up period

2006–2012

Study design

Cohort

1998–2012 Mean 4.4 years

Cohort

1995–2011 Median 2.9 years

Cohort

1996–2007 Median 62.7 months (IQR 25.0–110.7)

Cohort

2002–2011 Average 6.1 years

Cohort

Patient characteristics

Statin use

Cancer-specific mortality

All cause mortality

0 10–322 DDD 333–800 DDD P801 DDD Metastatic 0 10–322 DDD 333–800 DDD P801 DDD

HR 1.00 0.54 (0.40–0.72) 0.43 (0.31–0.61) 0.42 (0.28–0.62)

HR 1.00 0.56 (0.45–0.69) 0.48 (0.38–0.61) 0.37 (0.27–0.50)

HR 1.00 0.66 (0.42–1.01) 0.37 (0.18–0.79) 0.24 (0.03–1.74)

HR 1.00 0.73 (0.49–1.08) 0.41 (0.21–0.80) 0.38 (0.09–1.53)

241 stage II and III gastric cancer patients who underwent radical gastrectomy

Postdiagnosis Non-user User

11,772 men newly diagnosed with nonmetastatic prostate cancer

Postdiagnosis No Yes

723 patients diagnosed with primary inflammatory breast cancer

Postdiagnosis L-statin users No Yes H-statin users No Yes

HR 1.00 1.169 (0.570– 2.397)

HR 1.00 0.76 (0.66–0.88)

HR 1.00 0.86 (0.78–0.95)

HR 1.00 1.46 (0.73–2.90) HR 1.00 0.80 (0.43–1.49)

1117 patients treated with transurethral resection of the bladder for NMIBC

Postdiagnosis No Yes

HR 1.00 1.23 (0.69–2.19)

HR 1.00 1.14 (0.89–1.44)

1001 prostate cancer patients of all stages

Prediagnosis No Yes

HR 1.00 0.19 (0.06–0.56)

HR 1.00 0.45 (0.10–2.01)

Covariate adjustment

Age group, sex, Lauren’s classification, tumor invasion, lymph node invasion, tumor differentiation, adjuvant chemotherapy, Charlson comorbidity index, lymphovascular invasion, perineural invasion and tumor size Age, year of prostate cancer diagnosis, ethnicity, excessive alcohol use, smoking status, obesity, chronic kidney disease, myocardial infarction, ischemic stroke, transient ischemic attack, peripheral artery disease, previous cancers, prostate-specific antigen level, Gleason score, metformin, sulfonylureas, thiazolidinediones, insulins, other oral antihypoglycemic agents, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, b-blockers, diuretics, other antihypertensive drugs, aspirin, other nonsteroidal anti-inflammatory drugs, a-reductase inhibitors, prediagnostic statin use, prostate-specific antigen testing activity, prostatectomy, radiation therapy, chemotherapy, and androgen deprivation therapy Radiation therapy, hormonal receptor status and HER2 status as the stratification factors and adjusted for lymphatic/vascular invasion for progression-free survival and lymphatic/vascular invasion, nuclear grade and surgery within 1 year for overall survival and disease-specific survival None

Age at diagnosis, Gleason score, stage at diagnosis, diagnostic PSA level, primary treatment approach, race, first-degree family history of prostate cancer, BMI, smoking status, lifetime alcohol consumption, aspirin use, non-aspirin NSAID use, history of diabetes mellitus, and history of prostate cancer screening

S. Zhong et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

Please cite this article in press as: Zhong S et al. Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.04.005

Table 1 (continued)

First author Year

Country

Follow-up period

Study design

Patient characteristics

Statin use

Lavie et al. (2013) [20]

Israel

2003–>2010 9 years

Cohort

150 ovarian cancer cases

Postdiagnosis No Yes Postdiagnosis No Yes

274 endometrial cancer cases Mace et al. (2013) [30]

USA

2000–2012 5 years

Cohort

Xylinas et al. (2013) [64]

11 international institutions

1987–2007 Median 45 months (IQR 20–81)

Cohort

Eindhoven et al. (2012) [57]

