Mark A. Preston

Metformin Use and Prostate Cancer Risk

BACKGROUND Metformin may decrease prostate cancer (PCa) risk by reducing hyperinsulinemia-associated carcinogenesis or through direct effects on cancer cells. OBJECTIVE To evaluate the association between metformin use and PCa diagnosis. DESIGN, SETTING, AND PARTICIPANTS We used the Danish Cancer Registry and the Aarhus University Prescription Database to conduct a nested case-control study among men residing in northern Denmark from 1989 to 2011. We identified 12 226 cases of PCa and used risk-set sampling to select 10 population controls per case (n=122,260) from among men alive on the index date and born in the same year. A sensitivity analysis was conducted using subjects who had prostate-specific antigen (PSA) testing prior to 1 yr before the index date. INTERVENTION Metformin exposure was assessed using prescriptions redeemed before the index date. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. The association between metformin use and PCa diagnosis was determined, controlling for diabetes severity and other potential confounders. RESULTS AND LIMITATIONS Metformin users were at decreased risk of PCa diagnosis compared with never-users (adjusted OR [aOR]: 0.84; 95% CI, 0.74-0.96). Diabetics on no medication (aOR: 0.98; 95% CI, 0.89-1.09) or on other oral hypoglycemics (aOR: 0.98; 95% CI, 0.86-1.10) did not have a reduced risk of PCa, while users of insulin did have a reduced risk (aOR: 0.77; 95% CI, 0.64-0.93). In the PSA-tested group, metformin use was associated with decreased risk of PCa compared with nonuse (aOR: 0.66; 95% CI, 0.51-0.86). Diabetics on no medication (aOR: 1.03; 95% CI, 0.86-1.24), diabetics on other oral hypoglycemics (aOR: 0.92; 95% CI, 0.70-1.20), and insulin users (aOR: 0.83; 95% CI, 0.56-1.24) did not have a statistically significant reduced risk of cancer. CONCLUSIONS Metformin use was associated with decreased risk of PCa diagnosis, whereas diabetics using other oral hypoglycemics had no decreased risk. PATIENT SUMMARY We studied the relationship between metformin (a diabetic medication) and prostate cancer in Denmark. We found that metformin reduced the risk of prostate cancer diagnosis, whereas other oral antidiabetic medications did not.

Gleason 6 prostate cancer: Translating biology into population health

PURPOSE Gleason 6 (3+3) is the most commonly diagnosed prostate cancer among men with prostate specific antigen screening, the most histologically well differentiated and is associated with the most favorable prognosis. Despite its prevalence, considerable debate exists regarding the genetic features, clinical significance, natural history, metastatic potential and optimal management. MATERIALS AND METHODS Members of the Young Urologic Oncologists in the Society of Urologic Oncology cooperated in a comprehensive search of the peer reviewed English medical literature on Gleason 6 prostate cancer, specifically focusing on the history of the Gleason scoring system, histological features, clinical characteristics, practice patterns and outcomes. RESULTS The Gleason scoring system was devised in the early 1960s, widely adopted by 1987 and revised in 2005 with a more restrictive definition of Gleason 6 disease. There is near consensus that Gleason 6 meets pathological definitions of cancer, but controversy about whether it meets commonly accepted molecular and genetic criteria of cancer. Multiple clinical series suggest that the metastatic potential of contemporary Gleason 6 disease is negligible but not zero. Population based studies in the U.S. suggest that more than 90% of men newly diagnosed with prostate cancer undergo treatment and are exposed to the risk of morbidity for a cancer unlikely to cause symptoms or decrease life expectancy. Efforts have been proposed to minimize the number of men diagnosed with or treated for Gleason 6 prostate cancer. These include modifications to prostate specific antigen based screening strategies such as targeting high risk populations, decreasing the frequency of screening, recommending screening cessation, incorporating remaining life expectancy estimates, using shared decision making and novel biomarkers, and eliminating prostate specific antigen screening entirely. Large nonrandomized and randomized studies have shown that active surveillance is an effective management strategy for men with Gleason 6 disease. Active surveillance dramatically reduces the number of men undergoing treatment without apparent compromise of cancer related outcomes. CONCLUSIONS The definition and clinical relevance of Gleason 6 prostate cancer have changed substantially since its introduction nearly 50 years ago. A high proportion of screen detected cancers are Gleason 6 and the metastatic potential is negligible. Dramatically reducing the diagnosis and treatment of Gleason 6 disease is likely to have a favorable impact on the net benefit of prostate cancer screening.

