Daniel A. Barocas

What Percentage of Patients With Newly Diagnosed Carcinoma of the Prostate are Candidates for Surveillance? An Analysis of the CaPSURE™ Database

PURPOSE Active surveillance is an option for men with clinically localized prostate cancer and may be suitable for those with very low risk disease. We determined the percentage of men in a large prostate cancer registry who met criteria predictive of latent prostate cancer. We also assessed the percentage of men meeting these criteria who chose surveillance. MATERIALS AND METHODS We conducted an observational study of 1,886 men diagnosed with clinically localized prostate cancer between 1999 and 2004 from the CaPSURE database. Outcomes were percent of men meeting Epstein surveillance criteria (prostate specific antigen less than 10 ng/ml, clinical T1 or T2a, prostate specific antigen density less than 0.15, fewer than 1 of 3 biopsy cores positive, and absence of Gleason pattern 4 and 5 on biopsy) and percent selecting surveillance stratified by risk group. RESULTS Of 1,886 men with all 5 criteria documented 16.4% (310 of 1,886) met all 5 surveillance criteria and 9.0% (28 of 310) of men in this very low risk category actually chose surveillance compared with 4.3% (68 of 1,576) of patients in other risk groups (p <0.01). On multivariable analysis of the entire cohort older age was the only demographic predictor of surveillance. Being in the very low risk group was also a predictor of surveillance. CONCLUSIONS Of men presenting with localized prostate cancer 16% met the criteria for very low risk disease. However, only a small subset of eligible men chose active surveillance, suggesting that it may be underused in the management of very low risk prostate cancer.

National Trends in the Use of Partial Nephrectomy: A Rising Tide That Has Not Lifted All Boats

PURPOSE Treatment of organ confined renal masses with partial nephrectomy has durable oncologic outcomes comparable to radical nephrectomy. Partial nephrectomy is associated with lower risk of chronic kidney disease and in some series with better overall survival. We report a contemporary analysis on national trends of partial nephrectomy use to determine partial nephrectomy use over time, and whether nontumor related factors such as structural attributes of the treating institution or patient characteristics are associated with the underuse of partial nephrectomy. MATERIALS AND METHODS We performed an analysis of the NIS (National Inpatient Sample), which contains 20% of all United States inpatient hospitalizations. We included patients who underwent radical or partial nephrectomy for a renal mass between 2002 and 2008. Survey weights were applied to obtain national estimates of nephrectomy use and to evaluate nonclinical predictors of partial nephrectomy. RESULTS A total of 46,396 patients were included in the study for a weighted sample of 226,493. There was an increase in partial nephrectomy use from 15.3% in 2002 to 24.7% in 2008 (p <0.001). On multivariate analysis hospital attributes (urban teaching status, nephrectomy volume, geographic region) and patient socioeconomic status (higher income ZIP code and private/HMO payer) were independent predictors of partial nephrectomy use. CONCLUSIONS Since 2002 the national use of partial nephrectomy for the management of renal masses has increased. However, the adoption of partial nephrectomy at smaller, rural and nonacademic hospitals lags behind that of larger hospitals, urban/teaching hospitals and higher volume centers. A lower rate of partial nephrectomy use among patients without private insurance and those living in lower income ZIP code areas highlights the underuse of partial nephrectomy as a quality of care concern.

Trends in the Use of Perioperative Chemotherapy for Localized and Locally Advanced Muscle-invasive Bladder Cancer: A Sign of Changing Tides

BACKGROUND Despite the documented survival benefit conferred by neoadjuvant (NAC) and adjuvant chemotherapy (AC), there has been a slow adoption of guideline recommendations for the use of perioperative chemotherapy (POC) in patients with muscle-invasive bladder cancer (MIBC). OBJECTIVE To evaluate temporal trends in POC utilization and identify factors influencing POC delivery in a representative cohort of patients with MIBC. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study identifying factors associated with receipt of POC and evaluating temporal changes in NAC and AC utilization. We included patients from the National Cancer Data Base (NCDB) with no prior malignancy who ultimately underwent radical cystectomy for ≥ cT2/cN0/cM0 MIBC between 2006 and 2010. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Relationships between demographic and hospital factors and the likelihood of receiving POC were evaluated using Pearson chi-square and Wilcoxon rank-sum tests, and multivariable logistic regression. Temporal changes in NAC and AC use were detected using a linear test of trend. RESULTS AND LIMITATIONS A total of 5692 patients met our inclusion criteria. POC use increased from 29.5% in 2006 to 39.8% in 2010 (p < 0.001). NAC use increased from 10.1% in 2006 to 20.8% in 2010 (p = 0.005); AC remained stable between 18.1% and 21.3% (p = 0.68). Multivariable modeling revealed advanced age, increasing comorbidity, lack of insurance, increased travel distance, geographic location outside the northeastern United States, and lower income as negatively associated with POC receipt (all p < 0.05). Limitations include retrospective design and potential sampling bias, excluding patients treated at non-NCDB facilities. CONCLUSIONS POC use for MIBC increased from 2006 to 2010, with this increase disproportionately due to rising NAC utilization. Nonetheless, there is persistent variation in the likelihood of receiving POC secondary to nonclinical factors. PATIENT SUMMARY When retrospectively analyzing a representative cohort of patients undergoing radical cystectomy for muscle-invasive bladder cancer between 2006 and 2010, we noted that preoperative chemotherapy rates increased steadily while use of chemotherapy after surgery remained stable. Factors related to access to care significantly influenced receipt of chemotherapy.