The Netherlands

2000–2005 Median 5 years (Range 3–9)

Cohort

Lakha et al. (2012) [27]

UK

1999–2009

Cohort

Cancer-specific mortality

All cause mortality

Covariate adjustment Age

HR 1.00 0.24 (0.06–0.78) HR 1.00 0.35 (0.12–0.96)

407 patients with primary rectal adenocarcinoma who received neoadjuvant therapy then proctectomy

Postdiagnosis Non-user User

HR 1.00 0.62 (0.32–1.18)

HR 1.00 0.81 (0.49–1.35)

2490 patients with UTUC treated with radical nephroureterectomy

Postdiagnosis No Yes

HR 1.00 0.86 (0.72–1.03)

HR 1.00 0.83 (0.72–0.95)

5647 patients who underwent percutaneous coronary intervention

Prediagnosis Non-user User

HR 1.00 0.48 (0.34–0.67)

309 CRC patients aged 16– 79 years

Prediagnosis No Yes Postdiagnosis No Yes

Age, BMI, ASA class III/IV (relative to I/II), and pathological stage

Standard clinicopathologic factors

Age, sex, indication, prior MI, prior PCI, prior CABG, diabetes, hypertension, current smoking, family history of coronary disease, multivessel disease and the use of beta blockers, angiotensin-converting enzyme inhibitors, calcium antagonists, nitrates, diuretics, digitalis and anticoagulants

HR 1.00 0.60 (0.327–1.32)

HR 1.00 0.59 (0.28–1.24)

HR 1.00 0.54 (0.19–1.50)

HR 1.00 0.61 (0.26–1.41)

Marcella et al. (2012) [15]

USA

1997–2000

Casecontrol

380 cases aged 55–79 who died from prostate cancer; 380 matched controls

Prediagnosis No Yes

0.37 (0.23–0.60)

Nielsen et al. (2012) [62]

Denmark

1995–2009 Median 2.6 years (Range 0–15)

Cohort

295,925 patients aged 40 or older who received a diagnosis of cancer

Prediagnosis No Yes

HR 1.00 0.85 (0.82–0.87)

Haukka et al. (2012) [60]

Finland

1997–2005 Mean 4.4 years (IQR 1.8–6.6)

Cohort

336,618 pairs of individuals

Prediagnosis No statin Statin

RR 1.00 0.53 (0.43–0.64)

Chae et al. (2011) [10]

USA

1999–2008 Median 55 months; maximal 118 months

Cohort

Ng et al. (2011) [28]

USA

1999–2009 Median 6.5 (Range 4.4– 7.3)

Cohort

Age, sex, region of residence, family history of CRC, past medical history of cancer, past medical history of bowel disease, BMI, smoking, physical activity, and regular NSAID intake

Education level, body mass index, waist size, number of comorbidities and matched for race and age, and antihypertensive medication use HR 1.00 0.85 (0.83–0.87)

Age at diagnosis; cancer stage; status with regard to chemotherapy, radiotherapy, diagnosis of cardiovascular disease before cancer, and diagnosis of diabetes mellitus before cancer; year of birth; sex; race and ethnic descent; highest level of education; and size of residential area

S. Zhong et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

Baseline diseases, sex, age, follow-up time, statin group, and interaction term between statin and follow-up time

703 stage II/III breast cancer patients

Postdiagnosis Non-user User

HR 1.00 0.98 (0.56–1.70)

842 stage III colon cancer patients with regional lymph node metastases but no distant metastases who received surgical resection then adjuvant bolus 5fluorouracil or leucovorin

Postdiagnosis No Yes

HR 1.00 1.16 (0.77–1.72)

Age, race, menopausal status, family and smoking history, diabetes, hormonal receptor, and Her–2/ Neu status, as well as hormonal therapy Age, sex, family history of colorectal cancer, baseline performance status, depth of invasion through bowel wall, number of positive lymph nodes, perineural invasion, extravascular invasion, postoperative carcinoembryonic antigen, treatment arm, body mass index, physical activity, Western pattern diet, consistent aspirin use, and KRAS mutation status (continued on next page)

