Cathee Till

Men with Low Serum Cholesterol Have a Lower Risk of High-Grade Prostate Cancer in the Placebo Arm of the Prostate Cancer Prevention Trial

Background: Several prospective studies suggest that use of cholesterol-lowering statin drugs is inversely associated with advanced stage and possibly high-grade prostate cancer. One study reported that men with low cholesterol had a lower risk of high-grade prostate cancer. Given these findings, we investigated the association between low serum cholesterol and prostate cancer risk in the Prostate Cancer Prevention Trial. Methods: We conducted a cohort study of 5,586 men ages ≥55 years who were randomized to the placebo arm of the Prostate Cancer Prevention Trial between 1993 and 1996. Serum cholesterol was measured enzymatically at entry. By the end of follow-up, 1,251 prostate cancer cases were confirmed. We used logistic regression to calculate the multivariable odds ratio (OR) of total, and Gleason 2 to 6 (n = 993), 7 (n = 199), and 8 to 10 (n = 59) prostate cancer comparing low serum (normal, <200 mg/dL) to high-serum (borderline and elevated cholesterol, ≥200 mg/dL) cholesterol. Results: Men with low cholesterol had a lower risk of Gleason 8 to 10 prostate cancer [OR, 0.41; 95% confidence interval (CI), 0.22-0.77] than men with high cholesterol. No association was present for prostate cancer overall (OR, 0.97; 95% CI, 0.85-1.11), Gleason 2 to 6 disease (OR, 1.03; 95% CI, 0.89-1.18), or Gleason 7 disease (OR, 0.93; 95% CI, 0.69-1.24). Conclusion: These prospective results support that men with low cholesterol have a reduced risk of high-grade prostate cancer. These and other contemporary data that suggest that cholesterol metabolism should be investigated further in the etiology of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2807–13)

An Empirical Evaluation of Guidelines on Prostate-specific Antigen Velocity in Prostate Cancer Detection

BACKGROUND The National Comprehensive Cancer Network and American Urological Association guidelines on early detection of prostate cancer recommend biopsy on the basis of high prostate-specific antigen (PSA) velocity, even in the absence of other indications such as an elevated PSA or a positive digital rectal exam (DRE). METHODS To evaluate the current guideline, we compared the area under the curve of a multivariable model for prostate cancer including age, PSA, DRE, family history, and prior biopsy, with and without PSA velocity, in 5519 men undergoing biopsy, regardless of clinical indication, in the control arm of the Prostate Cancer Prevention Trial. We also evaluated the clinical implications of using PSA velocity cut points to determine biopsy in men with low PSA and negative DRE in terms of additional cancers found and unnecessary biopsies conducted. All statistical tests were two-sided. RESULTS Incorporation of PSA velocity led to a very small increase in area under the curve from 0.702 to 0.709. Improvements in predictive accuracy were smaller for the endpoints of high-grade cancer (Gleason score of 7 or greater) and clinically significant cancer (Epstein criteria). Biopsying men with high PSA velocity but no other indication would lead to a large number of additional biopsies, with close to one in seven men being biopsied. PSA cut points with a comparable specificity to PSA velocity cut points had a higher sensitivity (23% vs 19%), particularly for high-grade (41% vs 25%) and clinically significant (32% vs 22%) disease. These findings were robust to the method of calculating PSA velocity. CONCLUSIONS We found no evidence to support the recommendation that men with high PSA velocity should be biopsied in the absence of other indications; this measure should not be included in practice guidelines.

Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial

Inflammation may be involved in prostate cancer development and progression. This study examined the associations between inflammation-related phospholipid fatty acids and the 7-year-period prevalence of prostate cancer in a nested case-control analysis of participants, aged 55-84 years, in the Prostate Cancer Prevention Trial during 1994-2003. Cases (n = 1,658) were frequency matched to controls (n = 1,803) on age, treatment, and prostate cancer family history. Phospholipid fatty acids were extracted from serum, and concentrations of ω-3, ω-6, and trans-fatty acids (TFAs) were expressed as proportions of the total. Logistic regression models estimated odds ratios and 95% confidence intervals of associations of fatty acids with prostate cancer by grade. No fatty acids were associated with low-grade prostate cancer risk. Docosahexaenoic acid was positively associated with high-grade disease (quartile 4 vs. 1: odds ratio (OR) = 2.50, 95% confidence interval (CI): 1.34, 4.65); TFA 18:1 and TFA 18:2 were linearly and inversely associated with risk of high-grade prostate cancer (quartile 4 vs. 1: TFA 18:1, OR = 0.55, 95% CI: 0.30, 0.98; TFA 18:2, OR = 0.48, 95% CI: 0.27, 0.84). The study findings are contrary to those expected from the pro- and antiinflammatory effects of these fatty acids and suggest a greater complexity of effects of these nutrients with regard to prostate cancer risk.