Multicenter Assessment of Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer

BACKGROUND The efficacy of neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (BCa) was established primarily with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), with complete response rates (pT0) as high as 38%. However, because of the comparable efficacy with better tolerability of gemcitabine and cisplatin (GC) in patients with metastatic disease, GC has become the most commonly used regimen in the neoadjuvant setting. OBJECTIVE We aimed to assess real-world pathologic response rates to NAC with different regimens in a large, multicenter cohort. DESIGN, SETTING, AND PARTICIPANTS Data were collected retrospectively at 19 centers on patients with clinical cT2-4aN0M0 urothelial carcinoma of the bladder who received at least three cycles of NAC, followed by radical cystectomy (RC), between 2000 and 2013. INTERVENTION NAC and RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome was pathologic stage at cystectomy. Univariable and multivariable analyses were used to determine factors predictive of pT0N0 and ≤pT1N0 stages. RESULTS AND LIMITATIONS Data were collected on 935 patients who met inclusion criteria. GC was used in the majority of the patients (n=602; 64.4%), followed by MVAC (n=183; 19.6%) and other regimens (n=144; 15.4%). The rates of pT0N0 and ≤pT1N0 pathologic response were 22.7% and 40.8%, respectively. The rate of pT0N0 disease for patients receiving GC was 23.9%, compared with 24.5% for MVAC (p=0.2). There was no difference between MVAC and GC in pT0N0 on multivariable analysis (odds ratio: 0.89 [95% confidence interval, 0.61-1.34]; p=0.6). CONCLUSIONS Response rates to NAC were lower than those reported in prospective randomized trials, and we did not discern a difference between MVAC and GC. Without any evidence from randomized prospective trials, the best NAC regimen for invasive BCa remains to be determined. PATIENT SUMMARY There was no apparent difference in the response rates to the two most common presurgical chemotherapy regimens for patients with bladder cancer.

Effect of the USPSTF Grade D Recommendation against Screening for Prostate Cancer on Incident Prostate Cancer Diagnoses in the United States.

PURPOSE In October 2011 the USPSTF (U.S. Preventive Services Task Force) issued a draft guideline discouraging prostate specific antigen based screening for prostate cancer (grade D recommendation). We evaluated the effect of the USPSTF guideline on the number and distribution of new prostate cancer diagnoses in the United States. MATERIALS AND METHODS We identified incident cancers diagnosed between January 2010 and December 2012 in NCDB (National Cancer Database). We performed an interrupted time series to evaluate the trend of new prostate cancers diagnosed each month before and after the draft guideline with colon cancer as a comparator. RESULTS Incident monthly prostate cancer diagnoses decreased by -1,363 cases (12.2%, p<0.01) in the month after the USPSTF draft guideline and continued to decrease by 164 cases per month relative to baseline (-1.8%, p<0.01). In contrast monthly colon cancer diagnoses remained stable. Diagnoses of low, intermediate and high risk prostate cancers decreased significantly but new diagnoses of nonlocalized disease did not change. Subgroups of age, comorbidity, race, income and insurance showed comparable decreases in incident prostate cancer following the draft guideline. CONCLUSIONS There was a 28% decrease in incident diagnoses of prostate cancer in the year after the USPSTF draft recommendation against prostate specific antigen screening. This study helps quantify the potential benefits (reduced harms of over diagnosis and overtreatment of low risk disease and disease found in elderly men) and potential harms (missed opportunities to diagnose important cancers in men who may benefit from treatment) of this guideline.