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Please cite this article in press as: Zhong S et al. Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.04.005

Table 1 (continued)

8

First author Year

Country

Follow-up period

Study design

Patient characteristics

Statin use

Katz et al. (2010) [16]

USA

1990–2006 Median 4 years (Range 0–16)

Cohort

7042 men who underwent radical prostatectomy or radiotherapy for prostate cancer

Postdiagnosis RP No Yes RT No Yes

Nowakowski et al. (2010) [22]

USA

Samaras et al. (2010) [23]

Switzerland

Gardette et al. (2009) [59]

France

Siddiqui et al. (2009) [29]

USA

van Gestel et al. (2009) [63]

The Netherlands

Elmore et al. (2008) [21]

USA

Graf et al. (2008) [33]

Germany

2002–2007 Median 47 months (Range 13–80)

Cohort

2001–2009 Median 24.4 months (Range 2.27–98)

Cohort

1991– Mean 9.6 years

Cohort

1997–2003 5 years

Cancer-specific mortality

All cause mortality

Age, race, BMI, comorbid illness, smoking status at diagnosis, and androgen-deprivation therapy HR 1.00 0.35 (0.21–0.58) HR 1.00 0.59 (0.37–0.94)

228 DLBCL patients aged age 18 years or older

Postdiagnosis No Yes

HR 1.00 0.89 (0.42–1.90)

145 DLBCL patients who received R-CHOP as firstline therapy

Postdiagnosis No Yes

HR 1.00 0.58 (0.07–4.55)

7855 men aged 50–59 years at baseline

Prediagnosis No Yes

Casecontrol

1309 male patients with a new diagnosis of CRC

Prediagnosis Non-user User

1990–2006 Median 5 years (IQR 2.0–9.1)

Cohort

3371 patients with peripheral arterial disease who underwent vascular surgery

Prediagnosis No Yes

1996–2001

Cohort

126 patients with advanced stage (III/IV) epithelial ovarian cancer undergoing primary cytoreductive surgery followed by at least 6 cycles of platinum-based chemotherapy

Postdiagnosis Non-user User

RR 1.00 0.45 (0.23–0.88)

183 patients with early HCC (1 nodule < 5 cm or 3 nodules < 3 cm each) who received transarterial chemoembolization

Postdiagnosis No Yes

HR 1.00 0.66 (0.45–0.99)

2003–2008

Cohort

Covariate adjustment

International prognostic index

Not state

Center, age, educational level, histories of cardiovascular and severe chronic diseases, hypertension, and diabetes, smoking habits, alcohol consumption, physical activity, waist circumference, and HDL and non-HDL cholesterol

HR 1.00 0.41 (0.16–1.06)

Age and NSAIDs use OR 1.00 0.7 (0.6–0.9) Age, gender, type of surgery, diabetes, smoking, hypercholestrolaemia, corticosteroids, aspirin and propensity score

HR 1.00 0.82 (0.57–1.20

Age, stage, grade, and suboptimal cytoreduction

Not state

IQR, interquartile range; RCC, renal cell carcinoma; GBM, glioblastoma multiforme; CRC, colorectal cancer; DLBCL, diffuse large B cell lymphoma; NMIBC, non-muscle-invasive bladder cancer; UTUC, upper tract urothelial carcinoma; HCC, hepatocellular carcinoma; R-CHOP, rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone; DDD, defined daily dose; L-statin, lipophilic statin; H-statin, weakly lipophilic to hydrophilic statins; RP, radical prostatectomy; RT, radiotherapy; HR, hazard ratio; OR, odds ratio; RR, relative risk; NSAID, non-steroidal anti-inflammatory drug; BMI, body mass index.

S. Zhong et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

Please cite this article in press as: Zhong S et al. Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.04.005

Table 1 (continued)

S. Zhong et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

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Fig. 2. Pooled analyses and subgroup analyses by cancer type for the association between post-diagnostic statin use and all-cause mortality. The squares and horizontal lines correspond to the study-specific hazard ratio and 95% CIs. The area of the square is proportional to the inverse of the sum of the between studies variance and the studyspecific variance. The diamond represents the pooled multivariate hazard ratio and 95% CI. The dotted line of the diamond indicates the bounds of the 95% prediction interval.

