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Prostate Cancer and Prostatic Disease (2013) 16, 367–371 & 2013 Macmillan Publishers Limited All rights reserved 1365-7852/13 www.nature.com/pcan

ORIGINAL ARTICLE

Impact of statin use on biochemical recurrence in patients treated with radical prostatectomy M Rieken1,2, LA Kluth1,3, E Xylinas1,4, C Seitz5, H Fajkovic5, PI Karakiewicz6, Y Lotan7, A Briganti8, W Loidl9, T Faison1, JJ Crivelli1, DS Scherr1, A Bachmann2, AK Tewari1, A Kautzky-Willer10, K Pummer11 and SF Shariat1,5 BACKGROUND: The impact of statin use on biochemical recurrence (BCR) in patients treated with radical prostatectomy (RP) remains controversial. METHODS: We retrospectively evaluated 6842 patients who underwent RP for clinically localized prostate cancer (PC) between 2000 and 2011. Uni- and multivariable cox regression models addressed the association of statin use with BCR. RESULTS: Overall, 2275 (33.3%) patients used statins. Statin users were older and had a higher rate of positive surgical margins than patients not using statins (P-values p0.05). Within a median follow-up of 25 months (interquartile range: 8–42 months), 778 (11.4%) patients experienced BCR. Actuarial estimate 5-years BCR-free survival was 82%±1 for patients without statin use and 84±1% for patients using statins (P ¼ 0.05); statin use was not associated with BCR (hazard ratio: 0.88, 95% confidence interval: 0.76–1.03, P ¼ 0.10) after adjusting for the effects of standard clinicopathologic features. CONCLUSIONS: In PC patients undergoing RP, statin use was not independently associated with lower risk of BCR. Prostate Cancer and Prostatic Disease (2013) 16, 367–371; doi:10.1038/pcan.2013.31; published online 3 September 2013 Keywords: statins; radical prostatectomy; biochemical recurrence

INTRODUCTION Radical prostatectomy (RP) is the most widely used treatment in patients with clinically localized prostate cancer (PC).1 Unfortunately, up to 40% of patients experience disease recurrence during long-term follow-up (FU) despite apparently successful surgery.2 Statins or 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors are widely used medications for hypercholesterolemia. In recent years, there is a constant increase in numbers of statin users.3 Studies showed that lowering of lowdensity lipoprotein cholesterol significantly reduced the incidence of major vascular events such as myocardial infarction or coronary death, stroke or coronary revascularization procedure.4 Interestingly, statin use has been associated as well with reduced cancer-related mortality.5 The impact of statin use on the incidence and natural history of PC remains controversial. A recent meta-analysis on statin use and risk of PC including a total of 27 studies with 1.9 million male subjects provided further evidence that statins may reduce the risk of both having any PC and clinically significant PC.6 Moreover, in PC patients treated with external-beam radiation therapy, statin use has may be associated with a reduced risk of biochemical recurrence (BCR).7–9 However, in one study, the beneficial effect was limited to high-risk patients9 and another could not detect any association of statin use with PC outcomes after external-beam radiation therapy.10 A total of seven studies investigated the association of statin use with BCR in PC patients treated with RP. Of these, five studies showed no association,11–15 whereas in one study statin 1

use was associated with increased16 and in one study with decreased17 risk of BCR. As previous studies cover heterogeneous, limited sized cohorts, a further analysis of the association of statin use with BCR after RP for PC in a large cohort is warranted. For this purpose, we assessed a multicenter cohort of patients treated with RP for clinically localized PC. Based on the previously published literature, we hypothesized that statin use is not associated with BCR after RP for PC.