Trichomonosis and subsequent risk of prostate cancer in the Prostate Cancer Prevention Trial

We previously observed a positive association between a history of trichomonosis, a sexually transmitted infection caused by the protozoan, Trichomonas vaginalis, and prostate cancer risk in the Health Professionals Follow‐up Study. To determine the reproducibility of this finding, we conducted a second, prospective investigation of trichomonosis and prostate cancer in the Prostate Cancer Prevention Trial. Participants were men (≥55 years of age) with no evidence of prostate cancer at enrollment (n = 18,882). Men were screened annually for prostate cancer, and if not diagnosed during the trial, were offered an end‐of‐study prostate biopsy. Cases were a sample of men diagnosed with prostate cancer on any biopsy after visit 2 or on their end‐of‐study biopsy (n = 616). Controls were men not diagnosed with prostate cancer during the trial or on their end‐of‐study biopsy (n = 616). Controls were frequency‐matched to cases by age, treatment arm, and family history of prostate cancer. Serum from visit 2 was tested for anti‐T. vaginalis IgG antibodies. No association was observed between T. vaginalis serostatus and prostate cancer. 21.5% of cases and 24.8% of controls had low seropositivity, and 15.2% and 15.0% had high seropositivity. Compared to seronegative men, the odds ratio of prostate cancer for men with low seropositivity was 0.83 [95% confidence interval (CI): 0.63–1.09), and that for men with high seropositivity was 0.97 (95% CI: 0.70–1.34). Given the original strong biologic rationale and potential for prevention, additional studies are warranted to help resolve discrepancies between study findings and to further investigate this hypothesis from a variety of different approaches.

Plasma Vitamin D and Prostate Cancer Risk; Results from the Selenium and Vitamin E Cancer Prevention Trial

Background: In vitro, animal, and ecological studies suggest that inadequate vitamin D intake could increase prostate cancer risk, but results of biomarker-based longitudinal studies are inconsistent. Methods: Data for this case (n = 1,731) and cohort (n = 3,203) analysis are from the Selenium and Vitamin E Cancer Prevention Trial. Cox proportional hazard models were used to test whether baseline plasma vitamin D (25-hydroxy) concentration, adjusted for season of blood collection, was associated with the risk of total and Gleason score 2–6, 7–10, and 8–10 prostate cancer. Results: There were U-shaped associations of vitamin D with total cancer risk: compared with the first quintile, HRs were 0.83 [95% confidence interval (CI), 0.66–1.03; P = 0.092], 0.74 (95% CI, 0.59–0.92; P = 0.008), 0.86 (95% CI, 0.69–1.07; P = 0.181), and 0.98 (95% CI, 0.78–1.21; P = 0.823), for the second through fifth quintiles, respectively. For Gleason 7–10 cancer, corresponding HRs were 0.63 (95% CI, 0.45–0.90; P = 0.010), 0.66 (95% CI, 0.47–0.92; P = 0.016), 0.79 (95% CI, 0.56–1.10; P = 0.165), and 0.88 (95% CI, 0.63–1.22; P = 0.436). Among African American men (n = 250 cases), higher vitamin D was associated with reduced risk of Gleason 7–10 cancer only: in the a posteriori contrast of quintiles 1–2 versus 3–5, the HR was 0.55 (95% CI, 0.31–0.97; P = 0.037), with no evidence of dose–response or a U-shaped association. Conclusions: Both low and high vitamin D concentrations were associated with increased risk of prostate cancer, and more strongly for high-grade disease. Impact: The optimal range of circulating vitamin D for prostate cancer prevention may be narrow. Supplementation of men with adequate levels may be harmful. Cancer Epidemiol Biomarkers Prev; 23(8); 1494–504. ©2014 AACR.

Comorbidities and Risk of Chemotherapy-Induced Peripheral Neuropathy Among Participants 65 Years or Older in Southwest Oncology Group Clinical Trials

