D.M. Somford

Relationship between Apparent Diffusion Coefficients at 3.0-T MR Imaging and Gleason Grade in Peripheral Zone Prostate Cancer

PURPOSE To retrospectively determine the relationship between apparent diffusion coefficients (ADCs) obtained with 3.0-T diffusion-weighted (DW) magnetic resonance (MR) imaging and Gleason grades in peripheral zone prostate cancer. MATERIALS AND METHODS The requirement to obtain institutional review board approval was waived. Fifty-one patients with prostate cancer underwent MR imaging before prostatectomy, including DW MR imaging with b values of 0, 50, 500, and 800 sec/mm(2). In prostatectomy specimens, separate slice-by-slice determinations of Gleason grade groups were performed according to primary, secondary, and tertiary Gleason grades. In addition, tumors were classified into qualitative grade groups (low-, intermediate-, or high-grade tumors). ADC maps were aligned to step-sections and regions of interest annotated for each tumor slice. The median ADC of tumors was related to qualitative grade groups with linear mixed-model regression analysis. The accuracy of the median ADC in the most aggressive tumor component in the differentiation of low- from combined intermediate- and high-grade tumors was summarized by using the area under the receiver operating characteristic (ROC) curve (A(z)). RESULTS In 51 prostatectomy specimens, 62 different tumors and 251 step-section tumor lesions were identified. The median ADC in the tumors showed a negative relationship with Gleason grade group, and differences among the three qualitative grade groups were statistically significant (P < .001). Overall, with an increase of one qualitative grade group, the median ADC (±standard deviation) decreased 0.18 × 10(-3) mm(2)/sec ± 0.02. Low-, intermediate-, and high-grade tumors had a median ADC of 1.30 × 10(-3) mm(2)/sec ± 0.30, 1.07 × 10(-3) mm(2)/sec ± 0.30, and 0.94 × 10(-3) mm(2)/sec ± 0.30, respectively. ROC analysis showed a discriminatory performance of A(z) = 0.90 in discerning low-grade from combined intermediate- and high-grade lesions. CONCLUSION ADCs at 3.0 T showed an inverse relationship to Gleason grades in peripheral zone prostate cancer. A high discriminatory performance was achieved in the differentiation of low-, intermediate-, and high-grade cancer.

Magnetic Resonance Imaging Guided Prostate Biopsy in Men With Repeat Negative Biopsies and Increased Prostate Specific Antigen

PURPOSE Undetected cancer in repeat transrectal ultrasound guided prostate biopsies in patients with increased prostate specific antigen greater than 4 ng/ml is a considerable concern. We investigated the tumor detection rate of tumor suspicious regions on multimodal 3 Tesla magnetic resonance imaging and subsequent magnetic resonance imaging guided biopsy in 68 men with repeat negative transrectal ultrasound guided prostate biopsies. We compared results to those in a matched transrectal ultrasound guided prostate biopsy population. Also, we determined the clinical significance of detected tumors. MATERIALS AND METHODS A total of 71 consecutive patients with prostate specific antigen greater than 4 ng/ml and 2 or greater negative transrectal ultrasound guided prostate biopsy sessions underwent multimodal 3 Tesla magnetic resonance imaging. In 68 patients this was followed by magnetic resonance imaging guided biopsy directed toward tumor suspicious regions. A matched multisession transrectal ultrasound guided prostate biopsy population from our institutional database was used for comparison. The clinical significance of detected tumors was established using accepted criteria, including prostate specific antigen, Gleason grade, stage and tumor volume. RESULTS The tumor detection rate of multimodal 3 Tesla magnetic resonance imaging guided biopsy was 59% (40 of 68 cases) using a median of 4 cores. The tumor detection rate was significantly higher than that of transrectal ultrasound guided prostate biopsy in all patient subgroups (p <0.01) except in those with prostate specific antigen greater than 20 ng/ml, prostate volume greater than 65 cc and prostate specific antigen density greater than 0.5 ng/ml/cc, in which similar rates were achieved. Of the 40 patients with identified tumors 37 (93%) were considered highly likely to harbor clinically significant disease. CONCLUSIONS Multimodal magnetic resonance imaging is an effective technique to localize prostate cancer. Magnetic resonance imaging guided biopsy of tumor suspicious regions is an accurate method to detect clinically significant prostate cancer in men with repeat negative biopsies and increased prostate specific antigen.

