Robert J. Hamilton

The Influence of Statin Medications on Prostate-specific Antigen Levels

BACKGROUND Recent data suggest that statin use may be associated with a reduced risk of advanced prostate cancer. However, the influence of statins on prostate-specific antigen (PSA) levels and what effect this could potentially have on prostate cancer diagnosis are unknown. METHODS We conducted a longitudinal study of 1214 men who were prescribed a statin between 1990 and 2006 at the Durham Veterans Affairs Medical Center who were free of prostate cancer, had not undergone prostate surgery or taken medications known to alter androgen levels and who had at least one PSA value within 2 years before and at least one PSA value within 1 year after starting a statin. The change in PSA from before to after statin treatment was analyzed as a continuous variable using the Wilcoxon signed rank test. The association between change in PSA and change in cholesterol parameters (low-density lipoprotein [LDL], high-density lipoprotein [HDL], and total cholesterol) was analyzed using multivariate linear regression. All statistical tests were two-sided. RESULTS Mean (SD) age when starting statins was 60.3 (8.3) years; median prestatin PSA concentration was 0.9 (1.9) ng/mL; and mean prestatin LDL cholesterol concentration was 144 (34) mg/dL. After starting a statin, the median LDL decline was 27.5%, and the median PSA decline was 4.1% (P < .001, for both comparisons). Changes in PSA concentration were strongly associated with statin dose and changes in LDL levels. For every 10% decrease in LDL after starting a statin, PSA levels declined by 1.64 (95 % confidence interval [CI] = 0.64% to 2.65%, p = .001). Among men most likely to be under consideration for prostate biopsy (prestatin PSA levels > or =2.5 ng/mL, n = 188), those with >41% declines in LDL (highest quartile) after starting a statin experienced a 17.4% (95% CI = 10.0% to 24.9%) decline in serum PSA. CONCLUSIONS PSA levels declined by a statistically significant extent after initiation of statin treatment. The reduction was most pronounced among men with the largest LDL declines and those with PSA levels that would make them candidates for prostate biopsy. By lowering PSA levels, statins may complicate cancer detection, although further studies are needed to quantify the clinical significance of this effect.

Statin use and risk of prostate cancer and high-grade prostate cancer: results from the REDUCE study.

Background:Statins are associated with lower PSA levels. As PSA is the primary method for prostate cancer (PC) screening, this confounds any associations between statins and risk of being diagnosed with PC. Thus, we examined the association between statins and cancer and high-grade cancer in REDUCE, where biopsies were largely PSA-independent.Methods:Post-hoc secondary analysis of REDUCE, which was a prospective multinational randomized controlled trial of dutasteride vs placebo for 4 years among men aged 50–75 years with PSA of 2.5–10.0 ng ml−1 and a negative biopsy at baseline, and included PSA-independent biopsies mandated at 2- and 4-years. Analyses were limited to men who underwent at least one biopsy while under study (n=6729). The association between baseline statin use and risk of overall, high-grade (Gleason ⩾7) or low-grade (Gleason ⩽6) PC vs no cancer was examined using multinomial logistic regression adjusting for age, race, baseline PSA, prostate volume, rectal examination findings, body mass index (BMI), comorbidities, smoking, alcohol intake and treatment arm.Results:Of 6729 men who had at least one biopsy while on study, 1174 (17.5%) were taking a statin at baseline. Men taking statins were older, had lower PSA levels, higher BMI values and lower serum testosterone and dihydrotestosterone levels, though differences, were slight. Statin use was not associated with overall PC diagnosis (multivariable OR 1.05, 95% CI 0.89–1.24, P=0.54). When stratified by grade, statin use was not associated with low-grade (multivariable OR 1.03, 95% CI 0.85–1.25, P=0.75) or high-grade cancer (multivariable OR 1.11, 95% CI 0.85–1.45, P=0.46). The major limitation is the inclusion of only men with a negative baseline biopsy.Conclusions:Among men with a negative baseline biopsy and follow-up biopsies largely independent of PSA, statins were not associated with cancer or high-grade cancer.

Association between Statins and Prostate Tumor Inflammatory Infiltrate in Men Undergoing Radical Prostatectomy

