Browsing by Author "Freedland, Stephen J"

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    5-α reductase inhibitors and prostate cancer prevention: where do we turn now?
    (BMC Med, 2011-09-15) Hamilton, Robert J; Freedland, Stephen J
    With the lifetime risk of being diagnosed with prostate cancer so great, an effective chemopreventive agent could have a profound impact on the lives of men. Despite decades of searching for such an agent, physicians still do not have an approved drug to offer their patients. In this article, we outline current strategies for preventing prostate cancer in general, with a focus on the 5-α-reductase inhibitors (5-ARIs) finasteride and dutasteride. We discuss the two landmark randomized, controlled trials of finasteride and dutasteride, highlighting the controversies stemming from the results, and address the issue of 5-ARI use, including reasons why providers may be hesitant to use these agents for chemoprevention. We further discuss the recent US Food and Drug Administration ruling against the proposed new indication for dutasteride and the change to the labeling of finasteride, both of which were intended to permit physicians to use the drugs for chemoprevention. Finally, we discuss future directions for 5-ARI research.
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    A lifestyle intervention of weight loss via a low-carbohydrate diet plus walking to reduce metabolic disturbances caused by androgen deprivation therapy among prostate cancer patients: carbohydrate and prostate study 1 (CAPS1) randomized controlled trial.
    (Prostate cancer and prostatic diseases, 2019-09) Freedland, Stephen J; Howard, Lauren; Allen, Jenifer; Smith, Jordan; Stout, Jennifer; Aronson, William; Inman, Brant A; Armstrong, Andrew J; George, Daniel; Westman, Eric; Lin, Pao-Hwa

    Purpose

    The objective of this study was to test a low-carbohydrate diet (LCD) plus walking to reduce androgen deprivation therapy (ADT)-induced metabolic disturbances.

    Materials and methods

    This randomized multi-center trial of prostate cancer (PCa) patients initiating ADT was designed to compare an LCD (≤20g carbohydrate/day) plus walking (≥30 min for ≥5 days/week) intervention vs. control advised to maintain usual diet and exercise patterns. Primary outcome was change in insulin resistance by homeostatic model assessment at 6 months. To detect 20% reduction in insulin resistance, 100 men were required. The study was stopped early after randomizing 42 men due to slow accrual. Secondary outcomes included weight, body composition, lipids, and prostate-specific antigen (PSA). Changes from baseline were compared between arms using rank-sum tests.

    Results

    At 6 months, LCD/walking reduced insulin resistance by 4% vs. 36% increase in control (p = 0.13). At 3 months, vs. control, LCD/walking arm significantly lost weight (7.8kg; p<0.001), improved insulin resistance (↑36%; p = 0.015), hemoglobin A1c (↓3.3%; p = 0.01), high-density lipoprotein (HDL) (↑13%; p = 0.004), and triglyceride (↓37%; p = 0.036). At 6 months, weight loss (10.6kg; p<0.001) and HDL (↑27%; p = 0.003) remained significant. LCD/walking preserved total body bone mineral count (p = 0.025), reduced fat mass (p = 0.002), lean mass (p = 0.036), and percent body fat (p = 0.004). There were no differences in PSA. Limitations include the effect of LCD, weight loss vs. walking instruction are indistinguishable, and small sample size.