Value of 3-T multiparametric magnetic resonance imaging and magnetic resonance-guided biopsy for early risk restratification in active surveillance of low-risk prostate cancer: a prospective multicenter cohort study

ObjectivesThe objective of this study was to evaluate the role of 3-T multiparametric magnetic resonance imaging (MP-MRI) and magnetic resonance–guided biopsy (MRGB) in early risk restratification of patients on active surveillance at 3 and 12 months of follow-up. Materials and MethodsWithin 4 hospitals participating in a large active surveillance trial, a side study was initiated. Pelvic magnetic resonance imaging, prostate MP-MRI, and MRGB were performed at 3 and 12 months (latter prostate MP-MRI and MRGB only) after prostate cancer diagnosis in 1 of the 4 participating hospitals. Cancer-suspicious regions (CSRs) were defined on prostate MP-MRI using Prostate Imaging Reporting And Data System (PI-RADS) scores.Risk restratification criteria for active surveillance discontinuance were (1) histopathologically proven magnetic resonance imaging suspicion of node/bone metastases and/or (2) a Gleason growth pattern (GGP) 4 and/or 5 and/or cancer multifocality (≥3 foci) in MRGB specimens of a CSR on MP-MRI. ResultsFrom 2009 to 2012, a total of 64 of 82 patients were consecutively and prospectively included and underwent MP-MRI and a subsequent MRGB. At 3 and 12 months of follow-up, 14% (9/64) and 10% (3/30) of the patients were risk-restratified on the basis of MP-MRI and MRGB. An overall CSR PI-RADS score of 1 or 2 had a negative predictive value of 84% (38/45) for detection of any prostate cancer and 100% (45/45) for detection of a GGP 4 or 5 containing cancer upon MRGB, respectively. A CSR PI-RADS score of 4 or higher had a sensitivity of 92% (11/12) for detection of a GGP 4 or 5 containing cancer upon MRGB. ConclusionsApplication of MP-MRI and MRGB in active surveillance may contribute in early identification of patients with GGP 4 or 5 containing cancers at 3 months of follow-up. If, during further follow-up, a PI-RADS score of 1 or 2 continues to have a negative predictive value for GGP 4 or 5 containing cancers, a PI-RADS standardized reported MP-MRI may be a promising tool for the selection of prostate cancer patients suitable for active surveillance.

Initial experience with identifying high-grade prostate cancer using diffusion-weighted MR imaging (DWI) in patients with a Gleason score </= 3 + 3 = 6 upon schematic TRUS-guided biopsy: a radical prostatectomy correlated series.

Introduction:Diffusion-weighted magnetic resonance (MR) imaging (DWI) might be able to fulfill the need to accurately identify high-grade prostate carcinoma, in patients initially selected for active surveillance in the Prostate Specific Antigen (PSA) screening era based on transrectal ultrasound-guided biopsy Gleason score. We aimed to determine whether DWI is able to correctly identify those patients with a biopsy Gleason score of ⩽3 + 3 = 6, but harboring Gleason 4 and/or 5 components in their radical prostatectomy (RP) specimen. Materials and Methods:Whole-mount RP specimens were used to identify regions of interest corresponding with tumor on the DWI-derived apparent diffusion coefficient (ADC) maps in 23 patients with a Gleason ⩽3 + 3 = 6 on biopsy. ADC values were correlated with RP Gleason grades. Statistical analysis was performed by calculating area under the receiver operating characteristic curve for identification of prostate cancer with Gleason 4 and/or 5 components using DWI, and Mann-Whitney U testing was performed to detect differences in median ADC values for tumors with presence of Gleason grade 4 and/or 5 versus a highest Gleason grade of ⩽3 on RP. Results:A diagnostic accuracy of median ADC values for identifying patients subject to transrectal ultrasound-guided biopsy undergrading with an area under the receiver operating characteristic curve of 0.88 was established using RP Gleason score as a reference. In patients harboring a Gleason 4 and/or 5 component, the median ADC was 0.86 × 10(−3) mm2/s (standard deviation ± 0.21), whereas patients harboring no Gleason 4 and/or 5 component displayed a median ADC of 1.16 × 10(−3) mm2/s (standard deviation ± 0.19) for the single tumor slice with the lowest median ADC (P < 0.002). Conclusions:DWI is able to predict the presence of high-grade tumor in patients with a Gleason ⩽3 + 3 = 6 on biopsy, providing important information for treatment decisions.

