Karen Hersey

Impact of Multiparametric Endorectal Coil Prostate Magnetic Resonance Imaging on Disease Reclassification Among Active Surveillance Candidates: A Prospective Cohort Study

PURPOSE We report magnetic resonance imaging findings among unselected men with low risk prostate cancer before active surveillance. MATERIALS AND METHODS We prospectively enrolled men with low grade, low risk, localized prostate cancer. All patients underwent multiparametric endorectal coil magnetic resonance imaging and were offered confirmatory biopsy within 1 year of imaging. The primary outcome was the impact of magnetic resonance imaging on identifying patients who were reclassified by confirmatory biopsy as no longer fulfilling active surveillance criteria. We further identified clinical parameters associated with reclassification. The cohort was stratified as patients with 1) normal magnetic resonance imaging, 2) cancer on magnetic resonance imaging concordant with initial biopsy (less than 1 cm) and 3) cancer on magnetic resonance imaging larger than 1 cm. We performed univariate analysis to assess differences in clinical parameters among the groups. RESULTS Magnetic resonance imaging did not detect cancer in 23 cases (38%) while magnetic resonance imaging and initial biopsy were concordant in 24 (40%). Magnetic resonance imaging detected a 1 cm or larger lesion in 13 patients (22%). Of the cases 18 (32.14%) were reclassified. When no cancer was identified on magnetic resonance imaging, only 2 cases (3.5%) were reclassified. The positive and negative predictive values for magnetic resonance imaging predicting reclassification were 83% (95% CI 73-93) and 81% (95% CI 71-91), respectively. Prostate specific antigen density was increased in patients with lesions larger than 1 cm on magnetic resonance imaging compared to those with no cancer on imaging (median 0.15 vs 0.07 ng/ml/cc, p=0.016). CONCLUSIONS Magnetic resonance imaging appears to have a high yield for predicting reclassification among men who elect active surveillance. Upon confirmation of our results magnetic resonance imaging may be used to better select and guide patients before active surveillance.

Dissecting the association between metabolic syndrome and prostate cancer risk: analysis of a large clinical cohort.

BACKGROUND A biologic rationale exists for the association between metabolic syndrome (MetS) and prostate cancer (PCa). However, epidemiologic studies have been conflicting. OBJECTIVE To evaluate the association between MetS and the odds of PCa diagnosis in men referred for biopsy. DESIGN, SETTING, AND PARTICIPANTS Patients without prior PCa diagnosis undergoing prostate biopsy were identified from a large prostate biopsy cohort (in Toronto, Canada). The definition of MetS was based on the most recent interim joint consensus definition, requiring any three of five components (obesity, elevated blood pressure, diabetes or impaired fasting glucose, low high-density lipoprotein-cholesterol, and hypertriglyceridemia). Both the individual components of MetS and the cumulative number of MetS components were evaluated. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The outcomes were PCa detection overall, clinically significant PCa (CSPC; defined as any Gleason pattern ≥ 4, >50% involvement of a single biopsy core, or more than one of three total number of cores involved), and intermediate- or high-grade PCa (I-HGPC; Gleason 7-10). Tests for trend and multivariable logistic regression analyses were performed. RESULTS AND LIMITATIONS Of 2235 patients, 494 (22.1%) had MetS. No individual MetS component was independently associated with PCa. However, increasing number of MetS components was associated with higher PCa grade (p<0.001), as well as progressively higher odds of PCa outcomes (three or more; ie, MetS) compared with no MetS components: Odds ratios were 1.54 for PCa overall (95% confidence interval [CI], 1.17-2.04; p=0.002), 1.56 for CSPC (95% CI, 1.17-2.08; p=0.002), and 1.56 for I-HGPC (95% CI, 1.16-2.10; p=0.003) in multivariable analyses. The main limitation is the retrospective design. CONCLUSIONS Although the individual MetS components are not independently associated with PCa outcomes, MetS is significantly associated with higher odds of PCa diagnosis, CSPC, and I-HGPC. There is a biologic gradient between the number of MetS components and the risk of PCa, as well as cancer grade. PATIENT SUMMARY Metabolic syndrome is a collection of metabolic abnormalities that increases ones risk for heart disease. Our study shows that an increasing degree of metabolic abnormality is also associated with an increased risk of diagnosis of overall and aggressive prostate cancer.

