Clinical Research

Relationship of statins to clinical presentation and biochemical outcomes after radical prostatectomy in Korean patients

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Abstract

The aim of this study was to determine whether or not statins influence biochemical recurrence (BCR) in Korean patients undergoing surgical treatment for prostate cancer. We reviewed data from 687 men who underwent radical retropubic prostatectomy and who did not receive neoadjuvant treatment. Of these patients, 87 reported the use of preoperative statins at surgery. BCR-free survival was determined after exclusion of 78 patients with lymph node metastases and/or who received immediate adjuvant treatment. Patients on statin therapy were more likely to have a co-morbid disease (P<0.05). Mean PSA (9.6 vs 13.6 ng ml−1, P=0.002) and PSA density (0.27 vs 0.38 ng ml−1 ml−1, P<0.001) were significantly lower in patients on statins. However, in the multivariable linear regression model, statin use was not associated with a decrease in PSA. Overall BCR for the entire cohort was not significantly different between the statin and nonstatin groups. On multivariate analysis, positive surgical margin and seminal vesicle invasion were independent risk factors for BCR-free survival, whereas other variables, including statin use, were not significant in predicting the risk of BCR. Patients with positive surgical margin and seminal vesicle invasion had a 2.1- (odds ratio, 2.15; 95% confidence interval, 1.29–3.57; P=0.003) and 2.2-fold risk (odds ratio, 2.21; 95% confidence interval, 1.25–3.89; P=0.006) of BCR. Preoperative statin use is not associated with reduced BCR following radical prostatectomy.

Introduction

Statins are a class of commonly used cholesterol-lowering medications that specifically inhibit the 3-hydroxy-3-methyl-glutaryl reductase pathway. Statin medications have demonstrated effects in reducing cardiovascular morbidity in patients with low high-density lipoprotein or increased low-density lipoprotein.1 Although the main clinical utility of these agents has been for vascular end-points, these agents have also been observed to affect other conditions. Long-term follow-up data from epidemiological studies have suggested an antineoplastic activity of statins, as evidenced by significant reductions in cancer risk in statin users.2, 3

In treatment of prostate cancer, basic science reports have provided evidence to support statin use and a reduction in cancer progression.4, 5 PSA decreased in patients who were prescribed statin medications.6, 7 Statin use has also been associated with a reduction in the risk of presenting with advanced disease.8, 9, 10, 11 However, the benefit of statin use on clinical presentation and therapeutic outcomes for Asian patients with prostate cancer is less well known.

Materials and methods

Patients

Approval of the study was obtained from the institutional review board. We identified consecutive 687 men who underwent radical retropubic prostatectomy and who did not receive neoadjuvant treatment between May 1997 and April 2009. Patient characteristics, including current medication use, were reviewed retrospectively. Data required for inclusion in this study included demographics, biopsy results and pathological parameters. All 3-hydroxy-3-methyl-glutaryl-co-enzyme A reductase inhibitors were included in the statin group and dose, duration or indication of statin was not considered. The 1977 International Union Against Cancer-American Joint Committee on Cancer TNM system was used for staging and the Gleason system was used for grading. On the basis of the classification scheme of D’Amico et al.,12 patients were stratified into three groups.

Histological analysis

Radical prostatectomy specimens were handled and processed in a standard manner, where all prostatic tissue was embedded. Total tumor volume and tumor volume of each cancer focus were calculated using the formula 0.4 × length × width × cross-sectional thickness, that is, number of cross sections × section thickness.13 Then, percentage of tumor volume was calculated as the total tumor volume divided by the prostate volume.

Follow-up

Patients were followed at serial intervals with PSA assay, physical examination or other tests, as clinically indicated. The median follow-up time was 38.0 months (range: 3–143 months).

Statistical analysis

Student’s t-test, χ2-test, Fisher’s exact test and Armitage test were used as appropriate for the descriptive statistics of statin vs nonstatin use. Multiple linear regression analyses were performed to examine the question of whether or not statin medication would make a significant contribution to serum PSA level. Clinical characteristics, including age, body mass index (BMI) and total prostate volume were entered into the model. Because of the association of PSA with diabetes status,14 the presence or absence of diabetes was also included in the model.

To identify the factors that could predict pathological findings, odds ratios and P-values for trends were estimated by multivariate logistic regression analyses. Several variables were used for these analyses, namely, age at surgery, BMI, serum PSA level, clinical stage, biopsy Gleason score and statin use.

Biochemical recurrence (BCR)-free survival was determined in 609 patients after exclusion of 78 patients (n=70 for nonstatin user and n=8 for statin user) with lymph node metastases and/or who received immediate adjuvant treatment. BCR was defined as the definition of a single PSA of 0.2 ng ml−1 or greater with another increasing value.15 The Kaplan–Meier method was used to evaluate the risk of BCR. Cox proportional hazards model was used to examine the effect of statin use, controlling for clinical and pathological findings.