MATERIALS AND METHODS Patient selection and data collection This was an institutional review board-approved study, with all participating sites providing the necessary institutional data-sharing agreements before initiation of the study. A computerized databank was generated for data transfer. After combining the data sets, reports were generated for each variable to identify data inconsistencies and other data integrity problems. Through regular communication with all sites, resolution of all identified anomalies was achieved before analysis. Before analysis, the database was closed and the final data set was produced. A total of six North American and European centers provided data (Department of Urology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA; Department of Urology, University of Montreal, Montreal, QC, Canada; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Urology, Urological Research Institute, San Raffaele Scientific Institute, Milan, Italy; Prostate Cancer Center, Hospital Barmherzige Schwestern Linz, Linz,

Department of Urology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA; 2Department of Urology, University Hospital Basel, Basel, Switzerland; Department of Urology, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany; 4Department of Urology, Cochin Hospital, Assistance Publique-Hopitaux de Paris, Paris Descartes University, Paris, France; 5Department of Urology, Medical University of Vienna, Vienna, Austria; 6Department of Urology, University of Montreal, Montreal, Quebec, Canada; 7Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 8Department of Urology, Urological Research Institute, San Raffaele Scientific Institute, Milan, Italy; 9Prostate Cancer Center, Hospital Barmherzige Schwestern Linz, Linz, Austria; 10Unit of Gender Medicine, Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria and 11Department of Urology, Medical University of Graz, Graz, Austria. Correspondence: Professor SF Shariat, Department of Urology, Medical University of Vienna, Wa¨hringer Gu¨rtel 18-20, Vienna A-1090, Austria. E-mail: [email protected] Received 20 May 2013; revised 11 July 2013; accepted 30 July 2013; published online 3 September 2013 3

Statins use and prostate cancer outcomes M Rieken et al

368 Austria; Department of Urology, Medical University of Graz, Graz, Austria). The study cohort included 7447 patients with clinically localized PC treated with RP between 2000 and 2011. Patients with missing preoperative PSA (n ¼ 52), surgical margin status (n ¼ 3), lymph node status (n ¼ 23), RP Gleason-score (n ¼ 32) and/or missing FU data (n ¼ 495) were excluded from the analyses. This left 6842 patients for analysis. No patient received preoperative radiotherapy, hormonal treatment or chemotherapy. No patient had distant metastatic disease at the time of RP. Statin use at the time of diagnosis, regardless of statin type, dose or cumulative exposure, was recorded for each patient.

Pathological evaluation All surgical specimens were processed according to standard pathologic procedures as outlined elsewhere.18 Genito-urinary pathologists assigned pathologic stage, which was reassigned according to the 2007 American Joint Committee on Cancer Tumor, Node and Metastasis staging system when necessary. Lymphoid tissue removed was submitted for histological examination. The proportion of patients undergoing lymph-node dissection did not differ by statin use (statin use: 73.6%, no statin use: 72.1%, P ¼ 0.38). Positive pathological margin was defined as tumor cells in contact with the inked surface of the prostatectomy specimen.

FU FU was performed according to institutional protocols. Generally, patients were seen postoperatively quarterly within the first year, semiannually in the second year and annually thereafter. Digital rectal examination and PSA evaluation were performed at each visit. Only patients who reached undetectable PSA after surgery were included in the analysis. The primary end point BCR was defined as PSA value 40.2 ng ml 1 on two consecutive visits.1 The date of BCR was attributed to the day of the first rising PSA. No patient received immediate adjuvant radiotherapy. In case of BCR, adjuvant radiotherapy with or without hormonal treatment was initiated. In case of lymph node metastasis, immediate adjuvant androgen deprivation therapy was initiated.

Statistical analysis Associations of statin use with categorical variables were assessed using w2 test. Differences in continuous variables across two categories were analyzed using the Mann–Whitney U-test. BCR-free survival curves were generated using the Kaplan–Meier method; log-rank test was applied for pairwise comparison of survival. Univariable and multivariable Cox regression models addressed the association of statin use with BCR after RP. All P-values were two-sided and statistical significance was defined as a Pp0.05. Statistical analyses were performed using SPSS Statistics 20 (SPSS, IBM, Armonk, NY, USA).