Primary spermatic cord tumors: Disease characteristics, prognostic factors, and treatment outcomes

INTRODUCTION Experience with management of spermatic cord tumors (SCTs) is uncommon. We utilized a large population-based cancer registry to characterize the demographic, pathological, treatment characteristics, and outcomes of SCTs. MATERIAL AND METHODS The Surveillance, Epidemiology, and End Results database (1973-2007) was queried. RESULTS From the database, 362 patients were identified with SCT. The annual incidence of SCT was 0.3 cases per million and did not change over time. The most common histologic types were liposarcoma (46%), leiomyosarcoma (20%), histiocytoma (13%), and rhabdomyosarcoma (9%). The median age of diagnosis for rhabdomyosarcomas was (26.3 y), whereas for other SCTs, it was (64.7 y) (P<0.001). On multivariate analysis, a worse outcome was observed with undifferentiated tumor grade, distant disease, positive lymph nodes, and leiomyosarcoma or histiocytoma cell histology. CONCLUSION We describe the largest cohort of SCT studied to date. Liposarcoma was most common, while leiomyosarcoma and histiocytoma histologic subtypes were observed to be the most aggressive. Multivariate analysis revealed that tumor grade, stage, histologic type, and lymph node involvement were independently predictive of prognosis.

The Prognostic Significance of Capsular Incision Into Tumor During Radical Prostatectomy

BACKGROUND The prognostic significance of capsular incision (CapI) into tumor during radical prostatectomy (RP) with otherwise organ-confined disease remains uncertain. OBJECTIVE To evaluate the impact of CapI into tumor on oncologic outcome. DESIGN, SETTING, AND PARTICIPANTS A retrospective review of 8110 consecutive patients with prostate cancer treated at Ottawa Hospital and at Memorial Sloan-Kettering Cancer Center, both tertiary academic centers, between 1985 and 2008. INTERVENTION All patients underwent an open, laparoscopic or robotic RP. MEASUREMENTS Patients were divided into four pathologic categories: group 1 (CapI group), positive surgical margins (PSMs) without extraprostatic extension (EPE); group 2, negative surgical margins (NSMs) without EPE; group 3, NSM with EPE; group 4, PSMs with EPE. Estimates of recurrence-free survival were generated with the Kaplan-Meier method. Recurrence was defined as a prostate-specific antigen (PSA) >0.2 ng/ml and rising. Cox proportional hazards regression was used to estimate the hazard ratio (HR) for recurrence controlling for pretreatment PSA, RP date, RP Gleason sum, seminal vesicle invasion, and lymph node involvement. Pathologic categories were defined in the model by including the variables EPE and surgical margins (SMs) as well as their interaction. RESULTS AND LIMITATIONS Median follow-up was 37.3 mo. The 5-yr recurrence-free probability after RP for the CapI group was 77% (95% confidence interval [CI], 72-83). This was not only inferior to patients with NSMs and no EPE (log rank p<0.0001) but also to those with NSMs and EPE (log rank p=0.0002). In multivariate analysis the interaction between EPE and SM was not significant (p=0.26). In the adjusted model excluding the interaction term, patients with EPE had an increased risk for recurrence (HR: 1.80; 95% CI, 1.49-2.17; p<0.0001) as did those with positive margins (HR: 1.81; 95% CI, 1.51-2.15; p<0.0001). This was a retrospective study. CONCLUSIONS CapI into tumor has a significant impact on patient outcome following RP. Patients, who otherwise would have organ-confined disease, will now have a higher probability of recurrence than those with completely resected extraprostatic disease.