Statistical analysis was performed using commercially available software (SPSS, Chicago, IL, USA). All comparisons were made using two-sided tests with P<0.05 considered statistically significant.

Results

Characteristics of the cohort are listed in Table 1. We identified 87 patients who reported preoperative statin use at radical prostatectomy. The median time to exposure to any statin was 13 months (range: 2–82 months). These men had higher American Society of Anesthesiologists Score than those not on statins preoperatively. Men on statin therapy were more likely to have a diagnosis of hyperlipidemia (P<0.001), hypertension (P=0.002) or diabetes (P<0.001). Overall mean PSA (9.6 vs 13.6 ng ml−1, P=0.002) and PSA density (0.27 vs 0.38 ng ml−1 ml−1, P<0.001) were significantly lower in patients on statins. However, other clinical and biopsy variables were similar between groups. Also, no statistically significant differences in pathological variables, such as percentage of tumor volume, Gleason score, margin status, extracapsular extension, seminal vesicle invasion and lymph node metastases were observed.

Table 1 Patient characteristics

In the multivariable linear regression model, controlling for confounders, such as age, BMI, total prostate volume and history of diabetes, we found that only total prostate volume was associated with a decrease in PSA (P=0.016); however, statin therapy was not (Table 2). When history of diabetes was not included in the model, the same results were observed (data not shown).

Table 2 Multiple linear regression analysis for preoperative serum PSA

To identify the factors that are predictive of pathological findings, we conducted multivariate logistic regression analyses. Logistic regression analysis indicated that BMI, serum PSA levels, clinical stage and biopsy Gleason score were independent predictors for surgical positive margin. The multivariate analysis used in this study also showed that the odds ratio for extracapsular extension or seminal vesicle invasion was significantly increased for serum PSA level and biopsy Gleason score: serum PSA level of 10 ng ml−1 was associated with a 3.9-fold higher risk of extracapsular extension or seminal vesicle invasion than serum PSA level of <10 (odds ratio, 3.92; 95% confidence interval, 2.76–5.56; P<0.001), whereas a biopsy Gleason score of 7 was associated with a 3.0-fold higher chance of extracapsular extension or seminal vesicle invasion than a biopsy Gleason score of 6 (odds ratio, 3.04; 95% confidence interval, 2.14–4.32; P<0.001). The results are shown in Table 3.

Table 3 Multivariate predictors of pathological findings

The median follow-up time was 34 months (range: 3–109 months) for statin users and for nonstatin users was 38 months (range: 3–143 months) (P=0.344). At median follow-up of 38.0 months, BCR was observed in 145 (21.1%) patients. The median time to BCR was 15.0 months (range 2.0–88.0). Statins did not change the rate of BCR in 609 patients without lymph node metastases and who did not receive immediate adjuvant treatment. Overall BCR for the entire cohort did not differ significantly between the statin and nonstatin groups (Figure 1). Stratification by pretreatment risk group on the basis of classification scheme of D’Amico et al.12 demonstrated no difference in outcomes according to statin use (data not shown). On multivariate analysis, positive surgical margin and seminal vesicle invasion were independent risk factors for BCR-free survival, whereas other variables, including statin use, were not significant in predicting the risk of BCR. Patients with positive surgical margin and seminal vesicle invasion had a 2.1- (odds ratio, 2.15; 95% confidence interval, 1.29–3.57; P=0.003) and 2.2-fold risk (odds ratio, 2.21; 95% confidence interval, 1.25–3.89; P=0.006) of BCR (Table 4).

Figure 1
figure1

Biochemical recurrence based on preoperative statin therapy. Solid and dotted lines denote patients who received statin and no statin, respectively.

Table 4 Association of statin use with biochemical recurrence-free survival in multivariate Cox proportional hazard regression analysis

Discussion

Statin therapy as a chemoprevention for prostate cancer is biologically plausible. Statin drugs are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-co-enzyme A reductase, the enzyme that controls conversion of 3-hydroxy-3-methyl-glutaryl-co-enzyme A to mevalonate, an essential precursor of cholesterol, as well as numerous, potentially tumorigenic molecules.4, 16 In addition, cell signaling pathways that are essential for tumor cell adhesion and metastasis have been attenuated by statin administration, primarily through inactivation of RhoA.4 Statins have also shown proapoptotic, antiangiogenic and immunomodulatory effects.4, 5 However, evidence for prevention of overall prostate cancer by statins remains uncertain. Although some studies have reported a 50–65% reduced risk of prostate cancer in statin users compared with nonusers,16, 17 other studies have not confirmed an inverse association between statin use and risk of prostate cancer.2, 18, 19, 20 Furthermore, recent data have suggested that use of statins may actually increase the risk of prostate cancer. Long-term follow-up of the West of Scotland Coronary Prevention Study, a primary prevention trial involving middle-aged men, showed a significant increase in prostate cancer among men randomized to pravastatin, compared with placebo.21