    Conclusions

    In an underpowered study, LCD/walking did not improve insulin sensitivity at 6 months. Given most secondary outcomes were improved at 3 months with some remaining improved at 6 months and a secondary analysis showed that LCD/walking reduced insulin resistance over the study, supporting future larger studies of LCD/walking intervention to reduce ADT-induced disturbances.
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    Associations between Intake of Folate, Methionine, and Vitamins B-12, B-6 and Prostate Cancer Risk in American Veterans.
    (J Cancer Epidemiol, 2012) Vidal, Adriana C; Grant, Delores J; Williams, Christina D; Masko, Elizabeth; Allott, Emma H; Shuler, Kathryn; McPhail, Megan; Gaines, Alexis; Calloway, Elizabeth; Gerber, Leah; Chi, Jen-Tsan; Freedland, Stephen J; Freedland, Stephen J; Hoyo, Cathrine
    Prostate cancer (PC) is the second leading cause of cancer death in men. Recent reports suggest that excess of nutrients involved in the one-carbon metabolism pathway increases PC risk; however, empirical data are lacking. Veteran American men (272 controls and 144 PC cases) who attended the Durham Veteran American Medical Center between 2004-2009 were enrolled into a case-control study. Intake of folate, vitamin B12, B6, and methionine were measured using a food frequency questionnaire. Regression models were used to evaluate the association among one-carbon cycle nutrients, MTHFR genetic variants, and prostate cancer. Higher dietary methionine intake was associated with PC risk (OR = 2.1; 95%CI 1.1-3.9) The risk was most pronounced in men with Gleason sum <7 (OR = 2.75; 95%CI 1.32- 5.73). The association of higher methionine intake and PC risk was only apparent in men who carried at least one MTHFR A1298C allele (OR = 6.7; 95%CI = 1.6-27.8), compared to MTHFR A1298A noncarrier men (OR = 0.9; 95%CI = 0.24-3.92) (p-interaction = 0.045). There was no evidence for associations between B vitamins (folate, B12, and B6) and PC risk. Our results suggest that carrying the MTHFR A1298C variants modifies the association between high methionine intake and PC risk. Larger studies are required to validate these findings.
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    Bone scan positivity in non-metastatic, castrate-resistant prostate cancer: external validation study.
    (International braz j urol : official journal of the Brazilian Society of Urology, 2020-01) Johnston, Ashley W; Longo, Thomas A; Davis, Leah Gerber; Zapata, Daniel; Freedland, Stephen J; Routh, Jonathan C

    Introduction

    Tables predicting the probability of a positive bone scan in men with non-metastatic, castrate-resistant prostate cancer have recently been reported. We performed an external validation study of these bone scan positivity tables.

    Materials and methods

    We performed a retrospective cohort study of patients seen at a tertiary care medical center (1996-2012) to select patients with non-metastatic, castrate-resistant prostate cancer. Abstracted data included demographic, anthropometric, and disease-specific data such as patient race, BMI, PSA kinetics, and primary treatment. Primary outcome was metastasis on bone scan. Multivariable logistic regression was performed using generalized estimating equations to adjust for repeated measures. Risk table performance was assessed using ROC curves.

    Results

    We identified 6.509 patients with prostate cancer who had received hormonal therapy with a post-hormonal therapy PSA ≥2ng/mL, 363 of whom had non-metastatic, castrate-resistant prostate cancer. Of these, 187 patients (356 bone scans) had calculable PSA kinetics and ≥1 bone scan. Median follow-up after castrate-resistant prostate cancer diagnosis was 32 months (IQR: 19-48). There were 227 (64%) negative and 129 (36%) positive bone scans. On multivariable analysis, higher PSA at castrate-resistant prostate cancer (4.67 vs. 4.4ng/mL, OR=0.57, P=0.02), shorter time from castrate-resistant prostate cancer to scan (7.9 vs. 14.6 months, OR=0.97, P=0.006) and higher PSA at scan (OR=2.91, P<0.0001) were significantly predictive of bone scan positivity. The AUC of the previously published risk tables for predicting scan positivity was 0.72.

