Laurence Klotz

Increasing Hospital Admission Rates for Urological Complications After Transrectal Ultrasound Guided Prostate Biopsy

PURPOSE Transrectal ultrasound guided prostate biopsy is widely used to confirm the diagnosis of prostate cancer. The technique has been associated with significant morbidity in a small proportion of patients. MATERIALS AND METHODS We conducted a population based study of 75,190 men who underwent a transrectal ultrasound guided biopsy in Ontario, Canada, between 1996 and 2005. We used hospital and cancer registry administrative databases to estimate the rates of hospital admission and mortality due to urological complications associated with the procedure. RESULTS Of the 75,190 men who underwent transrectal ultrasound biopsy 33,508 (44.6%) were diagnosed with prostate cancer and 41,682 (55.4%) did not have prostate cancer. The hospital admission rate for urological complications within 30 days of the procedure for men without cancer was 1.9% (781/41,482). The 30-day hospital admission rate increased from 1.0% in 1996 to 4.1% in 2005 (p for trend <0.0001). The majority of hospital admissions (72%) were for infection related reasons. The probability of being admitted to hospital within 30 days of having the procedure increased 4-fold between 1996 and 2005 (OR 3.7, 95% CI 2.0-7.0, p <0.0001). The overall 30-day mortality rate was 0.09% but did not change during the study period. CONCLUSIONS The hospital admission rates for complications following transrectal ultrasound guided prostate biopsy have increased dramatically during the last 10 years primarily due to an increasing rate of infection related complications.

Reporting Magnetic Resonance Imaging in Men on Active Surveillance for Prostate Cancer: The PRECISE Recommendations—A Report of a European School of Oncology Task Force

BACKGROUND Published data on prostate magnetic resonance imaging (MRI) during follow-up of men on active surveillance are lacking. Current guidelines for prostate MRI reporting concentrate on prostate cancer (PCa) detection and staging. A standardised approach to prostate MRI reporting for active surveillance will facilitate the robust collection of evidence in this newly developing area. OBJECTIVE To develop preliminary recommendations for reporting of individual MRI studies in men on active surveillance and for researchers reporting the outcomes of cohorts of men having MRI on active surveillance. DESIGN, SETTING, AND PARTICIPANTS The RAND/UCLA Appropriateness Method was used. Experts in urology, radiology, and radiation oncology developed a set of 394 statements relevant to prostate MRI reporting in men on active surveillance for PCa. Each statement was scored for agreement on a 9-point scale by each panellist prior to a panel meeting. Each statement was discussed and rescored at the meeting. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Measures of agreement and consensus were calculated for each statement. The most important statements, derived from both group discussion and scores of agreement and consensus, were used to create the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) checklist and case report form. RESULTS AND LIMITATIONS Key recommendations include reporting the index lesion size using absolute values at baseline and at each subsequent MRI. Radiologists should assess the likelihood of true change over time (ie, change in size or change in lesion characteristics on one or more sequences) on a 1-5 scale. A checklist of items for reporting a cohort of men on active surveillance was developed. These items were developed based on expert consensus in many areas in which data are lacking, and they are expected to develop and change as evidence is accrued. CONCLUSIONS The PRECISE recommendations are designed to facilitate the development of a robust evidence database for documenting changes in prostate MRI findings over time of men on active surveillance. If used, they will facilitate data collection to distinguish measurement error and natural variability in MRI appearances from true radiologic progression. PATIENT SUMMARY Few published reports are available on how to use and interpret magnetic resonance imaging for men on active surveillance for prostate cancer. The PRECISE panel recommends that data should be collected in a standardised manner so that natural variation in the appearance and measurement of cancer over time can be distinguished from changes indicating significant tumour progression.

New variants at 10q26 and 15q21 are associated with aggressive prostate cancer in a genome-wide association study from a prostate biopsy screening cohort