RESULTS Association of statin use with clinicopathologic characteristics Table 1A shows the clinicopathologic characteristics of the 6842 patients and their association with statin use. A total of 2275 (33.3%) were taking statins at the time of RP. Statin users were older (P ¼ 0.05) and had a higher rate of positive surgical margins (PSMs; P ¼ 0.03) than patients not using statins. There were no significant differences in preoperative PSA, preoperative or RP Gleason sum, extracapsular extension, seminal vesicle invasion and lymph node metastasis between patients who used statins and those who did not. Association of statin use with BCR in the entire cohort Within a median FU of 25 months (interquartile range: 8–42), 538 (11.8%) patients without statin use and 240 (10.5%) patients with statin use experienced BCR (Figure 1). Actuarial estimates of BCRfree survival were 92±0%, 82±1% and 66±3% for patients without statin use and 94±1%, 84±1% and 71±3% for patients with statin use at 2, 5 and 10 years, respectively (Figure 1, P ¼ 0.05). In univariable cox regression analysis, statin use was associated with a decreased risk of BCR (Table 2, hazard ratio (HR): 0.86, 95% confidence interval (CI): 0.74–1.00, P ¼ 0.05). In multivariable analyses, age, preoperative PSA, RP Gleason sum, lymph Prostate Cancer and Prostatic Disease (2013), 367 – 371

node metastasis, PSMs, stage pT3a and pT3b were significantly associated with risk of recurrence, whereas statin use did not retain its significance (Table 2, HR: 0.88, 95% CI: 0.76–1.03, P ¼ 0.10). Association of statin use with BCR in subgroups In subgroup analysis of patients with PSM, 184 (28.3%) patients who did not take statins and 75 (20.2%) patients who took statins experienced BCR within a median FU of 26 months (interquartile range: 8–45). Actuarial estimates of BCR-free survival were 80±2%, 62±3% and 49±4% for patients without statin use and 86±2%, 71±3% and 65±4% for patients with statin use at 2, 5 and 10 years, respectively (Figure 2, P ¼ 0.007). In patients with PSM, clinicopathologic features were comparable between statin users and non-statin users (Table 1B). In multivariable cox regression analysis that adjusted for the effects of standard clinicopathologic features, statin use remained significantly associated with decreased risk of BCR (Table 2, HR: 0.76, 95% CI: 0.58–0.99, P ¼ 0.046). BCR-free survival did not show any significant difference between statin users and non-users in patients with RP Gleason sum p6 (P ¼ 0.39), RP Gleason sum ¼ 7 (P ¼ 0.20), RP Gleason sumX8 (P ¼ 0.34), without PSM (P ¼ 0.36), stage pT3a (P ¼ 0.11), stage pT3b (0.12) and with lymph node metastasis (P ¼ 0.97). DISCUSSION In our study, PC patients using statins had a lower rate of BCR than patients not taking statins in univariable, but not multivariable cox regression analyses. This observation is in line with five previously published studies11–15 and a recent meta-analysis,19 which could not reveal a significant association of statin use with BCR after RP. In contrast, Ritch et al. detected an increased risk of BCR in PC patients using statins after RP.16 In patients classified as D’Amico low-risk category, those taking statins had a significantly shorter BCR-free survival than patients not taking statins. In contrast, statin users in the intermediate and high-risk categories had no significant difference in BCR compared with non-users. The authors attributed the higher risk of BCR in D’Amico low-risk category patients taking statins to the reduction of PSA by statins, which has been described in various studies.20,21 A decrease in PSA may delay PC diagnosis and lead to an upstaging of the tumor. This would suggest that statin use may mask biologically aggressive disease. This is further supported by a significantly higher rate of patients with a pathological Gleason sum X7 in statin users compared with non-statin users in the study cohort.16 In addition, another study showed a significantly lower PSA in patients using statins and Gleason sum X7.12 However, it may be questioned if a PSA reduction is the explanation for the unfavorable outcome of statin users in the study because the rate of patients with a pathological Gleason sum X7 was also higher in the group of statin users in a study that found statin use to be associated with favorable outcome.17 Furthermore, our study and three other studies on the effect of statins on the outcome of PC after RP did not show a lower PSA in patients taking statins at the time of surgery.11,13,14 In contrast to the results of our and other previous studies, Hamilton et al.17 found statin use to be associated with decreased risk of BCR after RP after adjustment for clinical and pathological features. Adding Gleason-Score to their multivariable model generated the largest shift in HR for statin use. The authors found only doses X1 dose equivalent of 20 mg simvastatin to be associated with decreased risk of BCR. Age, PSA, Gleason sum and tumor stage were comparable to our study. In contrast, Hamilton et al. had a PSM rate of 45% (non-statin users) and 44% (statin users), whereas in our study, the rate of PSM was 14.3% and 16.3%, respectively. In addition, 20% of the patients in the study & 2013 Macmillan Publishers Limited