Comparison of Gonadotropin-Releasing Hormone Agonists and Orchiectomy: Effects of Androgen-Deprivation Therapy

IMPORTANCE Androgen-deprivation therapy (ADT) through surgical castration is equally effective as medical castration in controlling prostate cancer (PCa). However, the adverse effect profiles of both ADT groups have never been compared. OBJECTIVE To provide a comparative effectiveness analysis of the adverse effects of gonadotropin-releasing hormone agonists (GnRHa) vs bilateral orchiectomy in a homogeneous population. DESIGN, SETTING, AND PARTICIPANTS A population-based cohort of 3295 men with metastatic PCa between January 1995 and December 2009 66 years or older was selected from the Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database. EXPOSURES Orchiectomy or GnRHa. MAIN OUTCOMES AND MEASURES Any fractures, peripheral arterial disease, venous thromboembolism, cardiac-related complications, diabetes mellitus, and cognitive disorders. To minimize treatment group biases, the inverse probability of treatment was weighted using the propensity score. Multivariable competing risk regression models were performed with the adjustment of all-cause mortality. Secondary analyses examined the effect of increasing duration of GnRHa treatment. Multivariable logistic regression models examined expenditures. RESULTS Overall, 3295 men with a primary diagnosis of metastatic PCa treated with GnRHa or orchiectomy were identified between years 1995 and 2009, and in adjusted analyses, patients who received a bilateral orchiectomy had significantly lower risks of experiencing any fractures (hazard ratio [HR], 0.77; 95% CI, 0.62-0.94; P = .01), peripheral arterial disease (HR, 0.65; 95% CI, 0.49-0.87; P = .004), and cardiac-related complications (HR, 0.74; 0.58-0.94; P = .01) compared with those treated with GnRHa. No statistically significant difference was noted between orchiectomy and GnRHa for diabetes and cognitive disorders. In individuals treated with GnRHa for 35 months or more, the increased risk for GnRHa compared with orchiectomy was noted for fractures (HR, 1.80), peripheral arterial disease (HR, 2.25), venous thromboembolism (HR, 1.52), cardiac-related complications (HR, 1.69), and diabetes mellitus (HR, 1.88) (P ≤ .01 for all). At 12 months after PCa diagnosis, the median total expenditures was not significantly different between GnRHa and orchiectomy. CONCLUSIONS AND RELEVANCE Gonadotropin-releasing hormone agonist therapy is associated with higher risks of several clinically relevant adverse effects compared with orchiectomy.

Effectiveness of adjuvant chemotherapy after radical nephroureterectomy for locally advanced and/or positive regional lymph node upper tract urothelial carcinoma.

Purpose There is limited evidence to support the use of adjuvant chemotherapy (AC) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Against this backdrop, we hypothesized that such treatment is associated with overall survival (OS) benefit in patients with locally advanced and/or positive regional lymph node disease. Patients and Methods Within the National Cancer Database (2004 to 2012), we identified 3,253 individuals who received AC or observation after RNU for pT3/T4 and/or pN+ UTUC. Inverse probability of treatment weighting (IPTW) -adjusted Kaplan-Meier curves and Cox proportional hazards regression analyses were used to compare OS of patients in the two treatment groups. In addition, we performed exploratory analyses of treatment effect according to age, gender, Charlson comorbidity index, pathologic stage (pT3/T4N0, pT3/T4Nx and pTanyN+), and surgical margin status. Results Overall, 762 (23.42%) and 2,491 (76.58%) patients with pT3/T4 and/or pN+ UTUC received AC and observation, respectively, after RNU. IPTW-adjusted Kaplan-Meier curves showed that median OS was significantly longer for AC versus observation (47.41 [interquartile range,19.88 to 112.39] v 35.78 [interquartile range, 14.09 to 99.22] months; P < .001). The 5-year IPTW-adjusted rates of OS for AC versus observation were 43.90% and 35.85%, respectively. In IPTW-adjusted Cox proportional hazards regression analysis, AC was associated with a significant OS benefit (hazard ratio, 0.77 [95% CI, 0.68 to 0.88]; P < .001). This benefit was consistent across all subgroups examined (all P < .05), and no significant heterogeneity of treatment effect was observed (all Pinteraction > .05). Conclusion We report an OS benefit in patients who received AC versus observation after RNU for pT3/T4 and/or pN+ UTUC. Although our results are limited by the usual biases related to the observational study design, we believe that the present findings should be considered when advising post-RNU management of advanced UTUC, pending level I evidence.