Evaluation of diffusion-weighted MR imaging at inclusion in an active surveillance protocol for low-risk prostate cancer

PurposeWe aimed to determine whether diffusion-weighted magnetic resonance imaging, by means of the apparent diffusion coefficient (ADC), is able to guide magnetic resonance–guided biopsy in patients fit for active surveillance (AS) and identify patients harboring high-grade Gleason components not suitable for AS. Materials and MethodsOur study was approved by the institutional review board of all participating hospitals, and all patients signed informed consent at inclusion. Fifty-four consecutive patients with low-risk prostate cancer (PCa) underwent multiparametric magnetic resonance imaging (MP-MRI) at inclusion for AS. Cancer-suspicious regions (CSRs) upon 3-T MP-MRI were identified in all patients, and magnetic resonance–guided biopsy was performed in all CSRs to obtain histopathological verification. For all CSRs, a median ADC (mADC) was calculated. Wilcoxon signed ranks and Mann-Whitney tests was performed to detect differences between the groups. We used the area under the receiver operating characteristic curve to evaluate the accuracy of mADC to predict the presence of PCa in a CSR. Level of statistical significance was set at P < 0.05. ResultsMean mADC in the CSRs with PCa was 1.04 × 10−3 mm2/s (SD, 0.29), whereas the CSRs with no PCa displayed a mean mADC of 1.26 × 10−3 mm2/s (SD, 0.25; P < 0.001). Cancer-suspicious regions with a high-grade Gleason component displayed a mean mADC of 0.84 × 10−3 mm2/s (SD, 0.35) vs a mean mADC for the low-grade CSRs of 1.09 × 10−3 mm2/s (SD, 0.25; P < 0.05). A diagnostic accuracy of mADC for predicting the presence of PCa in a CSR with an area under the receiver operating characteristic curve of 0.73 was established (95% confidence interval, 0.61–0.84). ConclusionsMedian ADC is able to predict the presence and grade of PCa in CSRs identified by MP-MRI.

Pharmacokinetic Aspects of the Two Novel Oral Drugs Used for Metastatic Castration-Resistant Prostate Cancer: Abiraterone Acetate and Enzalutamide

Two novel oral drugs that target androgen signaling have recently become available for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Abiraterone acetate inhibits the synthesis of the natural ligands of the androgen receptor, whereas enzalutamide directly inhibits the androgen receptor by several mechanisms. Abiraterone acetate and enzalutamide appear to be equally effective for patients with mCRPC pre- and postchemotherapy. Rational decision making for either one of these drugs is therefore potentially driven by individual patient characteristics. In this review, an overview of the pharmacokinetic characteristics is given for both drugs and potential and proven drug–drug interactions are presented. Additionally, the effect of patient-related factors on drug disposition are summarized and the limited data on the exposure–response relationships are described. The most important pharmacological feature of enzalutamide that needs to be recognized is its capacity to induce several key enzymes in drug metabolism. The potency to cause drug–drug interactions needs to be addressed in patients who are treated with multiple drugs simultaneously. Abiraterone has a much smaller drug–drug interaction potential; however, it is poorly absorbed, which is affected by food intake, and a large interpatient variability in drug exposure is observed. Dose reductions of abiraterone or, alternatively, the selection of enzalutamide, should be considered in patients with hepatic dysfunction. Understanding the pharmacological characteristics and challenges of both drugs could facilitate decision making for either one of the drugs.