369 Table 1. Association of statin use with clinicopathologic characteristics of (A) 6842 patients treated with RP for clinically localized prostate cancer; (B) 1022 patients with positive surgical margins after RP Characteristics (A) All patients Number of patients (n, %) Age (years) Mean (s.d.) Median (IQR) Preoperative PSA (ng ml 1) Mean (s.d.) Median (IQR) Preoperative Gleason sum (n, %) p6 7 X8 RP Gleason sum (n, %) p6 7 X8 Extracapsular extension, pT3a (n, %) Seminal vesicle invasion, pT3b (n, %) Positive surgical margin (n, %) Lymph node metastasis

Total

No statin use

Statin use

P-value

6842

4567 (66.7)

2275 (33.3)

—

61.3 (6.7) 61.5 (9.3)

61.0 (6.7) 61.3 (9.3)

61.7 (6.5) 61.8 (9.1)

0.05

7.6 (5.9) 6.2 (4.5)

7.5 (6.0) 6.2 (4.5)

7.7 (5.5) 6.2 (4.4)

0.68

3762 (55.0) 2649 (38.7) 431 (6.3)

2478 (54.3) 1784 (39.1) 305 (6.7)

1284 (56.4) 865 (38.0) 126 (5.5)

0.09

2078 4245 519 1271 469 1022 771

1383 2837 347 849 315 651 522

695 1408 172 422 154 371 249

0.98

(B) Patients with positive surgical margins Number of patients (n, %) Age (years) Mean (s.d.) Median (IQR) Preoperative PSA (ng ml 1) Mean (s.d.) Median (IQR) Preoperative Gleason sum (n, %) p6 7 X8 RP Gleason sum (n, %) p6 7 X8 Extracapsular extension, pT3a (n, %) Seminal vesicle invasion, pT3b (n, %) Lymph node metastasis

(30.4) (62.0) (7.6) (18.6) (6.9) (14.9) (11.3)

(30.3) (62.1) (7.6) (18.6) (6.9) (14.3) (11.4)

(30.5) (61.9) (7.6) (18.5) (6.8) (16.3) (10.9)

0.97 0.84 0.03 0.55

1022

651 (63.7)

371 (36.3)

61.5 (6.6) 61.4 (9.3)

61.4 (6.6) 61.5 (9.0)

61.7 (6.7) 61.3 (10)

0.80

9.4 (7.7) 7.4 (5.8)

9.4 (7.7) 7.5 (6.0)

9.4 (7.8) 7.4 (5.8)

0.70

479 (46.9) 453 (44.3) 90 (8.8)

304 (46.7) 284 (43.6) 63 (9.7)

175 (47.2) 169 (45.6) 27 (7.3)

0.42

188 687 147 350 152 207

130 427 94 229 98 133

58 260 53 121 54 74

0.21

(18.4) (67.2) (14.4) (34.2) (14.9) (20.3)

(20.0) (65.6) (14.4) (35.2) (15.1) (20.4)

(15.6) (70.1) (14.3) (32.6) (14.6) (19.9)

—

0.41 0.83 0.85

Abbreviations: IQR, interquartile range; RP, radical prostatectomy.