Background: Cholesterol-lowering drugs known as statins have been reported to have significant anti-inflammatory properties. Given that inflammation may contribute to prostate cancer progression and that statins may reduce the risk for advanced prostate cancer, we investigated whether statin use was associated with reduced intratumoral inflammation in radical prostatectomy (RP) specimens. Methods: Inflammation within index tumors of 236 men undergoing RP from 1996 to 2004 was graded by a single pathologist as grade 0 (absent), 1 (mild: ≤10%), and 2 (marked: >10%). Preoperative statin use was analyzed by grouping subjects as statin users or nonusers. Type and dosage of statin was accounted for using dose equivalents with 20 mg simvastatin as reference. Logistic regression was used to determine the association between statin use and intratumoral inflammation controlling for age, race, body mass index, prostate-specific antigen, year of surgery, clinical stage, pathologic Gleason sum, surgical margin status, extracapsular extension, seminal vesicle invasion, prostate weight, time from prostate biopsy to RP, and nonsteroidal anti-inflammatory drug use. Results: Preoperative statin use was significantly associated with lower risk for any (grade ≥1) intratumoral inflammation (odds ratio, 0.31; 95% confidence interval, 0.10-0.98; P = 0.047) on multivariable analysis, with doses ≥20 mg simvastatin equivalents being more strongly associated (relative to nonuse; odds ratio, 0.22; 95% confidence interval, 0.06-0.79; P = 0.02). Conclusion: In a cohort of men undergoing RP, statin use was associated with significantly lower risk of any inflammation within prostate tumors. Impact: Given previous reports that inflammation is associated with advanced prostate cancer, and statin use is associated with decreased prostate cancer progression risk, our findings suggest that inhibition of inflammation within tumors may be a potential mechanism for purported anti–prostate cancer properties of statins. Cancer Epidemiol Biomarkers Prev; 19(3); 722–8

Review of recent evidence in support of a role for statins in the prevention of prostate cancer.

Purpose of review We examine the potential chemopreventive role statins may have in prostate cancer, highlight the basic science supporting this role and analyze the human data regarding the association between statin use and prostate cancer. Recent findings Basic scientific evidence suggests that, through cholesterol and noncholesterol-mediated mechanisms, statins inhibit many pathways of cancer formation and progression. A handful of observational studies found statin use was associated with reduced prostate cancer risk, though others found no association. In the last year, however, four large prospective studies have observed similar reductions in the risk of advanced prostate cancer with essentially no reduction in the risk of overall prostate cancer. This may, in part, explain why previous studies, including large metaanalyses of clinical trials of statins in the prevention of cardiovascular outcomes, did not observe any association between statin use and overall prostate cancer risk. Summary The exact association between statin medication use and prostate cancer, and whether this association is causal in nature, remains unclear. Recent evidence, however, is encouraging, particularly for reducing the risk of advanced disease. Thus, while at present there are insufficient data to recommend all men start taking a statin medication regardless of their cholesterol profile, the rationale to move forward with further research is clear.

A Negative Confirmatory Biopsy Among Men on Active Surveillance for Prostate Cancer Does Not Protect Them from Histologic Grade Progression

BACKGROUND Many men (21-52%) are reported to have no cancer on the second, also known as the confirmatory, biopsy (B2) for prostate cancer active surveillance (AS). If these men had a reduced risk of pathologic progression, particularly grade related, the intensity of their follow-up could be decreased. OBJECTIVE To investigate if men with no cancer on B2 are less likely to undergo subsequent pathologic progression. DESIGN, SETTING, AND PARTICIPANTS Men were identified from our tertiary care center AS prostate cancer database (1995-2012). Eligibility criteria were prostate-specific antigen (PSA) ≤ 10, cT2 or lower, no Gleason grade 4 or 5, three or fewer positive cores, and no core >50% involved. Only patients with three or more biopsies were selected and then dichotomized on cancer status (yes or no) at B2. INTERVENTION AS OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Pathologic progression was defined as grade (advancement in Gleason score) and/or volume (more than three positive cores, >50% core involved). Progression-free survival was compared. Predictors of progression were investigated using a Cox proportional hazards model. RESULTS AND LIMITATIONS Of the 286 patients remaining on AS after B2, 149 (52%) had no cancer and 137 (48%) had cancer. The median follow-up after B2 was 41 mo (interquartile range [IQR]: 26.5-61.9). Progression-free survival at 5 yr was 85.2% versus 67.3% for negative B2 versus cancer on B2, respectively (p = 0.002). Men with no cancer at B2 had a 53% reduction in risk of subsequent progression (hazard ratio [HR]: 0.47; 95% confidence interval [CI], 0.29-0.77; p = 0.003). Subanalysis showed prognostic indicators of volume-related progression were absence of cancer (HR: 0.36; 95% CI, 0.20-0.62; p = 0.0006) and PSA density (HR: 1.79; 95% CI, 1.12-2.89; p = 0.01). The only predictor of grade-related progression was age (HR: 1.05; 95% CI, 1.00-1.10; p = 0.04). Retrospective analysis was the major limitation of the study. CONCLUSIONS Absence of cancer on B2 is associated with a significantly decreased risk of volume-related but not grade-related progression. This must be considered when counseling men on AS.