Value of Serial Multiparametric Magnetic Resonance Imaging and Magnetic Resonance Imaging–guided Biopsies in Men with Low-risk Prostate Cancer on Active Surveillance After 1 Yr Follow-up

BACKGROUND Active surveillance (AS) aims to reduce overtreatment of low-risk prostate cancer (PC). Incorporating multiparametric magnetic resonance imaging (mp-MRI) and MR-guided biopsy (MRGB) in an AS protocol might contribute to more accurate identification of AS candidates. OBJECTIVE To evaluate the value of 3T mp-MRI and MRGB in PC patients on AS at inclusion and after 12-mo follow-up. DESIGN, SETTING, AND PARTICIPANTS Patients with cT1c-cT2 PC, prostate-specific antigen (PSA) ≤10ng/ml, PSA density <0.2ng/ml/ml, and Gleason scores (GSs) of ≤6 and ≤2 positive biopsy cores were included and followed in an AS protocol including mp-MRI and MRGB. The mp-MRI and MRGB were performed at <3 and 12 mo after diagnosis. Reclassification was defined as GS >6, >2 positive cores at repeat transrectal ultrasound-guided biopsy (TRUSGB), presence of PC in >3 separate cancer foci upon both MRGB and TRUSGB, or cT3 tumor on mp-MRI. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Reclassification rates, treatment after discontinuation, and outcome on radical prostatectomy after discontinuing AS were reported. Uni- and multivariate analyses were performed to identify predictors of reclassification after 1 yr. RESULTS AND LIMITATIONS From 2009 to 2013, a total of 111 of 158 patients were consecutively and prospectively included. Around initial diagnosis, 36 patients were excluded from the study protocol; mp-MRI+MRGB reclassified 25/111 (23%) patients, and 11 patients were excluded at own request. Reasons for reclassification were as follows: GS upgrade (15/25, 60%); cT3 disease (3/25, 12%); suspicion of bone metastases (1/25, 4%); and multifocal disease upon MRGB (6/25, 24%). Repeat examinations after 1 yr showed reclassification in 33/75 patients (44%). Reasons were the following: GS upgrade upon TRUSGB (9/33, 27%); volume progression upon TRUSGB (9/33, 27%); cT3 disease upon mp-MRI (1/33, 3%); GS upgrade upon MRGB (1/33, 3%); volume progression upon MRGB (1/33, 3%); multifocal disease upon MRGB (2/33, 6%); and upgrade or upstage upon both TRUSGB and MRGB (10/33, 30%). On logistic regression analysis, the presence of cancer at initial mp-MRI and MRGB examinations was the only predictor of reclassification after 1 yr (odds ratio 5.9, 95% confidence interval 2.0-17.6). CONCLUSIONS Although mp-MRI and MRGB are of additional value in the evaluation of PC patients on AS, the value of mp-MRI after 1 yr was limited. As a considerable percentage of GS ≥7 PC after 1 yr was detected only by TRUSGB, TRUSGB cannot be omitted yet. PATIENT SUMMARY More aggressive tumors are detected if low-risk prostate cancer patients are additionally monitored by magnetic resonance imaging. However, some high-grade tumors are detected only by transrectal ultrasound-guided biopsy.

Urinary cytokines in patients treated with intravesical mitomycin-C with and without hyperthermia.

ObjectivesTo explore whether urinary cytokine and chemokine (CK) levels differed between cold mitomycin-C (cold-MMC)-treated patients and chemohyperthermia (C-HT)-treated patients, to shed light on the possible molecular mechanisms that might explain the superior outcome of C-HT. Furthermore, CK-differences were explored between C-HT responders and C-HT non-responders.MethodsTwelve NMIBC patients were included. Nine received six-weekly C-HT, and three received four-weekly cold-MMC instillations. Urine was collected on 8–12 time points before and after every treatment. MDC, IL-2, IL-6, IL-8, IP-10, MCP-1 and RANTES were determined by Luminex®-analysis.ResultsElevated urinary CK levels were observed in both groups after treatment. In general, CK-peaks were lower in the cold-MMC group in comparison with levels in the C-HT group. Significant higher MCP-1 and IL-6 levels were observed in C-HT-treated patients. Additionally, significant cumulative effects were observed for IP-10 and IL-2. However, IP-10 and IL-2 levels did not significantly differ between treatments. MDC levels after the first week of treatment were significantly higher in the C-HT responders compared with the non-responders.ConclusionMMC treatment leads to elevated urinary CK levels with significantly higher MCP-1 and IL-6 levels in C-HT-treated patients. Increased MDC levels after the first C-HT instillation appear to be related to good clinical outcome and might be of additional value to personalize treatment. Studies involving more patients and longer follow-up are needed to substantiate this observation.