Efficacy of High-Intensity Local Treatment for Metastatic Urothelial Carcinoma of the Bladder: A Propensity Score–Weighted Analysis From the National Cancer Data Base

Purpose Evidence from studies of other malignancies has indicated that aggressive local treatment (LT), even in the presence of metastatic disease, is beneficial. Against a backdrop of stagnant mortality rates for metastatic urothelial carcinoma of the bladder (mUCB) at presentation, we hypothesized that high-intensity LT of primary tumor burden, defined as the receipt of radical cystectomy or ≥ 50 Gy of radiation therapy delivered to the bladder, affects overall survival (OS). Patients and Methods We identified 3,753 patients within the National Cancer Data Base who received multiagent systemic chemotherapy combined with high-intensity versus conservative LT for primary mUCB. Patients who received no LT, transurethral resection of the bladder tumor alone, or < 50 Gy of radiation therapy delivered to the bladder were included in the conservative LT group. Inverse probability of treatment weighting (IPTW) -adjusted Kaplan-Meier curves and Cox regression analyses were used to compare OS of patients who received high-intensity versus conservative LT. Results Overall, 297 (7.91%) and 3,456 (92.09%) patients with mUCB received high-intensity and conservative LT, respectively. IPTW-adjusted Kaplan-Meier curves showed that median OS was significantly longer in the high-intensity LT group than in the conservative LT group (14.92 [interquartile range, 9.82 to 30.72] v 9.95 [interquartile range, 5.29 to 17.08] months, respectively; P < .001). Furthermore, in IPTW-adjusted Cox regression analysis, high-intensity LT was associated with a significant OS benefit (hazard ratio, 0.56; 95% CI, 0.48 to 0.65; P < .001). Conclusion We report an OS benefit for individuals with mUCB treated with high-intensity versus conservative LT. Although the findings are subject to the usual biases related to the observational study design, these preliminary data warrant further consideration in randomized controlled trials, particularly given the poor prognosis associated with mUCB.

Body Mass Index and Metastatic Renal Cell Carcinoma: Clinical and Biological Correlations.

PURPOSE Obesity is an established risk factor for clear cell renal cell carcinoma (RCC); however, some reports suggest that RCC developing in obese patients may be more indolent. We investigated the clinical and biologic effect of body mass index (BMI) on treatment outcomes in patients with metastatic RCC. METHODS The impact of BMI (high BMI: ≥ 25 kg/m2 v low BMI: < 25 kg/m2) on overall survival (OS) and treatment outcome with targeted therapy was investigated in 1,975 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and in an external validation cohort of 4,657 patients. Gene expression profiling focusing on fatty acid metabolism pathway, in The Cancer Genome Atlas data set, and immunohistochemistry staining for fatty acid synthase (FASN) were also investigated. Cox regression was undertaken to estimate the association of BMI with OS, adjusted for the IMDC prognostic factors. RESULTS In the IMDC cohort, median OS was 25.6 months (95% CI, 23.2 to 28.6) in patients with high BMI versus 17.1 months (95% CI, 15.5 to 18.5) in patients with low BMI (adjusted hazard ratio, 0.84; 95% CI, 0.73 to 0.95). In the validation cohort, high BMI was associated with improved OS (adjusted hazard ratio, 0.83; 95% CI, 0.74 to 0.93; medians: 23.4 months [95% CI, 21.9 to 25.3 months] v 14.5 months [95% CI, 13.8 to 15.9 months], respectively). In The Cancer Genome Atlas data set (n = 61), FASN gene expression inversely correlated with BMI (P = .034), and OS was longer in the low FASN expression group (medians: 36.8 v 15.0 months; P = .002). FASN immunohistochemistry positivity was more frequently detected in IMDC poor (48%) and intermediate (34%) risk groups than in the favorable risk group (17%; P-trend = .015). CONCLUSION High BMI is a prognostic factor for improved survival and progression-free survival in patients with metastatic RCC treated with targeted therapy. Underlying biology suggests a role for the FASN pathway.