Purpose: To identify and examine polymorphisms of genes associated with aggressive and clinical significant forms of prostate cancer among a screening cohort. Experimental Design: We conducted a genome-wide association study among patients with aggressive forms of prostate cancer and biopsy-proven normal controls ascertained from a prostate cancer screening program. We then examined significant associations of specific polymorphisms among a prostate cancer screened cohort to examine their predictive ability in detecting prostate cancer. Results: We found significant associations between aggressive prostate cancer and five single nucleotide polymorphisms (SNPs) in the 10q26 (rs10788165, rs10749408, and rs10788165, p value for association 1.3 × 10−10 to 3.2 × 10−11) and 15q21 (rs4775302 and rs1994198, p values for association 3.1 × 10−8 to 8.2 × 10−9) regions. Results of a replication study done in 3439 patients undergoing a prostate biopsy, revealed certain combinations of these SNPs to be significantly associated not only with prostate cancer but with aggressive forms of prostate cancer using an established classification criterion for prostate cancer progression (odds ratios for intermediate to high-risk disease 1.8–3.0, p value 0.003–0.001). These SNP combinations were also important clinical predictors for prostate cancer detection based on nomogram analysis that assesses prostate cancer risk. Conclusions: Five SNPs were found to be associated with aggressive forms of prostate cancer. We demonstrated potential clinical applications of these associations.

A genome-wide association screen identifies regions on chromosomes 1q25 and 7p21 as risk loci for sporadic prostate cancer.

We conducted a genome-wide association study of 3090 sporadic prostate cancer patients and controls using the Affymetrix 10 000 SNP GeneChip. Initial screening of 40 prostate cancer cases and 40 non-cancer controls revealed 237 SNPs to be associated with prostate cancer (P<0.05). Among these SNPs, 33 were selected for further association analysis of 2069 men who had undergone a cancer-screening prostate biopsy. Results identified five loci as being significantly associated with increased prostate cancer risk in this larger sample (rs1930293, OR=1.7, P=0.03; rs717809-2p12, OR=1.3, P=0.03; rs494770-4q34, OR=1.3, P=0.01; rs2348763-7p21, OR=1.5, P=0.01; rs1552895-9p22, OR=1.5, P=0.002). To validate these association data, 61 additional HapMap tagSNPs spanning the latter five loci were genotyped in this subject cohort and an additional 1021 men (total subject number=3090). This analysis revealed tagSNP rs4568789 (chromosome 1q25) and tagSNP rs13225697 (chromosome 7p21) to be significantly associated with prostate cancer (P-values 0.009 and 0.008, respectively). Haplotype analysis revealed significant associations of prostate cancer with two allele risk haplotypes on both chromosome 1q25 (adjusted OR of 2.7 for prostate cancer, P=0.0003) and chromosome 7p21 (adjusted OR of 1.3, P=0.0004). As linkage data have identified a putative prostate cancer gene on chromosome 1q25 (HPC1), and microarray data have revealed the ETV1 oncogene to be overexpressed in prostate cancer tissue, it appears that chromosome 1q25 and 7p21 may be sites of gene variants conferring risk for sporadic and inherited forms of prostate cancer.

Patient selection for prostate focal therapy in the era of active surveillance: an International Delphi Consensus Project

Background:Whole-gland extirpation or irradiation is considered the gold standard for curative oncological treatment for localized prostate cancer, but is often associated with sexual and urinary impairment that adversely affects quality of life. This has led to increased interest in developing therapies with effective cancer control but less morbidity. We aimed to provide details of physician consensus on patient selection for prostate focal therapy (FT) in the era of contemporary prostate cancer management.Methods:We undertook a four-stage Delphi consensus project among a panel of 47 international experts in prostate FT. Data on three main domains (role of biopsy/imaging, disease and patient factors) were collected in three iterative rounds of online questionnaires and feedback. Consensus was defined as agreement in ⩾80% of physicians. Finally, an in-person meeting was attended by a core group of 16 experts to review the data and formulate the consensus statement.Results:Consensus was obtained in 16 of 18 subdomains. Multiparametric magnetic resonance imaging (mpMRI) is a standard imaging tool for patient selection for FT. In the presence of an mpMRI-suspicious lesion, histological confirmation is necessary prior to FT. In addition, systematic biopsy remains necessary to assess mpMRI-negative areas. However, adequate criteria for systematic biopsy remains indeterminate. FT can be recommended in D’Amico low-/intermediate-risk cancer including Gleason 4+3. Gleason 3+4 cancer, where localized, discrete and of favorable size represents the ideal case for FT. Tumor foci <1.5 ml on mpMRI or <20% of the prostate are suitable for FT, or up to 3 ml or 25% if localized to one hemi-gland. Gleason 3+3 at one core 1mm is acceptable in the untreated area. Preservation of sexual function is an important goal, but lack of erectile function should not exclude a patient from FT.Conclusions:This consensus provides a contemporary insight into expert opinion of patient selection for FT of clinically localized prostate cancer.