Drug–drug interaction potential in men treated with enzalutamide: Mind the gap

AIMS Metastatic castration-resistant prostate cancer (mCRPC) patients are generally older patients with several co-morbidities and are therefore at increased risk of complications due to drug-drug interactions (DDIs). We assessed the prevalence of potential DDIs in a cohort of mCRPC patients treated with enzalutamide. METHODS We conducted a retrospective review of pharmacy records to retrieve individual drug histories of mCRPC patients who started enzalutamide therapy in a tertiary care setting. Potential DDIs were analysed using two international drug interaction compendia: Lexicomp® and Micromedex® , and the Dutch drug database. Two potential pharmacodynamic DDIs were analysed. RESULTS A total of 105 records were evaluated for potential DDIs with enzalutamide. Of 205 different co-medications, 56 were flagged by at least one of the three compendia: Lexicomp, Micromedex and the Dutch drug database flagged for potential DDIs in 85%, 54% and 32%, respectively. Eighty-five per cent of DDIs were classified as major. The median number of co-medications per patient was 11 (range 1-26). The median (range) number of interactions per patient was 4 (0-10), 1 (0-5) and 0 (0-2) for Lexicomp, Micromedex and the Dutch drug database, respectively. In 23% and 45% of all patients, a potential DDI was found with PPIs and CNS depressants, respectively. CONCLUSIONS A high prevalence of potential DDIs was found. The inclusion and grading of potential DDIs was highly variable between the three drug interaction compendia. Physicians, nurses and pharmacists should be aware of this potential problem, which might require intensive monitoring or alternative treatment strategies to prevent suboptimal treatment of the co-morbidities in patients treated with enzalutamide.

VALUE OF 3 TESLA MULTI-MODALITY DIRECTED MR GUIDED BIOPSY TO DETECT PROSTATE CANCER IN PATIENTS AFTER AT LEAST TWO PREVIOUS NEGATIVE BIOPSIES AND ELEVATED PSA

(MRI), a novel platform that registers and fuses real-time US images with pre-procedure MRI was used. Feasibility and initial experience with MRUS fused targeted prostate biopsies with real time tracking performed outside MRI is described. METHODS: Under an IRB approved protocol patients with suspicion of prostate cancer (elevated PSA, history of prostate cancer) underwent a 3T endorectal-coil prostate MRI with T1, T2 weighted, dynamic contrast enhanced, diffusion weighted, and spectroscopy images. Lesions identified on MRI were scored for level of suspicion for cancer. A traditional 12-core US guided prostate biopsy was then performed. Subsequently, biopsies of MRI targeted lesions were performed using a custom probe and needle guide with spatial tracking within an electromagnetic field. Prostate US images were fused to MR images allowing for real-time US images and projected needle pathways on the corresponding MR location. RESULTS: 51 patients, mean age 62 (49-79) and mean PSA 8.1 (0.3 -46.9), underwent US-MR tracked fusion biopsy. 31 patients had prior prostate biopsy with 20 having known prostate cancer. 703 standard sextant biopsy cores and 352 tracked biopsy cores from 144 MRI targets were obtained. Core biopsies were analyzed by region (considered positive if at least 1 core at that region was positive). 18% (57/324) of the sextant regions and 25% (36/144) of the tracked regions were positive for cancer. 57% (29/51) of patients had positive biopsy with 19 (65%) on both sextant and tracked biopsy, 6 (21%) only positive on sextant biopsy and 4 (14%) on tracked biopsy only. Targets with increasing suspicion on MRI were more likely to be positive for cancer (see table). CONCLUSIONS: This phase I study demonstrates the feasibility and the clinical value (detecting 4 additional cases of cancer) of MR targeting of prostate lesions using real-time US images fused to preprocedure MRI and spatial tracking technology. Further studies are required to determine its role in cancer detection.