The association between nerve sparing and a positive surgical margin during radical prostatectomy

PURPOSE A positive surgical margin (SM) during radical prostatectomy (RP) increases risk of biochemical recurrence. We evaluated the effect of nerve-sparing procedures on risk of positive SM for pT2- and pT3-category tumors. We hypothesized that nerve sparing would increase rates of pT2 positive margins. METHODS We evaluated a historical cohort of 9,915 consecutive RP patients treated at The Ottawa Hospital or Memorial Sloan-Kettering Cancer Center from 2000 to 2010. Patients underwent open, laparoscopic, or robotic RP. The primary outcome was presence of a positive SM stratified by pathologic pT2 and pT3 categories. The association between nerve sparing and positive margin was adjusted for prostate-specific antigen, RP Gleason sum, surgical modality, surgical date, and location in the multivariable model. RESULTS Of 6,120 eligible patients, 3,958 (64.7%) had open RP, 1,566 (25.6%) had laparoscopic RP, and 596 (9.7%) had robotic RP. Approximately 8.6% (363/4,199) of patients with pT2-category disease and 25.2% (485/1,921) of patients with pT3-category disease had a positive margin. Patients with pT2-category disease who underwent a bilateral nerve-sparing procedure were more likely to have a positive margin when compared with those who underwent nerve resection on multivariable analysis (relative risk [RR] = 1.52, 95% CI: 0.97-2.39) after adjusting for confounders. Patients with pT3-category disease who underwent a bilateral nerve-sparing procedure had no associated increase in risk of positive margin after adjustment for other variables (RR = 0.96, 95% CI: 0.80-1.16). Prostate incision into tumor (pT2R1) was significantly more likely in patients treated with robotic surgery (RR = 1.76, 95% CI: 1.25-2.48) than in those with open surgery. There was no difference between laparoscopic and open RP (RR = 0.86, 95% CI: 0.65-1.12). CONCLUSIONS Bilateral nerve sparing is associated with increased risk of positive SMs in patients with pathologic T2-category disease during RP.

5α-Reductase inhibitors and risk of high-grade or lethal prostate cancer.

IMPORTANCE 5α-Reductase inhibitors (5ARIs) are widely used for benign prostatic hyperplasia despite controversy regarding potential risk of high-grade prostate cancer with use. Furthermore, the effect of 5ARIs on progression and prostate cancer death remains unclear. OBJECTIVE To determine the association between 5ARI use and development of high-grade or lethal prostate cancer. DESIGN, SETTING, AND PARTICIPANTS Prospective observational study of 38,058 men followed up for prostate cancer diagnosis and outcomes between 1996 and 2010 in the Health Professionals Follow-up Study. EXPOSURES Use of 5ARIs between 1996 and 2010. MAIN OUTCOMES AND MEASURES Cox proportional hazards models were used to estimate risk of prostate cancer diagnosis or development of lethal disease with 5ARI use, adjusting for possible confounders including prostate specific antigen testing. RESULTS During 448,803 person-years of follow-up, we ascertained 3681 incident prostate cancer cases. Of these, 289 were lethal (metastatic or fatal), 456 were high grade (Gleason sum [GS] 8-10), 1238 were GS 7, and 1600 were low grade (GS 2-6). A total of 2878 (7.6%) men reported use of 5ARIs between 1996 and 2010. After adjusting for confounders, men who reported ever using 5ARIs over the study period had a reduced risk of overall prostate cancer (hazard ratio [HR], 0.77; 95% CI, 0.65-0.91). 5ARI users had a reduced risk of GS 7 (HR, 0.67; 95% CI, 0.49-0.91) and low-grade (GS 2-6) prostate cancer (HR, 0.74; 95% CI, 0.57-0.95). 5ARI use was not associated with risk of high-grade (GS 8-10) prostate cancer (HR, 0.97; 95% CI, 0.64-1.46) or lethal disease (HR, 0.99; 95% CI, 0.58-1.69). Increased duration of use was associated with significantly lower risk of overall prostate cancer (HR for 1 year of additional use, 0.95; 95% CI, 0.92-0.99), localized (HR, 0.95; 95% CI, 0.90-1.00), and low-grade disease (HR, 0.92; 95% CI, 0.85-0.99). There was no association for lethal, high-grade, or grade 7 disease. CONCLUSIONS AND RELEVANCE While 5ARI use was not associated with developing high-grade or lethal prostate cancer, it was associated with a reduction in low-grade, GS 7, and overall prostate cancer. Because the number of patients with high-grade or lethal prostate cancer in our cohort was limited, we cannot rule out potential risk of harm with 5ARI use.