Reducing Biopsies and Magnetic Resonance Imaging Scans During the Diagnostic Pathway of Prostate Cancer: Applying the Rotterdam Prostate Cancer Risk Calculator to the PRECISION Trial Data

Background: Risk stratification in the diagnostic pathway of prostate cancer (PCa) can be used to reduce biopsies and magnetic resonance imaging (MRI) scans, while maintaining the detection of clinically significant PCa (csPCa). The use of highly discriminating and well-calibrated models will generate better clinical outcomes if context-dependent thresholds are used. Objective: To retrospectively assess the effect of the upfront use of the Rotterdam Prostate Cancer Risk Calculator (RPCRC) developed in a screening cohort and the RPCRC-MRI developed in a clinical cohort while exploring the need to adapt thresholds in biopsy-naïve men in the PRECISION (Prostate Evaluation for Clinically Important Disease: Sampling Using Image Guidance or Not?) trial. Design, setting, and participants: In the transrectal ultrasonography arm, we evaluated 188 men; in the MRI arm, we evaluated 206 (for the reduction of MRI scans) and 137 (for the reduction of targeted biopsies) men. Outcome measurements and statistical analysis: Performance was assessed by discrimination, calibration, and clinical utility. Results and limitations: The performance of the RPCRC was good. However, intercept adjustment was warranted. Net benefit was observed from a recalibrated probability of 32% for any PCa and 10% for csPCa. After recalibration and applying a threshold of 20% for any PCa or 10% for csPCa, 28% of all biopsies could have been reduced, missing five cases of csPCa. The uncalibrated RPCRC could reduce 35% of all MRI scans, with a threshold of 20% for any PCa or 4% for csPCa. In the MRI arm, performance was good without stressing recalibration. Net benefit was observed from a probability of 22% for any PCa and 7% for csPCa. With a threshold of 20% for any PCa or 4% for csPCa, 9% of all targeted biopsies could be reduced, missing one grade group 2 PCa. Conclusions: The performance of the RPCRC and RPCRC-MRI in men included in the PRECISION trial was good, but recalibration and adaptation of the risk threshold of the RPCRC are indicated to reach optimal performance. Patient summary: In this report, we show that risk stratification with the Rotterdam Prostate Cancer Risk Calculator has added value in reducing harm, but adjustment to reflect the characteristics of the patient cohort is indicated

Physiologically based pharmacokinetic/ pharmacodynamic model for the prediction of morphine brain disposition and analgesia in adults and children

Morphine is a widely used opioid analgesic, which shows large differences in clinical response in children, even when aiming for equivalent plasma drug concentrations. Age-dependent brain disposition of morphine could contribute to this variability, as developmental increase in blood-brain barrier (BBB) P-glycoprotein (Pgp) expression has been reported. In addition, age-related pharmacodynamics might also explain the variability in effect. To assess the influence of these processes on morphine effectiveness, a multi-compartment brain physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) model was developed in R (Version 3.6.2). Active Pgp-mediated morphine transport was measured in MDCKII-Pgp cells grown on transwell filters and translated by an in vitro-in vivo extrapolation approach, which included developmental Pgp expression. Passive BBB permeability of morphine and its active metabolite morphine-6-glucuronide (M6G) and their pharmacodynamic parameters were derived from experiments reported in literature. Model simulations after single dose morphine were compared with measured and published concentrations of morphine and M6G in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF), as well as published drug responses in children (1 day– 16 years) and adults. Visual predictive checks indicated acceptable overlays between simulated and measured morphine and M6G concentration-time profiles and prediction errors were between 1 and -1. Incorporation of active Pgp-mediated BBB transport into the PB-PK/PD model resulted in a 1.3-fold reduced brain exposure in adults, indicating only a modest contribution on brain disposition. Analgesic effect-time profiles could be described reasonably well for older children and adults, but were largely underpredicted for neonates. In summary, an age-appropriate morphine PB-PK/PD model was developed for the prediction of brain pharmacokinetics and analgesic effects. In the neonatal population, pharmacodynamic characteristics, but not brain drug disposition, appear to be altered compared to adults and older children, which may explain the reported differences in analgesic effect

Prostate cancer upgrading with serial prostate magnetic resonance imaging and repeat biopsy in men on active surveillance: are confirmatory biopsies still necessary?