BACKGROUND Neuropathy is a debilitating toxicity associated with various chemotherapy agents. We evaluated the association between common comorbid conditions and the development of peripheral neuropathy in patients treated with taxane-based chemotherapy. METHODS We examined the Southwest Oncology Group database to identify phase II and III trials that included taxane therapy from 1999 to 2011. We linked the Southwest Oncology Group clinical records to Medicare claims data according to Social Security number, sex, and date of birth. The following disease conditions potentially associated with peripheral neuropathy were evaluated: diabetes, hypothyroidism, hypercholesterolemia, hypertension, varicella zoster, peripheral vascular disease, and autoimmune diseases. Multivariate logistic regression was used to model the odds of experiencing grade 2 to 4 neuropathy. RESULTS A total of 1,401 patients from 23 studies were included in the analysis. Patients receiving paclitaxel were more likely to experience grade 2 to 4 neuropathy compared with docetaxel (25% v 12%, respectively; OR, 2.20; 95% CI, 1.52 to 3.18; P < .001). The inclusion of a platinum agent was also associated with greater neuropathy (OR, 1.68; 95% CI, 1.18 to 2.40; P = .004). For each increase in age of 1 year, the odds of neuropathy increased 4% (P = .006). Patients with complications from diabetes had more than twice the odds of having neuropathy (OR, 2.13; 95% CI, 1.31 to 3.46; P = .002) compared with patients with no diabetes. In contrast, patients with autoimmune disease were half as likely to experience neuropathy (OR, 0.49; 95% CI, 0.24 to 1.02; P = .06). The other conditions were not associated with neuropathy. CONCLUSION We found that in addition to drug-related factors, age and history of diabetes were independent predictors of the development of chemotherapy-induced peripheral neuropathy. Interestingly, we also observed that a history of autoimmune disease was associated with reduced odds of neuropathy. Patients with diabetic complications may choose to avoid paclitaxel or taxane plus platinum combination therapies if other efficacious options exist.

Serum 25-Hydroxyvitamin D Concentrations and Risk of Prostate Cancer: Results from the Prostate Cancer Prevention Trial

Background: Epidemiologic studies have reported inconsistent associations of vitamin D and prostate cancer risk; however, few have adequately controlled for detection bias related to prostate-specific antigen (PSA) screening, and the results of many studies may be affected by occult prostate cancers among controls. Methods: Data for this nested case–control analysis (n = 1,695 cases/1,682 controls) are from the Prostate Cancer Prevention Trial. Baseline serum was analyzed for 25-hydroxyvitamin D [25(OH)D]. The presence or absence of cancer was subsequently determined by prostate biopsy. Polytomous logistic regression models were used to estimate associations of 25(OH)D with risk of total, Gleason 2–6, Gleason 7, and Gleason 8–10 prostate cancer. Results are presented for placebo and finasteride arms separately and combined. Results: There were no associations of serum 25(OH)D with total prostate cancer risk. For Gleason 2–6 cancers, results were inconsistent across treatment arms with a suggestion of increased risk in the placebo arm only; however, there was no dose–response relationship. For Gleason 8–10 prostate cancers, 25(OH)D concentrations were associated with a linear decrease in risk among combined treatment arms [quartile 4 vs. 1: OR, 0.55; 95% confidence interval (CI), 0.32–0.94; Ptrend = 0.04]. These findings were somewhat stronger among men ≥65 versus 55–64 years at baseline (quartile 4 vs. 1: OR, 0.40; 95% CI, 0.18–0.88 vs. OR, 0.73; 95% CI, 0.35–1.52, respectively; Pinteraction = 0.52). Conclusions: Higher serum 25(OH)D may modestly increase risk of Gleason 2–6 disease and more substantially reduce risk of Gleason 8–10 prostate cancer. Impact: Vitamin D may have different effects for different stages of prostate cancers. Cancer Epidemiol Biomarkers Prev; 23(8); 1484–93. ©2014 AACR.

Finasteride Reduces the Risk of Incident Clinical Benign Prostatic Hyperplasia

BACKGROUND Despite the high prevalence of clinical benign prostatic hyperplasia (BPH) among older men, there remains a notable absence of studies focused on BPH prevention. OBJECTIVE To determine if finasteride prevents incident clinical BPH in healthy older men. DESIGN, SETTING, AND PARTICIPANTS Data for this study are from the Prostate Cancer Prevention Trial. After excluding those with a history of BPH diagnosis or treatment, or an International Prostate Symptom Score (IPSS) ≥ 8 at study entry, 9253 men were available for analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome was incident clinical BPH, defined as the initiation of medical treatment, surgery, or sustained, clinically significant urinary symptoms (IPSS >14). Finasteride efficacy was estimated using Cox proportional regression models to generate hazards ratios (HRs). RESULTS AND LIMITATIONS Mean length of follow-up was 5.3 yr. The rate of clinical BPH was 19 per 1000 person-years in the placebo arm and 11 per 1000 person-years in the finasteride arm (p<0.001). In a covariate-adjusted model, finasteride reduced the risk of incident clinical BPH by 40% (HR: 0.60; 95% confidence interval, 0.51-0.69; p<0.001). The effect of finasteride on incident clinical BPH was attenuated in men with a body mass index ≥ 30 kg/m(2) (p(interaction) = 0.04) but otherwise did not differ significantly by physical activity, age, race, current diabetes, or current smoking. The post hoc nature of the analysis is a potential study limitation. CONCLUSIONS Finasteride substantially reduces the risk of incident clinical BPH in healthy older men. These results should be considered in formulating recommendations for the use of finasteride to prevent prostate diseases in asymptomatic older men.