    Conclusion

    Previously published risk tables predicted bone scan positivity in men with non-metastatic, castrate-resistant prostate cancer with reasonable accuracy.
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    Importance of prostate volume in the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculators: results from the prostate biopsy collaborative group.
    (World J Urol, 2012-04) Roobol, Monique J; Schröder, FH; Hugosson, Jonas; Jones, J Stephen; Kattan, Michael W; Klein, Eric A; Hamdy, Freddie; Neal, David; Donovan, Jenny; Parekh, Dipen J; Ankerst, Donna; Bartsch, George; Klocker, Helmut; Horninger, Wolfgang; Benchikh, Amine; Salama, Gilles; Villers, Arnauld; Freedland, Stephen J; Moreira, Daniel M; Vickers, Andrew J; Lilja, Hans; Steyerberg, Ewout W
    OBJECTIVES: To compare the predictive performance and potential clinical usefulness of risk calculators of the European Randomized Study of Screening for Prostate Cancer (ERSPC RC) with and without information on prostate volume. METHODS: We studied 6 cohorts (5 European and 1 US) with a total of 15,300 men, all biopsied and with pre-biopsy TRUS measurements of prostate volume. Volume was categorized into 3 categories (25, 40, and 60 cc), to reflect use of digital rectal examination (DRE) for volume assessment. Risks of prostate cancer were calculated according to a ERSPC DRE-based RC (including PSA, DRE, prior biopsy, and prostate volume) and a PSA + DRE model (including PSA, DRE, and prior biopsy). Missing data on prostate volume were completed by single imputation. Risk predictions were evaluated with respect to calibration (graphically), discrimination (AUC curve), and clinical usefulness (net benefit, graphically assessed in decision curves). RESULTS: The AUCs of the ERSPC DRE-based RC ranged from 0.61 to 0.77 and were substantially larger than the AUCs of a model based on only PSA + DRE (ranging from 0.56 to 0.72) in each of the 6 cohorts. The ERSPC DRE-based RC provided net benefit over performing a prostate biopsy on the basis of PSA and DRE outcome in five of the six cohorts. CONCLUSIONS: Identifying men at increased risk for having a biopsy detectable prostate cancer should consider multiple factors, including an estimate of prostate volume.
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    Novel associations of UDP-glucuronosyltransferase 2B gene variants with prostate cancer risk in a multiethnic study.
    (BMC Cancer, 2013-11-22) Vidal, Adriana C; Tucker, Cocoa; Schildkraut, Joellen M; Richardson, Ricardo M; McPhail, Megan; Freedland, Stephen J; Hoyo, Cathrine; Grant, Delores J
    BACKGROUND: We have previously shown that a functional polymorphism of the UGT2B15 gene (rs1902023) was associated with increased risk of prostate cancer (PC). Novel functional polymorphisms of the UGT2B17 and UGT2B15 genes have been recently characterized by in vitro assays but have not been evaluated in epidemiologic studies. METHODS: Fifteen functional SNPs of the UGT2B17 and UGT2B15 genes, including cis-acting UGT2B gene SNPs, were genotyped in African American and Caucasian men (233 PC cases and 342 controls). Regression models were used to analyze the association between SNPs and PC risk. RESULTS: After adjusting for race, age and BMI, we found that six UGT2B15 SNPs (rs4148269, rs3100, rs9994887, rs13112099, rs7686914 and rs7696472) were associated with an increased risk of PC in log-additive models (p < 0.05). A SNP cis-acting on UGT2B17 and UGT2B15 expression (rs17147338) was also associated with increased risk of prostate cancer (OR = 1.65, 95% CI = 1.00-2.70); while a stronger association among men with high Gleason sum was observed for SNPs rs4148269 and rs3100. CONCLUSIONS: Although small sample size limits inference, we report novel associations between UGT2B15 and UGT2B17 variants and PC risk. These associations with PC risk in men with high Gleason sum, more frequently found in African American men, support the relevance of genetic differences in the androgen metabolism pathway, which could explain, in part, the high incidence of PC among African American men. Larger studies are required.
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    Serum metabolomic analysis of men on a low-carbohydrate diet for biochemically recurrent prostate cancer reveals the potential role of ketogenesis to slow tumor growth: a secondary analysis of the CAPS2 diet trial
    (Prostate Cancer and Prostatic Diseases) Chi, Jen-Tsan; Lin, Pao-Hwa; Tolstikov, Vladimir; Howard, Lauren; Chen, Emily Y; Bussberg, Valerie; Greenwood, Bennett; Narain, Niven R; Kiebish, Michael A; Freedland, Stephen J