Knowledge and Use of Finasteride for the Prevention of Prostate Cancer

Background: The knowledge about and use of chemopreventive agents for prostate cancer by physicians has not been described. The Prostate Cancer Prevention Trial (PCPT) showed that finasteride was effective in reducing the incidence of prostate cancer. We examined the influence of the PCPT on finasteride prescribing within the Veterans Health Administration (VHA). Methods: We assessed trends on monthly new and total prescriptions for finasteride filled within the VHA from January 2000 to December 2005. Additionally, all VHA urologists and a random sample of VHA primary care physicians (PCP) were surveyed about their use of finasteride. Results: The number of men starting finasteride grew over the study period. Publication of the PCPT was not significantly associated with any change in this pattern (P = 0.45). Fifty-seven percent of urologists and 40% of PCPs endorsed prescribing finasteride more frequently in 2006 than 5 years prior. However, among those who reported changing prescribing patterns, fewer than 2% reported being influenced by the PCPT. Sixty-four percent of urologists and 80% of PCPs never prescribe finasteride for prostate cancer chemoprevention; 55% of urologists cited concerns of inducing high-grade tumors, whereas 52% of PCPs did not know it could be used for chemoprevention. Conclusions: The number of men starting finasteride in the VHA increased over time, but the change did not seem to be due to increased use of finasteride for chemoprevention. Publication of the PCPT seemed to have little influence over the study period. Impact: Physicians may not readily accept the use of chemopreventive agents for prostate cancer. Cancer Epidemiol Biomarkers Prev; 19(9); 2164–71. ©2010 AACR.

Large Retroperitoneal Lymphadenopathy As a Predictor of Venous Thromboembolism in Patients With Disseminated Germ Cell Tumors Treated With Chemotherapy

PURPOSE Cisplatin-based chemotherapy, a mainstay of treatment for disseminated germ cell tumors (GCTs), is associated with venous thromboembolism (VTE). Many patients with disseminated GCTs have large retroperitoneal lymph node (RPLN) metastases that may cause venous stasis and increase the risk of VTE development. We hypothesized that there was an association between large RPLN and chemotherapy-associated VTE risk. PATIENTS AND METHODS The training cohort was composed of patients with disseminated GCT receiving first-line chemotherapy at Princess Margaret Cancer Centre between January 2000 and December 2010. Large RPLN was defined as more than 5 cm in maximal axial diameter. The predictive and discriminatory accuracies of a model using large RPLN in predicting VTE were compared with high-risk Khorana score (≥ 3) using logistic regression and area under receiver operator characteristic curves (AUROCs). The model was externally validated in a cohort of patients treated at the London Health Sciences Centre. RESULTS The training cohort comprised 216 patients, 21 (10%) of whom developed VTE during chemotherapy. VTE was associated with large RPLN (odds ratio [OR], 5.26; P = .001), high-risk Khorana score (OR, 11.8; P < .001), intermediate-/poor-risk disease (OR, 3.76; P = .005), and hospitalization during chemotherapy (OR, 4.24; P = .002). Large RPLN showed higher discriminatory accuracy than high-risk Khorana score (AUROC, 0.71 v 0.67, respectively). Superior discriminatory accuracy of large RPLN over high-risk Khorana score was validated in the London cohort (AUROC, 0.61 v 0.57, respectively). CONCLUSION Large RPLN is associated with VTE in patients with disseminated GCT and provides higher discriminatory accuracy than high-risk Khorana score. Results should be validated in larger, prospective studies. Prophylactic anticoagulation may be considered in high-risk patients.

Conditional Risk of Relapse in Surveillance for Clinical Stage I Testicular Cancer

BACKGROUND Patients on surveillance for clinical stage I (CSI) testicular cancer are counseled regarding their baseline risk of relapse. The conditional risk of relapse (cRR), which provides prognostic information on patients who have survived for a period of time without relapse, have not been determined for CSI testicular cancer. OBJECTIVE To determine cRR in CSI testicular cancer. DESIGN, SETTING, AND PARTICIPANTS We reviewed 1239 patients with CSI testicular cancer managed with surveillance at a tertiary academic centre between 1980 and 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: cRR estimates were calculated using the Kaplan-Meier method. We stratified patients according to validated risk factors for relapse. We used linear regression to determine cRR trends over time. RESULTS AND LIMITATIONS At orchiectomy, the risk of relapse within 5 yr was 42.4%, 17.3%, 20.3%, and 12.2% among patients with high-risk nonseminomatous germ cell tumor (NSGCT), low-risk NSGCT, seminoma with tumor size ≥3cm, and seminoma with tumor size <3cm, respectively. However, for patients without relapse within the first 2 yr of follow-up, the corresponding risk of relapse within the next 5 yr in the groups was 0.0%, 1.0% (95% confidence interval [CI] 0.3-1.7%), 5.6% (95% CI 3.1-8.2%), and 3.9% (95% CI 1.4-6.4%). Over time, cRR decreased (p≤0.021) in all models. Limitations include changes to surveillance protocols over time and few late relapses. CONCLUSIONS After 2 yr, the risk of relapse on surveillance for CSI testicular cancer is very low. Consideration should be given to adapting surveillance protocols to individualized risk of relapse based on cRR as opposed to static protocols based on baseline factors. This strategy could reduce the intensity of follow-up for the majority of patients. PATIENT SUMMARY Our study is the first to provide data on the future risk of relapse during surveillance for clinical stage I testicular cancer, given a patient has been without relapse for a specified period of time.