Comparative Analysis of Biopsy Upgrading in Four Prostate Cancer Active Surveillance Cohorts

Active surveillance (AS) is now the preferred approach for managing newly diagnosed, low-risk prostate cancer (1, 2). A recent guideline from the American Society of Clinical Oncology (2) supports the use of AS for low-risk prostate cancer and provides recommendations about the target population and surveillance protocol. However, the recommendations lack specific information about how AS should be implemented. Several studies in North America (36) and Europe (7) are investigating the outcomes of AS, but they involve different populations, follow-up durations, inclusion criteria, surveillance protocols, and definitions of progression that lead to treatment referral. Having data from several AS cohorts provides an opportunity to learn more about disease progression on AS. Recent analyses within specific cohorts (6, 8, 9) have pointed to prostate-specific antigen (PSA) level, number of prior stable biopsy results, PSA density, and history of any negative biopsy results as important predictors of progression. However, differences in AS implementation and adherence across cohorts preclude comparison of progression risks and prevent direct integration of results to inform best practices (10). This article brings together individual-level data from 4 of the largest North American AS studies to compare and integrate their information about prostate cancer progression on AS. We evaluated whether progression rates were consistent across cohorts after standardizing inclusion criteria and the definition of progression and after controlling for variable surveillance intervals and risks for competing treatments. In addition, we examined the expected consequences of more versus less frequent biopsies across AS studies. This cross-cohort analysis is critical to assessing representativeness of individual studies and to developing sound AS guidelines that balance timely intervention with the morbidity from intensive surveillance. Methods Data Sources Deidentified, individual-level data were obtained from the 4 AS cohorts after institutional review board approval. Records included patient age and year of diagnosis; clinical and pathologic information at diagnosis; and dates and results of all surveillance tests, including PSA values and biopsy results, dates of curative treatment, and vital status. Cohort inclusion criteria, surveillance strategies, and conditions for referral to treatment are summarized in Table 1. Table 1. Eligibility Criteria, Surveillance Protocol, and Definition of Progression in 4 Active Surveillance Studies Johns Hopkins University The Johns Hopkins University (JHU) (4) study began enrollment in 1995. Eligibility criteria are PSA density less than 0.15 g/L per mL, clinical stage T1c disease or lower, a Gleason score (GS) between 2 and 6, at most 2 positive biopsy cores, and at most 50% tumor in any single core. Men are monitored with a PSA test and digital rectal examination every 6 months and annual biopsies. Curative intervention is recommended for disease progression, defined as any adverse change on prostate biopsy. Canary Prostate Active Surveillance Study The Canary Prostate Active Surveillance Study (PASS) (3) began enrollment in 2008. Eligibility criteria are clinical stage T1 or T2 disease and either a 10-core biopsy less than 1 year before enrollment or at least 2 biopsies, 1 of which must be less than 1 year before enrollment (3). Men are monitored with PSA tests every 3 months, a digital rectal examination every 6 months, and biopsies at 6 to 12, 24, 48, and 72 months after enrollment. Curative intervention is recommended if either biopsy GS or volume increases (from 33% to >33% of cores containing cancer). University of Toronto The University of Toronto (UT) (5) study began enrollment in 1995. Between 1995 and 1999, eligibility criteria were a PSA level of 10 g/L or less and a GS between 2 and 6 for men younger than 70 years and a PSA level of 15 g/L or less and a GS of at most 3+4= 7 for men aged 70 years or older. In January 2000, eligibility criteria were expanded to include PSA levels of 20 g/L or less and GSs of at most 3+4= 7 in men with substantial comorbid conditions or a life expectancy less than 10 years. Men are monitored with PSA tests every 3 months for 2 years and every 6 months thereafter. A confirmatory biopsy is done within 12 months of the initial biopsy and then every 3 to 4 years until the patient reaches age 80 years. Curative intervention is recommended in cases of histologic upgrading on repeated biopsy or clinical progression between biopsies (or PSA kinetics before 2009). University of California, San Francisco The University of California, San Francisco (UCSF) (6), study began enrollment in 1990. Eligibility criteria have evolved over time and are currently a PSA level of 10 g/L or less, clinical stage T1 or T2 disease, a biopsy GS between 2 and 6, at most 33% positive biopsy cores, and at most 50% tumor in any single core. Selected patients who do not satisfy these criteria may be enrolled, and these make up more than 30% of the cohort (6). Men are monitored with a confirmatory biopsy within 12 months of the initial biopsy and every 12 to 24 months thereafter. Curative intervention is recommended for any biopsy reclassification. Statistical Analysis Exclusion Criteria and End Point Definitions Patients diagnosed