Previous research has suggested decreased serum PSA among statin users.6, 7 A recent longitudinal study from a large veterans affairs cohort demonstrated that initiation of statin therapy was associated with a significant decline in serum PSA level.8 This could potentially impact the risk of prostate cancer detection and presumably lead to detection bias due to fewer prostate biopsies among statin users. Moreover, statin users might be more likely to be diagnosed at an advanced stage in the future. Whether or not the PSA decreasing effect of statins bears clinical significance and really delays prostate cancer diagnostics remains to be determined. There is a growing body of data to support lowered the risk of advanced prostate cancer by statins. Findings from four recent large-prospective studies have demonstrated reduced risk of advanced prostate cancer in statin users.8, 9, 10, 11 Although the underlying biological mechanisms through which statins are associated with decreased prostate cancer progression risk are not well defined, Banez et al.22 have suggested that inhibition of inflammation by statin intake may be a potential mechanism that could explain why men on statins have a lower risk of advanced prostate cancer. These results suggest that PSA-associated bias could not explain the inverse association of statins with advanced prostate cancer.

In addition to potential preventive effects, statins have also been examined in the role of augmenting prostate cancer therapies; however, conflicting results have been reported with regard to the question of whether or not statin use is associated with a decreased risk of PSA progression for men undergoing brachytherapy or radiation therapy.23, 24, 25 After adjusting for differences in treatment year and multiple prognostic factors, Soto et al.23 demonstrated that statin use did not affect BCR-free survival. Moyad et al.24 studied 938 men treated with brachytherapy and compared outcomes for men taking statins with those for nonstatin users. Statin users had lower PSA values, less cancer in biopsy specimens and smaller prostate volumes. Although they tended to have improved prostate cancer-specific and overall survival, findings from multivariate analysis showed no significant association with regard to statin use and survival outcome. Gutt et al.25 evaluated 691 men with clinically localized or locally advanced prostate cancer who underwent treatment with external-beam radiation therapy. They found a significant association between statin use and decreased PSA recurrence. These studies suggest that statins may function as a radiosensitizer.24, 25

Therefore, it may be hypothesized that presurgical statin use would decrease the risk of prostate cancer progression after surgery. Few studies are available to determine whether or not statins can reduce prostate cancer recurrence after radical prostatectomy.26 Furthermore, no studies have tested this postulate in Asian patients with prostate cancer. Loeb et al.27 compared the features of clinical and pathological tumors between 504 users of statins and 847 patients who were not users. They found that use of statins might be associated with more favorable pathological features at radical prostatectomy.27 Krane et al.26 also found that serum PSA is significantly lower in patients on preoperative statins compared with those not taking these medications; however, statin therapy was not associated with an overall decreased risk of BCR.

In the present study, we sought to identify a potential outcome benefit that may be provided by these agents in a retrospective review of prostate cancer patients treated with radical prostatectomy. In our cohort, although statin users had a significantly lower PSA level at diagnosis, statin use lost its statistical significance when adjusted by confounding factors. Statin users were not older and did not have larger BMI; however, they had more chronic illnesses. We found that statin use was not associated with more favorable prostate cancer features and did not significantly reduce the risk for recurrence after radical prostatectomy. Moreover, the duration of statin use was not associated with outcome after radical prostatectomy (data not shown). Ultimately, a prospective randomized trial including Asian patients with prostate cancer will be necessary to firmly establish a role for statin therapy and its effect on therapeutic outcomes.

Some limitation of this study should be mentioned. First, because the findings represent the clinical experience of a single center, the sample size of patients taking statins was small. Therefore, well-designed prospective randomized trials, including large population, need to be performed. Second, in the statin groups, dose and duration of statin was not considered in the present study. Furthermore, we did not have data on the cholesterol level of the patients. Third, BMI of our cohort was much lower than that for Caucasian population and statin users did not have larger BMI. This may be the result of differences in body frame, which alter the relationship between body fat and BMI. Thus, our results may not be applicable to other races. Finally, the median follow-up time interval was relatively short. However, serum PSA is the most sensitive indicator of recurrence after definitive local therapy for prostate cancer and BCR is widely used as an early end point to assess treatment success.

Conclusions

Overall, in this cohort of Korean men presenting for radical prostatectomy, pretreatment PSA was significantly lower in patients on statin therapy. However, when including potential confounders, an interaction between PSA and statins did not exist. In addition, preoperative statin use has not been associated with reduced BCR following radical prostatectomy.

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Correspondence to H H Kim.

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The authors declare no conflict of interest.

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Ku, J., Jeong, C., Park, Y. et al. Relationship of statins to clinical presentation and biochemical outcomes after radical prostatectomy in Korean patients. Prostate Cancer Prostatic Dis 14, 63–68 (2011) doi:10.1038/pcan.2010.39

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Keywords

  • prostatic neoplasm
  • prostatectomy
  • HMG-CoA reductase inhibitors
  • statin
  • biochemical outcome

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