Progression From High-Grade Prostatic Intraepithelial Neoplasia to Cancer: A Randomized Trial of Combination Vitamin-E, Soy, and Selenium

PURPOSE High-grade prostatic intraepithelial neoplasia (HGPIN) is a putative precursor of invasive prostate cancer (PCa). Preclinical evidence suggests vitamin E, selenium, and soy protein may prevent progression of HGPIN to PCa. This hypothesis was tested in a randomized phase III double-blind study of daily soy (40 g), vitamin E (800 U), and selenium (200 μg) versus placebo. PATIENTS AND METHODS Three hundred three men in 12 Canadian centers were analyzed. The main eligibility criterion was confirmed HGPIN in at least one of two biopsies within 18 months of random assignment. Treatment was administered daily for 3 years. Follow-up prostate biopsies occurred at 6, 12, 24, and 36 months postrandomization. The primary end point was time to development of invasive PCa. Kaplan-Meier plots and log-rank tests were used to compare two treatment groups for this end point. RESULTS For all patients, the median age was 62.8 years. The median baseline prostate-specific antigen (PSA; n = 302) was 5.41 ug/L; total testosterone (n = 291) was 13.4 nmol/L. Invasive PCa developed among 26.4% of patients. The hazard ratio for the nutritional supplement to prevent PCa was 1.03 (95% CI, 0.67 to 1.60; P = .88). Gleason score distribution was similar in both groups with 83.5% of cancers graded Gleason sum of 6. Baseline age, weight, PSA, and testosterone did not predict for development of PCa. The supplement was well tolerated with flatulence reported more frequently (27% v 17%) among men receiving micronutrients. CONCLUSION This trial does not support the hypothesis that combination vitamin E, selenium, and soy prevents progression from HGPIN to PCa.

Randomized clinical trial of vitamin D3 doses on prostatic vitamin D metabolite levels and ki67 labeling in prostate cancer patients.

CONTEXT Vitamin D3 might benefit prostate cancer (PCa) patients because prostate cells can locally synthesize the active hormone calcitriol. OBJECTIVE Our objective was to determine the effects of oral vitamin D3 on vitamin D metabolites and PCa proliferative activity in prostate tissue. DESIGN AND SETTING We conducted a double-blind randomized clinical trial at surgical oncology clinics in Toronto, Canada. PATIENTS PCa patients (Gleason 6 or 7) participated in the study. Of 66 subjects who were enrolled, 63 completed the dosing protocol. INTERVENTION Vitamin D3 (400, 10 000, or 40 000 IU/d) was orally administered before radical prostatectomy. MAIN OUTCOME MEASURES We evaluated vitamin D metabolite levels and Ki67 labeling in surgical prostate tissue. Safety measures, PTH, and prostate-specific antigen (PSA) were also assessed. RESULTS Prostate tissue and serum levels of vitamin D metabolites, including calcitriol, increased dose dependently (P < .03) and were significantly higher in the 40 000-IU/d group than in every other dose group (P < .03). Prostate vitamin D metabolites correlated positively with serum levels (P < .0001). Ki67 measures did not differ significantly among vitamin D dose groups. However, cross-sectional analysis indicated that the calcitriol level attained in prostate was inversely associated with Ki67 intensity and Ki67 (3+) percent positive nuclei in PCa and benign tissue (P < .05). Safety measures did not change adversely with dosing. Compared with the 400-IU/d group, serum PTH and PSA were lower in the combined higher-dose groups at the end of the study (P < .02). CONCLUSIONS Oral vitamin D3 raised prostate calcitriol levels (level 1 evidence) and modestly lowered both PSA and PTH. Although Ki67 expression did not differ among dose groups, its levels correlated inversely with prostate calcitriol. These suggestions of clinical benefit justify continued clinical research.

Obesity Is Associated with Risk of Progression for Low-risk Prostate Cancers Managed Expectantly

BACKGROUND Active surveillance (AS) is an expectant management strategy for prostate cancer (PCa). The impact of obesity on progression is not well characterized in this population. OBJECTIVE To determine if obesity is associated with progression in men on AS for low-risk PCa. DESIGN, SETTING, AND PARTICIPANTS Men undergoing AS for low-risk PCa (no Gleason pattern ≥4, three or fewer cores involved or one-third or less of the total number of cores involved, and no core with >50% cancer involvement) were identified at our institution. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The outcomes were pathologic progression (defined as no longer meeting low-risk criteria on follow-up biopsy) and therapeutic progression (defined as intent to initiate active treatment). Kaplan-Meier curves and multivariable logistic regression and Cox proportional hazards models were used, with separate models for reclassification at confirmatory biopsy (first biopsy after diagnostic biopsy) and progression beyond confirmatory biopsy. RESULTS AND LIMITATIONS In this cohort of 565 men (median follow-up: 48 mo), 124 (22%) were obese (body mass index [BMI] ≥30kg/m(2)). Pathologic and therapeutic progression occurred in 168 men (30%) and 172 men (30%), respectively. No association was noted between obesity and risk of progression at the confirmatory biopsy. However, beyond confirmatory biopsy, obesity was associated with a greater probability of pathologic progression (p=0.007) and therapeutic progression (p=0.007) in Kaplan-Meier analyses. In adjusted Cox models, each 5-unit increase in BMI was associated with an increased risk of pathologic progression (hazard ratio [HR]: 1.5; 95% confidence interval [CI], 1.1-2.1; p=0.02) and therapeutic progression (HR: 1.4; 95% CI, 1.0-1.9; p=0.05). The main limitation is the retrospective design, limiting the ability to assess BMI changes over time. CONCLUSIONS Obesity was associated with a significantly increased risk of progression beyond the confirmatory biopsy. This suggests an increased risk of long-term biologic progression rather than solely misclassification. PATIENT SUMMARY As opposed to immediate active treatment (surgery or radiation), active surveillance (AS) involves closely monitoring low-risk prostate cancers and only using active treatment if there are signs of progression. Our study is the first to suggest that obesity is associated with a higher risk of cancer progression while on AS. Further research is needed to determine if diet and exercise can decrease the risk of cancer progression while on AS.