Predicting the Probability of 90-Day Survival of Elderly Patients With Bladder Cancer Treated With Radical Cystectomy

PURPOSE Despite the increased morbidity and mortality of radical cystectomy in elderly individuals with bladder cancer numerous studies show that surgery can provide a survival benefit. We sought to better identify patients at substantial risk for postoperative mortality. MATERIALS AND METHODS We evaluated 220 consecutive patients 75 years old or older treated with radical cystectomy for bladder cancer at a single institution from 2000 to 2008. The analytical cohort comprised 169 patients with complete preoperative data available. A Cox proportional hazards model was used to determine the value of precystectomy clinical information to predict 90-day survival after radical cystectomy. Results were used to create a nomogram predicting the probability of 90-day survival after radical cystectomy. The model was then subjected to 200 bootstrap resamples for internal validation. RESULTS Of the 220 patients 28 (12.7%) died within 90 days of surgery. Older age (HR 2.30, 95% CI 1.22-4.32) and lower preoperative albumin (HR 2.50, 95% CI 1.40-4.45) were significant predictors of 90-day mortality. We developed a nomogram based on patient age, clinical stage, Charlson comorbidity index and albumin to predict the likelihood of 90-day mortality with 75% accuracy. Internal validation showed a bootstrap adjusted concordance index of 71%. CONCLUSIONS We developed a nomogram that provides individualized risk estimations to predict the probability of 90-day mortality, potentially enhancing preoperative counseling and providing clinicians with an added tool to individualize treatment decisions in this challenging patient population. These data suggest that albumin is a strong predictor of postoperative mortality and show the importance of assessing this variable before surgery.

The relationship between perioperative blood transfusion and overall mortality in patients undergoing radical cystectomy for bladder cancer

OBJECTIVES The relationship between perioperative blood transfusion (PBT) and oncologic outcomes is controversial. In patients undergoing surgery for colon cancer and several other solid malignancies, PBT has been associated with an increased risk of mortality. Yet, the urologic literature has a paucity of data addressing this topic. We sought to evaluate whether PBT affects overall survival following radical cystectomy (RC) for patients with bladder cancer. METHODS The medical records of 777 consecutive patients undergoing RC for urothelial carcinoma of the bladder were reviewed. PBT was defined as transfusion of red blood cells during RC or within the postoperative hospitalization. The primary outcome was overall survival. Clinical and pathologic variables were compared using χ(2) tests, and Cox multivariate survival analyses were performed. RESULTS A total of 323 patients (41.6%) underwent PBT. In the univariate analysis, PBT was associated with increased overall mortality (HR 1.40, 95% CI 1.11-1.78). Additionally, an independent association was demonstrated in a non-transformed Cox regression model (HR, 95% CI 1.01-1.36) but not in a model utilizing restricted cubic splines (HR 1.03, 95% CI 0.77-1.38). The c-index was 0.78 for the first model and 0.79 for the second. CONCLUSIONS In a traditional multivariate model, mirroring those that have been applied to this question in the general surgery literature, we demonstrated an association between PBT and overall mortality after RC. However, this relationship is not observed in a second statistical model. Given the complex nature of adequately controlling for confounding factors in studies of PBT, a prospective study will be necessary to fully elucidate the independent risks associated with PBT.

Oxidative stress measured by urine F2-isoprostane level is associated with prostate cancer

PURPOSE Oxidative stress is implicated in prostate cancer by several lines of evidence. We studied the relationship between the level of F2-isoprostanes, a validated biomarker of oxidative stress, and prostate cancer and high grade prostatic intraepithelial neoplasia. MATERIALS AND METHODS This case-control analysis within the Nashville Mens Health Study included men recruited at prostate biopsy. Body morphometrics, health history and urine were collected from more than 2,000 men before biopsy. F2-isoprostanes were measured by gas chromatography/mass spectrometry within an age matched sample of Nashville Mens Health Study participants that included 140 patients with high grade prostatic intraepithelial neoplasia, 160 biopsy negative controls and 200 prostate cancer cases. Multivariable linear and logistic regression was used to determine the associations between F2-isoprostane level, and high grade prostatic intraepithelial neoplasia and prostate cancer. RESULTS Mean patient age was 66.9 years (SD 7.2) and 10.1% were nonwhite. Adjusted geometric mean F2-isoprostane levels were higher in patients with prostate cancer (1.82, 95% CI 1.66-2.00) or high grade prostatic intraepithelial neoplasia (1.82, 95% CI 1.68-1.96) than in controls (1.63, 95% CI 1.49-1.78, p <0.001), but were similar across Gleason scores (p = 0.511). The adjusted odds of high grade prostatic intraepithelial neoplasia and prostate cancer increased with increasing F2-isoprostane quartile (p-trend = 0.015 and 0.047, respectively) and the highest F2-isoprostane quartile was associated with significantly increased odds of prostate cancer (OR 2.44, 95% CI 1.17-5.09, p = 0.017). CONCLUSIONS Pre-diagnosis urine F2-isoprostane level is increased in men with high grade prostatic intraepithelial neoplasia or prostate cancer, suggesting urinary F2-isoprostane provides a biomarker for the role for oxidative stress in prostate carcinogenesis. F2-isoprostanes may also serve to estimate the efficacy of interventions targeting oxidative stress mechanisms in prostate cancer prevention or treatment.