Discussion The present meta-analysis investigated the relationship between statin use and mortality in cancer involving 947,410 participants for prediagnosis statin use and 104,811 participants for postdiagnosis statin use with cancer survival outcomes. The summary results, as derived from thirty-nine cohort studies and two case-control studies, indicated that the average effect of statin use post- or prediagnosis was beneficial for overall survival and cancer-specific survival. However, statin use after diagnosis may not always be beneficial in an individual setting (95% PI: 0.49– 1.32 for all-cause mortality; and 95% PI: 0.49–1.21 for cancerspecific mortality) considering the significant heterogeneity between studies. With respect to the effect of prediagnosis statin

use on cancer-specific mortality, statin use will be beneficial in most settings (95% PI: 0.45–1.06), although there was significant heterogeneity. Five studies have explored the effect of statin use on survival of breast cancer patients [5,9–12]. The two most recent studies [5,9] reported a beneficial effect on survival of breast cancer patients who used statin before or after diagnosis. Although the other three studies showed no effect, Chae et al., found that breast cancer patients who took statins more than 6 months have a reduced risk of breast cancer recurrence [10], Brewer et al. showed that weakly lipophilic to hydrophilic statins were associated with significantly improved progression-free survival compared with no statin [11], and Desai et al. reported that prior statin use was associated with lower breast cancer stage at diagnosis [12].

Please cite this article in press as: Zhong S et al. Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.04.005

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S. Zhong et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

Fig. 3. Pooled analyses and subgroup analyses by cancer type for the association between post-diagnostic statin use and cancer-specific mortality. The squares and horizontal lines correspond to the study-specific hazard ratio and 95% CIs. The area of the square is proportional to the inverse of the sum of the between studies variance and the studyspecific variance. The diamond represents the pooled multivariate hazard ratio and 95% CI. The dotted line of the diamond indicates the bounds of the 95% prediction interval.

Fig. 4. Pooled analyses and subgroup analyses by cancer type for the association between prediagnostic statin use and all-cause and cancer-specific mortality. The squares and horizontal lines correspond to the study-specific hazard ratio and 95% CIs. The area of the square is proportional to the inverse of the sum of the between studies variance and the study-specific variance. The diamond represents the pooled multivariate hazard ratio and 95% CI. The dotted line of the diamond indicates the bounds of the 95% prediction interval.

The association between statin use and mortality in colorectal cancer patients was evaluated in eight studies [4,26–32], five of which showed no association [4,27,28,30,32]. Only the three

largest studies [26,29,31] showed a statistically significant reduction in mortality for colorectal cancer patients who used statins. In the study of Siddiqui et al. [29], the long-term statin use prior

Please cite this article in press as: Zhong S et al. Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.04.005

S. Zhong et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

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Fig. 5. Meta-analysis of HRs for all-cause mortality and cancer-specific mortality per increment of 365 DDDs or per increment of 1 year duration of statin use.

to diagnosis was associated with a less advanced tumor stage, a higher prevalence of right-sided tumors, a lower frequency of distant metastases, and a better survival rate. In the two largest,

population-based cohort studies, a reduced death risk was observed in colorectal cancer patients who used statin before or after diagnosis [26]. In addition, although Mace et al. failed to

Please cite this article in press as: Zhong S et al. Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.04.005

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S. Zhong et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