Objectives: To investigate whether serial prostate magnetic resonance imaging (MRI) may guide the utility of repeat targeted (TBx) and systematic biopsy (SBx) when monitoring men with low-risk prostate cancer (PCa) at 1-year of active surveillance (AS). Patients and Methods: We retrospectively included 111 consecutive men with low-risk (International Society of Urological Pathology [ISUP] Grade 1) PCa, who received protocolled repeat MRI with or without TBx and repeat SBx at 1-year of AS. TBx was performed in Prostate Imaging-Reporting and Data System (PI-RADS) score ≥3 lesions (MRI-positive men). Upgrading defined as ISUP Grade ≥2 PCa (I), Grade ≥2 with cribriform growth/intraductal carcinoma PCa (II), and Grade ≥3 PCa (III) was investigated. Upgrading detected by TBx only (not by SBx) and SBx only (not by TBx) was investigated in MRI-positive and -negative men, and related to radiological progression on MRI (Prostate Cancer Radiological Estimation of Change in Sequential Evaluation [PRECISE] score). Results: Overall upgrading (I) was 32% (35/111). Upgrading in MRI-positive and -negative men was 48% (30/63) and 10% (5/48) (P < 0.001), respectively. In MRI-positive men, there was upgrading in 23% (seven of 30) by TBx only and in 33% (10/30) by SBx only. Radiological progression (PRECISE score 4–5) in MRI-positive men was seen in 27% (17/63). Upgrading (I) occurred in 41% (seven of 17) of these MRI-positive men, while this was 50% (23/46) in MRI-positive men without radiological progression (PRECISE score 1–3) (P = 0.534). Overall upgrading (II) was 15% (17/111). Upgrading in MRI-positive and -negative men was 22% (14/63) and 6% (three of 48) (P = 0.021), respectively. In MRI-positive men, there was upgrading in three of 14 by TBx only and in seven of 14 by SBx only. Overall upgrading (III) occurred in 5% (five of 111). Upgrading in MRI-positive and -negative men was 6% (four of 63) and 2% (one of 48) (P = 0.283), respectively. In MRI-positive men, there was upgrading in one of four by TBx only and in two of four by SBx only. Conclusion: Upgrading is significantly lower in MRI-negative compared to MRI-positive men with low-risk PCa at 1-year of AS. In serial MRI-negative men, the added value of repeat SBx at 1-year surveillance is limited and should be balanced individually against the harms. In serial MRI-positive men, the added value of repeat SBx is substantial. Based on this cohort, SBx is recommended to be performed in combination with TBx in all MRI-positive men at 1-year of AS, also when there is no radiological progression

Risk-Based Selection for Active Surveillance:Results of the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) Initiative

PURPOSE: We sought to identify and validate known predictors of disease reclassification at 1 or 4 years to support risk-based selection of patients suitable for active surveillance. MATERIALS AND METHODS: An individual participant data meta-analysis using data from 25 established cohorts within the Movember Foundations GAP3 Consortium. In total 5,530 men were included. Disease reclassification was defined as any increase in Gleason grade group at biopsy at 1 and 4 years. Associations were estimated using random effect logistic regression models. The discriminative ability of combinations of predictors was assessed in an internal-external validation procedure using the AUC curve. RESULTS: Among the 5,570 men evaluated at 1 year, we found 815 reclassifications to higher Gleason grade group at biopsy (pooled reclassification rate 13%, range 0% to 31%). Important predictors were age, prostate specific antigen, prostate volume, T-stage and number of biopsy cores with prostate cancer. Among the 1,515 men evaluated at 4 years, we found 205 reclassifications (pooled reclassification rates 14%, range 3% to 40%), with similar predictors. The average areas under the receiver operating characteristic curve at internal-external validation were 0.68 and 0.61 for 1-year and 4-year reclassification, respectively. CONCLUSIONS: Disease reclassification occurs typically in 13% to 14% of biopsies at 1 and 4 years after the start of active surveillance with substantial between-study heterogeneity. Current guidelines might be extended by considering prostate volume to improve individualized selection for active surveillance. Additional predictors are needed to improve patient selection for active surveillance

Risk-Based Selection for Active Surveillance: Results of the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) Initiative

PURPOSE: We sought to identify and validate known predictors of disease reclassification at 1 or 4 years to support risk-based selection of patients suitable for active surveillance. MATERIALS AND METHODS: An individual participant data meta-analysis using data from 25 established cohorts within the Movember Foundations GAP3 Consortium. In total 5,530 men were included. Disease reclassification was defined as any increase in Gleason grade group at biopsy at 1 and 4 years. Associations were estimated using random effect logistic regression models. The discriminative ability of combinations of predictors was assessed in an internal-external validation procedure using the AUC curve. RESULTS: Among the 5,570 men evaluated at 1 year, we found 815 reclassifications to higher Gleason grade group at biopsy (pooled reclassification rate 13%, range 0% to 31%). Important predictors were age, prostate specific antigen, prostate volume, T-stage and number of biopsy cores with prostate cancer. Among the 1,515 men evaluated at 4 years, we found 205 reclassifications (pooled reclassification rates 14%, range 3% to 40%), with similar predictors. The average areas under the receiver operating characteristic curve at internal-external validation were 0.68 and 0.61 for 1-year and 4-year reclassification, respectively. CONCLUSIONS: Disease reclassification occurs typically in 13% to 14% of biopsies at 1 and 4 years after the start of active surveillance with substantial between-study heterogeneity. Current guidelines might be extended by considering prostate volume to improve individualized selection for active surveillance. Additional predictors are needed to improve patient selection for active surveillance