Measurement of peri‐prostatic fat thickness using transrectal ultrasonography (TRUS): a new risk factor for prostate cancer

Study Type – Prognosis (cohort)

A phase I trial of pre-operative radiotherapy for prostate cancer: clinical and translational studies.

BACKGROUND AND PURPOSE Selected patients undergoing radical prostatectomy for localized prostate cancer can be at high-risk for pT3 disease and require subsequent radiotherapy. In a phase I trial, we investigated the feasibility of pre-operative radiotherapy for this patient subset. MATERIALS AND METHODS Eligibility criteria were: T1/T2N0M0 tumors plus (i) Gleason >or=7, PSA>10 ng/ml and <35 ng/ml, or (ii), PSA >15 ng/ml and less <35 ng/ml (any Gleason). Patients received 25 Gy in five fractions of radiotherapy followed by radical prostatectomy. Trial endpoints included intra-operative morbidity and late toxicity following combined treatment. We also stained pre- and post-radiotherapy prostate samples for DNA damage response proteins. RESULTS Between 2001 and 2004, 15 patients were entered on trial. Thirteen patients completed combined-modality treatment. Only one patient had signs of intra-operative inflammation. No patient had post-operative complication. There was no severe late gastrointestinal toxicity. Late genitourinary toxicity consisted of severe urinary incontinence in 2 of 13 patients. From a translational standpoint, irradiated prostate tumor tissues had long-term activation of the CDK-inhibitor p21(WAF) associated with reduced cell proliferation. CONCLUSION Intra-operative morbidity is low following short-course, pre-operative radiotherapy. A phase II trial is planned to fully document biochemical response with this combined-modality approach.

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.

Recovery of erectile function after unilateral and bilateral cavernous nerve interposition grafting during radical pelvic surgery.

PURPOSE The use of cavernous nerve interposition grafting to preserve erectile function in men who require neurovascular bundle resection for cancer control is controversial. We report outcomes and predictors of cavernous nerve interposition grafting in men undergoing unilateral grafting during radical prostatectomy or bilateral grafting during radical cystectomy and prostatectomy with autologous nerve grafts. MATERIALS AND METHODS We retrospectively reviewed the electronic records of 36 patients who underwent cavernous nerve interposition grafting between 2003 and 2006. Postoperatively erectile function was assessed with the International Index of Erectile Function 15-item questionnaire. Predictors of potency, including age at surgery, time since surgery and prostate specific antigen at surgery, were assessed by univariate analysis. RESULTS A total of 33 patients (92% response rate) were followed for a median of 32, 25 and 11 months after bilateral grafting during radical cystectomy (10), unilateral grafting during radical prostatectomy (20), and bilateral grafting during radical cystectomy and prostatectomy (3), respectively. The rate of potency, defined as the ability to attain and maintain erection sufficient for penetration at least 50% of the time with or without phosphodiesterase-5 inhibitors, was 31% (5 of 13 men) for unilateral grafts, 38% (5 of 16) for bilateral grafts and 30% (3 of 10) for bilateral grafts during radical cystectomy. Age at surgery was the only significant determinant of potency and it showed an inverse relationship in the bilateral nerve graft group (p = 0.02). CONCLUSIONS Cavernous nerve interposition grafting appears to have a role in the recovery of erectile function. To our knowledge this study represents the largest series of cavernous nerve interposition grafting during cystectomy and it suggests that this should be considered during bilateral neurovascular bundle resection.

Phase II, randomised, double-blind, placebo-controlled trial of methylphenidate for reduction of fatigue levels in patients with prostate cancer receiving LHRH-agonist therapy.

To investigate whether methylphenidate can alleviate fatigue, as measured by the Functional Assessment of Cancer Therapy: Fatigue subscale, in men with prostate cancer (PCa) treated with a luteinizing hormone‐releasing hormone (LHRH) for a minimum of 6 months, and to assess changes in global fatigue and quality of life (QoL) as measured by the Bruera Global Fatigue Severity Scale (BFS) and the Medical Outcomes Study 36‐Item Short‐Form Health Survey (SF‐36), respectively.