found an association between statin use and mortality in colorectal cancer patients, they showed that rectal cancer patients with use of statins had a better response to neoadjuvant chemoradiation (65.7% versus 48.7%, P = 0.004) and lower median regression grade (1 versus 2, P = 0.01) [16]. There are six studies on the relationship of statin use and mortality in prostate cancer patients [13–18]. The study by Katz et al. reported a reduced risk of all-cause mortality in prostate cancer patients who used statins after treatment with radical prostatectomy or radiotherapy [16]. Another study [17] also evaluated the effect of statins on the survival of men receiving prostate cancer treatment but found no effect. The investigators ascribed this nonresult to the adjustment for comorbidity. They expected that statins are used more often with increased comorbidity, which is significantly associated with worse survival. In the largest, prescription database study [13], statin use after diagnosis was associated with a better survival for prostate cancer patients, and this beneficial effect was stronger in those who also used statins before diagnosis. Grytli et al. found that prostate cancer patients who used statins both pre- and postdiagnosis had a lower risk of death from prostate cancer [18]. The other two studies [14,15] which have assessed statin use prior to diagnosis also showed a protective effect against prostate cancer death. Clinical data remain inconclusive regarding the effect of statins on human cancer, although much evidence suggested statins may exhibit anticancer properties through inducing cell cycle arrest and apoptosis, sensitizing cancer cells to specific chemotherapies, inhibiting invasion and angiogenesis, inducting tumor differentiation, and reducing cholesterol [66]. Several randomized controlled trials have assessed the statin use on mortality in cancer patients [67–72]. Strandberg et al. showed that mortality from cancer was slightly, although non-significantly, reduced in patients with coronary heart disease who used simvastatin before a diagnosis of cancer relative to those who used placebo [67]. In study by Han et al., the authors found that gefitinib plus simvastatin showed longer progression-free survival compared with gefitinib alone in non–small cell lung cancer patients with wild-type EGFR nonadenocarcinomas [68]. A study of 83 advanced hepatocellular carcinoma patients showed that pravastatin prolonged the survival of the patients [72]. However, the other three studies showed that adding statin to chemotherapy in advanced pancreatic cancer [70] or advanced gastric cancer [69,71] did not provide clinical benefit, although it also did not result in increased toxicity. As expected, there is significant heterogeneity among included studies. Several reasons may account for the heterogeneity. First, statins may play a different role in different cancer types. Even the same cancer focus has different grades and stages. Second, differences between statins may exist since the hydrophilic statins have a decreased ability to penetrate cell membranes, which may contribute to different effect on cancer death. Third, misclassification of statin use is likely to impact on the effect estimates of statin use. There are nine studies assessed the exposure to statins based on self-reported, while the others obtained exposure data from prescription database or medical record (Table S1). Self-reported data are not expected to be accurately recalled. Fourth, the included studies are varying in time periods of exposure assessment and follow-up period. Fifth, some of the included studies have excluded deaths in the year after diagnosis using a lag, while others have not. All of these may explain the differing results and significant heterogeneity among included studies. The potential limitations of our study should be considered when interpreting the results. First, we only used all-cause mortality and cancer-specific mortality as outcome, and studies which have investigated other outcomes (e.g., cancer recurrence) and

statin use were not included. Second, in the subgroup analysis, the sample size of each subgroup was relatively small not having enough statistical power to explore the real association. Third, we have not assessed the impact of prediagnosis statin use on the relationship between statin use after cancer diagnosis and patient survival with limited information from original article. So did prediagnosis statin use, without assessment the impact of postdiagnosis statin use. Fourth, although many of the studies had adjusted for important risk factors, unmeasured factors related to statin use may also have influenced results of individual studies. Fifth, there is some evidence of publication for prediagnosis statin use. We only included published studies and a number of meeting abstracts were excluded from present study. Sixth, a number of included studies [4,8,10,11,16–18,20– 23,25,27,34,56,59,61,63,64] may suffer from immortal time bias [73]. Seventh, the dose–response analyses were performed with limit studies in mixed cancer types; therefore, the results should be interpreted with caution. In conclusion, the average effect of statin use, both prediagnosis and postdiagnosis, is beneficial for overall survival and cancerspecific survival. However, statin use may not always be beneficial in an individual setting, especially for postdiagnosis statin use. The full potential effect of statin use on mortality of cancer patients should be further accessed through randomized controlled trials in the future.

Conflict of interest The authors declare no conflict of interest.

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ctrv.2015.04.005.

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Please cite this article in press as: Zhong S et al. Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.04.005

Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies.

Previous studies have examined the effect of statin use on the mortality in cancer patients, but the results are inconsistent. A meta-analysis was per...
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