The effect of metformin on cancer-specific survival outcomes in diabetic patients undergoing radical cystectomy for urothelial carcinoma of the bladder

PURPOSE Metformin, a first-line oral therapy for diabetes, has anticancer properties. Our objective was to evaluate the association between metformin use and oncologic outcomes in diabetic patients undergoing radical cystectomy (RC) for bladder cancer (BC). METHODS A single-institution retrospective cohort (January 1997-June 2013) of diabetic patients undergoing RC was assembled. Medication use was assessed at time of surgery. Outcome measures were recurrence-free survival (RFS), BC-specific survival (BCSS), and overall survival (OS). Multivariable Cox proportional hazards models were used. To create parsimonious models, the change of estimate approach (10% threshold) was used as a variable selection strategy for final model inclusion separately for each outcome measure. RESULTS Of 421 patients, 85 (20%) had diabetes. There were 39 (46%) patients on metformin therapy. Among diabetic patients, there were 21 patients with BC recurrence, 16 who died of BC, and 30 who died overall. In univariate analyses, metformin use among diabetic patients was associated with improved RFS (hazard ratio = 0.54, 95% CI: 0.33-0.88, P = 0.013) and trended toward improved BCSS (hazard ratio = 0.65, 95% CI: 0.40-1.07, P = 0.087), but not with OS (P = 0.87). In multivariable models, metformin use among diabetic patients was associated with significantly improved RFS (adjusted hazard ratio = 0.38, 95% CI: 0.20-0.72, P = 0.003) and BCSS (adjusted hazard ratio = 0.57, 95% CI: 0.35-0.91, P = 0.019), but not with OS (P = 0.89). Use of other oral hypoglycemic agents or insulin was not associated with oncologic outcomes. CONCLUSIONS Our study is among the first to report an association between metformin use and improved RFS and BCSS in diabetic patients undergoing RC. Given its low cost and demonstrated safety among nondiabetic patients, further studies are warranted to evaluate potential therapeutic and preventive roles of metformin in BC.

A Phase II, Randomized, Open-Label Study of Neoadjuvant Degarelix versus LHRH Agonist in Prostate Cancer Patients Prior to Radical Prostatectomy

Purpose: Degarelix, a new gonadotropin-releasing hormone (GnRH) receptor antagonist with demonstrated efficacy as first-line treatment in the management of high-risk prostate cancer, possesses some theoretical advantages over luteinizing hormone–releasing hormone (LHRH) analogues in terms of avoiding “testosterone flare” and lower follicle-stimulating hormone (FSH) levels. We set out to determine whether preoperative degarelix influenced surrogates of disease control in a randomized phase II study. Experimental Design: Thirty-nine patients were randomly assigned to one of three different neoadjuvant arms: degarelix only, degarelix/bicalutamide, or LHRH agonist/bicalutamide. Treatments were given for 3 months before prostatectomy. Patients had localized prostate cancer and had chosen radical prostatectomy as primary treatment. The primary end point was treatment effect on intratumoral dihydrotestosterone levels. Results: Intratumoral DHT levels were higher in the degarelix arm than both the degarelix/bicalutamide and LHRH agonist/bicalutamide arms (0.87 ng/g vs. 0.26 ng/g and 0.23 ng/g, P < 0.01). No significant differences existed for other intratumoral androgens, such as testosterone and dehydroepiandrosterone. Patients in the degarelix-only arm had higher AMACR levels on immunohistochemical analysis (P = 0.01). Serum FSH levels were lower after 12 weeks of therapy in both degarelix arms than the LHRH agonist/bicalutamide arm (0.55 and 0.65 vs. 3.65, P < 0.01), and inhibin B levels were lower in the degarelix/bicalutamide arm than the LHRH agonist/bicalutamide arm (82.14 vs. 126.67, P = 0.02). Conclusions: Neoadjuvant degarelix alone, compared with use of LHRH agonist and bicalutamide, is associated with higher levels of intratumoral dihydrotestosterone, despite similar testosterone levels. Further studies that evaluate the mechanisms behind these results are needed. Clin Cancer Res; 23(8); 1974–80. ©2016 AACR.