1.0

Biochemical recurrence-free survival

Statin use

p=0.05

0.8

No Statin use

0.6

0.4

0.2


2-years±SE

5-years±SE

10-years±SE

No statin use

92%±0

82%±1

66%±3

Statin use

94%±1

84%±1

71%±3

0.0 0

12

24

36

48

60

72

84

96

108

120

Time after radical prostatectomy in months Patient numbers at risk for biochemical recurrence Months

0

12

24

36

48

60

72

84

96

108

120

No statin use

4567

3710

2727

1628

1102

707

446

293

207

112

34

Statin use

2275

1857

1478

864

589

375

263

150

106

69

28

Figure 1. Kaplan–Meier curves depicting biochemical recurrence-free survival in 6842 patients with clinically localized prostate cancer treated with radical prostatectomy according to their statin use. & 2013 Macmillan Publishers Limited

Prostate Cancer and Prostatic Disease (2013), 367 – 371


370 Table 2. Univariable and multivariable Cox regression analyses predicting biochemical recurrence in patients treated with radical prostatectomy for prostate cancer Patient subgroup

Univariable

a

All patients No lymph node metastasisb Lymph node metastasisb Negative surgical marginsc Positive surgical marginsc Stage pT3ad Stage pT3bd RP Gleason sump6e RP Gleason sum ¼ 7e RP Gleason sumX8e

Multivariable

HR

95% CI

P value

HR

95% CI

P value

0.86 0.85 1.01 0.92 0.69 0.80 0.77 0.85 0.88 0.85

0.74–1.00 0.72–0.99 0.56–1.82 0.76–1.1 0.53–0.91 0.61–1.05 0.56–1.07 0.59–1.24 0.73–1.07 0.60–1.19

0.05 0.04 0.97 0.36 0.007 0.11 0.12 0.39 0.20 0.34

0.88 0.88 0.96 0.96 0.76 0.81 0.83 0.92 0.86 0.93

0.76–1.03 0.75–1.03 0.53–1.75 0.79–1.16 0.58–0.99 0.62–1.07 0.60–1.15 0.63–1.34 0.71–1.05 0.66–1.31

0.10 0.10 0.90 0.67 0.046 0.13 0.26 0.67 0.13 0.66

Abbreviations: CI, confidence interval; HR, hazard ratio; RP, radical prostatectomy. Multivariable Cox regression analysis adjusted for: aStatin use, age (continuous), preoperative PSA (continuous), RP Gleason Score (categorized by p6, ¼ 7, X8, referent: p6), positive lymph nodes, positive surgical margins, stage pT3a, stage T3b. b Statin use, age (continuous), preoperative PSA (continuous), RP Gleason Score (categorized by p6, ¼ 7, X8, referent: p6), positive surgical margins, stage pT3a, stage T3b. c Statin use, age (continuous), preoperative PSA (continuous), RP Gleason Score (categorized by p6, ¼ 7, X8, referent: p6), positive lymph nodes, stage pT3a, stage T3b. d Statin use, age (continuous), preoperative PSA (continuous), RP Gleason Score (categorized by p6, ¼ 7, X8, referent: p6), positive lymph nodes, positive surgical margins, stage T3b. e Statin use, age (continuous), preoperative PSA (continuous), positive lymph nodes, positive surgical margins, stage pT3a, stage T3b. HRs in relation to statin use (users versus on-users), stratified by tumor characteristics.


1.0

0.8

Statin use

p=0.007

0.6

No Statin use 0.4

0.2


2-years±SE

5-years±SE

No statin use

80%±2

62%±.3

10-years±SE

49%±4

Statin use

86%±2

71%±3

65%±4

0.0 0

12

24

36

48

60

72

84

96

108

120

Time after radical prostatectomy in months Patient numbers at risk for biochemical recurrence Months

0

12

24

36

48

60

72

84

96

108

120

No statin use

651

503

374

252

168

104

58

34

23

8

2

Statin use

371

286

235

146

104

67

38

24

15

8

1

Figure 2. Kaplan–Meier curves depicting biochemical recurrence-free survival in 1022 patients with clinically localized prostate cancer and positive surgical margins after treated with radical prostatectomy according to their statin use.