before 1995, older than 80 years at enrollment, or with a GS of 7 or more at diagnosis were excluded from the analysis to obtain a more homogeneous population (Supplement Table 1). Further, we standardized the definition of disease progression to focus exclusively on biopsy upgradingthat is, the first point at which a biopsy GS of 7 or more is reached. We also defined competing treatments as initiation of active treatment in the absence of biopsy upgrading, such as in response to increased biopsy volume or increased PSA growth. Accounting for differences in risks for competing treatments is important because cohorts with a high frequency of competing treatments may seem to have a lower risk for biopsy upgrading than similar cohorts with a low frequency of competing treatments even if their underlying risk for biopsy upgrading is similar. Supplement. Supplemental Materials Estimating the Underlying Risks for Upgrading The empirical risk for upgrading is affected by both the surveillance protocol and the frequency of competing treatment. Our first objective was to compare underlying risks for upgrading across surveillance cohortsrisks that would be seen in the absence of competing treatments. A standard approach for obtaining underlying risks, the KaplanMeier curve, is valid only if the competing event is independent of the event of interest. In the AS setting, upgrading and treatment initiation may be dependent. For example, if patients with higher PSA levels or PSA velocities tend to initiate treatment more frequently, this could induce dependence between initiating treatment and upgrading risk. When a dependent competing risk is present, the KaplanMeier approach is biased (11, 12). However, a commonly used alternative, the cumulative incidence estimate, captures the risk for the event of interest in the presence of the competing event and can therefore be sensitive to the competing risk. For example, 2 cohorts could have the same underlying risk for upgrading, but 1 with a higher incidence of competing treatment would seem to have a lower incidence of upgrading. To overcome this problem, we first evaluated the dependence of the 2 events using a regression model that allowed both events to depend on patient age and PSA kinetics. Allowing risks for both upgrading and competing treatment to depend on these common patient variables enabled us to capture their potential dependence on each other. For example, if the risks for upgrading and treatment initiation both increased with PSA velocity, the 2 risks would be positively correlated. In practice, we estimated a joint model for the evolution of the patient variables and the risks for upgrading and treatment initiation (1315). After fitting the joint model, we extracted the risk for upgrading in the absence of competing treatments using standard statistical formulas for obtaining marginal from conditional data summaries. This avoided the limitations of the KaplanMeier and cumulative incidence approaches. The joint model had the following 3 components. First, the PSA model was a linear mixed-effects model for log PSA that captured heterogeneity in patient PSA kinetics, which comprised baseline PSA and PSA velocity, defined as the annual percentage change in the PSA level. Second, the model for time to upgrading was a Weibull regression that modeled the risk for upgrading given patient age and PSA kinetics. This model assumed that biopsy GS had no misclassification error. Thus, patients with all biopsy GSs between 2 and 6 were right censored for the event of upgrading (that is, their upgrading event could occur only after the end of their follow-up), and patients with an observed biopsy GS of 7 or higher must have upgraded after the prior biopsy but before this biopsy. Third, the model for time to competing treatment was another Weibull regression that modeled the risk for treatment initiation given patient age and PSA kinetics. We used Bayesian methods to estimate the 3 models simultaneously (Section 1 of the Supplement). We did not attempt to model pathologic GS because previous work encountered substantial difficulties in doing so using serial biopsies among men receiving AS (16). Predicting Consequences Under More Versus Less Intensive Surveillance Protocols Using the fitted joint model, we simulated times to upgrading in each cohort in the absence of competing treatments. We then superimposed surveillance protocols that involved regular biopsies every 1, 2, 3, and 4 years to determine the earliest point at which a biopsy would detect the upgrade. To acknowledge the clinical value of a confirmatory biopsy, w

Semantics in active surveillance for men with localized prostate cancer — results of a modified Delphi consensus procedure

This study is linked to a larger project, The Movember Foundations Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative, which is a collaboration between institutions, hospitals and research centres from the USA, Canada, Australia, Singapore, Japan, Korea, UK, Ireland, the Netherlands, France, Sweden, Finland, Switzerland, Italy and Spain. The Movember Foundation has invested 1,664,950 euros in GAP3 to create the largest centralized prostate cancer active surveillance database to date. This funder did not have any role in the study design, collection, analysis or interpretation of data, or in the drafting of this paper. For information, contact M.J.R. m.roobol@erasmusmc.nl.