Adverse Health Events Following Intermittent and Continuous Androgen Deprivation in Patients With Metastatic Prostate Cancer

IMPORTANCE Although intermittent androgen-deprivation therapy (ADT) has not been associated with better overall survival in prostate cancer (PC), it has the potential for lower adverse effects. To our knowledge, the incidence of long-term adverse health events has not been reported. OBJECTIVE To examine long-term late events in elderly patients randomized to intermittent or continuous ADT to determine whether late cardiovascular and endocrine events would be lower in patients treated with intermittent ADT. DESIGN, SETTING, AND PARTICIPANTS This was a secondary analysis of a multicenter clinical trial using linkage between patient data from S9346, a randomized SWOG trial of intermittent vs continuous ADT in men with metastatic PC, and corresponding Medicare claims. EXPOSURE Intermittent or continuous ADT. MAIN OUTCOMES AND MEASURES The main outcome was to identify long-term adverse health events by treatment arm. Patients were classified as having an adverse health event if they had any hospital claim--or at least 2 physician or outpatient claims at least 30 days apart--for any of the following diagnoses: ischemic and thrombotic events, endocrine events, sexual dysfunction, dementia, and depression. To incorporate time from beginning of observation through evidence of an event, we determined the cumulative incidence of each event. Competing risks Cox regression was used, adjusting for covariates. RESULTS In total, 1134 eligible US-based male patients with metastatic PC were randomized to continuous vs intermittent ADT in the S9346 trial. A total of 636 of trial participants (56%) had at least 1 year of continuous Medicare parts A and B coverage and no health maintenance organization participation. The median age was 71.3 years. The most common long-term events were hypercholesterolemia (31%) and osteoporosis (19%). The 10-year cumulative incidence of ischemic and thrombotic events differed by arm; 24% for continuous and 33%for intermittent ADT (hazard ratio, 0.69; P = .02). There were no statistically significant differences by arm in any other adverse health events. CONCLUSIONS AND RELEVANCE Contrary to our hypothesis that intermittent ADT would reduce long-term health-related events compared with continuous ADT, we found that older men assigned to intermittent ADT had no apparent reduction in bone, endocrine, or cognitive events and an increased incidence of ischemic and thrombotic events. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00002651.

Plasma tocopherols and risk of prostate cancer in the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed higher prostate cancer incidence in men supplemented with high-dose α-tocopherol. We, therefore, examined whether presupplementation plasma α-tocopherol or γ-tocopherol was associated with overall or high-grade prostate cancer. A stratified case–cohort sample that included 1,746 incident prostate cancer cases diagnosed through June 2009 and a subcohort of 3,211 men was derived from the SELECT trial of 35,533 men. Plasma was collected at entry from 2001 to 2004, and median follow-up was 5.5 years (range, 0–7.9 years). Incidence of prostate cancer as a function of plasma α-tocopherol, γ-tocopherol, and supplementation with α-tocopherol or selenomethionine was estimated by the hazard ratio (HR). Plasma γ-tocopherol was not associated with prostate cancer. Men with higher α-tocopherol concentrations seemed to have risk similar to that of men with lower concentrations [overall HR for fifth (Q5) vs. first quintile (Q1), 1.21; 95 % confidence interval (CI), 0.88–1.66; P-trend = 0.24; in the trial placebo arm, Q5 HR, 0.85; 95% CI, 0.44–1.62; P-trend = 0.66]. We found a strong positive plasma α-tocopherol association among men receiving the trial selenomethionine supplement [Q5 HR, 2.04; 95% CI, 1.29–3.22; P-trend = 0.005]. A positive plasma α-tocopherol–prostate cancer association also seemed limited to high-grade disease (Gleason grade, 7–10; overall Q5 HR, 1.59; 95% CI, 1.13–2.24; P-trend = 0.001; among men receiving selenomethionine, Q5 HR, 2.12; 95% CI, 1.32–3.40; P-trend = 0.0002). Our findings indicate that higher plasma α-tocopherol concentrations may interact with selenomethionine supplements to increase high-grade prostate cancer risk, suggesting a biologic interaction between α-tocopherol and selenium itself or selenomethionine. Cancer Prev Res; 7(9); 886–95. ©2014 AACR.