by Hamilton et al. received postoperative radiation therapy and 6% combined radiotherapy and hormonal therapy. As studies and meta-analyses have shown a beneficial effect of statins in PC patients undergoing radiotherapy, the high rate of patients with radiotherapy might have influenced study results in this subgroup.19 To explore the influence of clinicopathologic features on the association of statin use with outcomes after RP, we performed a subgroup analysis. In our analysis, BCR-free survival did not show any significant difference between statin users and non-users in patients when Prostate Cancer and Prostatic Disease (2013), 367 – 371

categorizing according to Gleason sum (p 6; ¼ 7; X8) without PSM, with stage pT3a and pT3b, and with lymph node metastasis. Similar findings of subgroup analysis stratified by Gleason sum or D’Amico category were reported from previous studies.12,14 BCR was found to be lower in PC patients with PSM taking statins compared with those not taking statins. Furthermore, in the subgroup of patients with PSM, statin use was independently associated with a decreased risk of BCR. This association has not been described previously. A possible explanation for this observation is that statins may only exert their potentially & 2013 Macmillan Publishers Limited


371 antiproliferative effect in the presence of tumor tissue. RP significantly alters the natural history of the cancer, abrogating the potentially antiproliferative effect of statins. As in patients with PSM remaining tumor tissue can be assumed, statins may exert a measurable antiproliferative effect in this situation only. To date, the potentially antiproliferative mechanism of statins remains unclear. Low-density lipoprotein increased the relative cell number of PC cell lines, but reduced the number of normal epithelial cells at high concentrations in vitro.22 Statins have also been shown to significantly reduce the migration and colony formation of PC–3 cells in human bone marrow stroma.23 Moreover, statins have been shown to inhibit proliferation, induce cell cycle arrest, induce apoptosis in vitro and inhibit angiogenesis in mice xenograft models.24 Furthermore, statins also have anti-inflammatory properties.25,26 As inflammation is affecting PC growth, statins may reduce PC progression by inhibiting inflammation. In a study on patients undergoing RP, statin intake before surgery was shown to be significantly associated with reduced risk of inflammation surrounding malignant glands within RP specimens.27 Recent evidence also suggests a role of tumor suppression through statins in high concentration by inhibition of small GTPases involved in cell proliferation, survival, inflammation, angiogenesis and metastasis.24 However, further basic and translational research are necessary to elucidate the association between statins and PC progression in certain subgroups of patients like those with PSM. Our study has several limitations. These include the retrospective design. As a multi-center study, the cohort of patients underwent RP by several surgeons and several pathologists analyzed the pathological specimens. However, all physicians were dedicated to uro-oncology. Furthermore, the mean FU of the study is relatively short as we experienced a high loss to FU. More specific to this study, we did not have any information on type, dosage and duration of statin intake before and after RP. Furthermore, information on the body mass index of patients was missing, so that we could not adjust for this potential prognostic factor.28 In addition, we were not able to account for the effects of smoking and diabetes mellitus, which may have an influence on the risk of BCR and may differ by statin use. Furthermore, significant differences in the rate of PSMs between statin users and non-users may have influenced the observed in favor of statin users. Moreover, we did not adjust our subgroup analysis for multiple comparisons. Despite its limitations, our study, to the best of our knowledge, incorporates the largest cohort of patients published so far on statin use and outcomes after RP. In conclusion, in PC patients undergoing RP, statin use was not independently associated with lower risk of BCR. The potential effect of statin use on PC development and outcome needs further investigation through epidemiologic and translational basic research.

CONFLICT OF INTEREST M. Rieken received Grant Support from Swiss National Science Foundation. A. Bachmann is the company consult for American Medical Systems, Caris Life Sciences, Olympus, Orion Pharma, Schering. S.F. Shariat is the member of Advisory Board for Ferring Pharmaceuticals. The remaining authors declare no conflict of interest.

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& 2013 Macmillan Publishers Limited

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