The RAZOR (randomized open vs robotic cystectomy) trial: Study design and trial update

The purpose of the RAZOR (randomized open vs robotic cystectomy) study is to compare open radical cystectomy (ORC) vs robot‐assisted RC (RARC), pelvic lymph node dissection (PLND) and urinary diversion for oncological outcomes, complications and health‐related quality of life (HRQL) measures with a primary endpoint of 2‐year progression‐free survival (PFS). RAZOR is a multi‐institutional, randomized, non‐inferior, phase III trial that will enrol at least 320 patients with T1–T4, N0–N1, M0 bladder cancer with ≈160 patients in both the RARC and ORC arms at 15 participating institutions. Data will be collected prospectively at each institution for cancer outcomes, complications of surgery and HRQL measures, and then submitted to trial data management services Cancer Research and Biostatistics (CRAB) for final analyses. To date, 306 patients have been randomized and accrual to the RAZOR trial is expected to conclude in 2014. In this study, we report the RAZOR trial experimental design, objectives, data safety, and monitoring, and accrual update. The RAZOR trial is a landmark study in urological oncology, randomizing T1–T4, N0–N1, M0 patients with bladder cancer to ORC vs RARC, PLND and urinary diversion. RAZOR is a multi‐institutional, non‐inferiority trial evaluating cancer outcomes, surgical complications and HRQL measures of ORC vs RARC with a primary endpoint of 2‐year PFS. Full data from the RAZOR trial are not expected until 2016–2017.

Obesity, body composition, and prostate cancer

BackgroundEstablished risk factors for prostate cancer have not translated to effective prevention or adjuvant care strategies. Several epidemiologic studies suggest greater body adiposity may be a modifiable risk factor for high-grade (Gleason 7, Gleason 8-10) prostate cancer and prostate cancer mortality. However, BMI only approximates body adiposity, and may be confounded by centralized fat deposition or lean body mass in older men. Our objective was to use bioelectric impedance analysis (BIA) to measure body composition and determine the association between prostate cancer and total body fat mass (FM) fat-free mass (FFM), and percent body fat (%BF), and which body composition measure mediated the association between BMI or waist circumference (WC) with prostate cancer.MethodsThe study used a multi-centered recruitment protocol targeting men scheduled for prostate biopsy. Men without prostate cancer at biopsy served as controls (n = 1057). Prostate cancer cases were classified as having Gleason 6 (n = 402), Gleason 7 (n = 272), or Gleason 8-10 (n = 135) cancer. BIA and body size measures were ascertained by trained staff prior to diagnosis, and clinical and comorbidity status were determined by chart review. Analyses utilized multivariable linear and logistic regression.ResultsBody size and composition measures were not significantly associated with low-grade (Gleason 6) prostate cancer. In contrast, BMI, WC, FM, and FFM were associated with an increased risk of Gleason 7 and Gleason 8-10 prostate cancer. Furthermore, BMI and WC were no longer associated with Gleason 8-10 (ORBMI = 1.039 (1.000, 1.081), ORWC = 1.016 (0.999, 1.033), continuous scales) with control for total body FFM (ORBMI = 0.998 (0.946, 1.052), ORWC = 0.995 (0.974, 1.017)). Furthermore, increasing FFM remained significantly associated with Gleason 7 (ORFFM = 1.030 (1.008, 1.052)) and Gleason 8-10 (ORFFM = 1.044 (1.014, 1.074)) after controlling for FM.ConclusionsOur results suggest that associations between BMI and WC with high-grade prostate cancer are mediated through the measurement of total body FFM. It is unlikely that FFM causes prostate cancer, but instead provides a marker of testosterone or IGF1 activities involved with retaining lean mass as men age.