Clinical Significance of Perineural Invasion in Men With Grade Group 1 Prostate Cancer on Active Surveillance.

PURPOSE: We aimed to evaluate the clinical significance of perineural invasion in men on active surveillance for Grade Group 1 prostate cancer. MATERIALS AND METHODS: We identified 1,969 men with Grade Group 1 prostate cancer and at least 1 follow-up biopsy. A time-dependent Cox model and a logistic regression model were used to assess the association between biopsy-detected perineural invasion and grade reclassification (defined as the detection of Grade Group ≥2 prostate cancer on a surveillance biopsy), and adverse pathology (defined as Grade Group ≥3 ± seminal vesicle invasion ± lymph node involvement) at radical prostatectomy, respectively. RESULTS: The 198 men with perineural invasion detected during active surveillance had lower rates of grade reclassification-free survival than those without perineural invasion (P < .001). On multivariable analysis perineural invasion was significantly associated with grade reclassification (HR 3.25, 95% CI 2.54-4.16, P < .001); an association that persisted in the multiparametric magnetic resonance imaging subset. At radical prostatectomy, men with biopsy-detected perineural invasion had more extraprostatic extension than men without perineural invasion (Relative Risk 1.71, 95% CI 1.15-2.56). However, on multivariable analysis biopsy-detected perineural invasion was not associated with adverse pathology (OR 0.68, 95% CI 0.27-1.68, P = .40) and these patients did not exhibit more biochemical recurrence at 5 years (P > .05). CONCLUSIONS: Perineural invasion during active surveillance was associated with grade reclassification. At radical prostatectomy biopsy-detected perineural invasion patients exhibited more extraprostatic extension but biopsy-detected perineural invasion was not independently associated with more adverse pathology. In addition, these patients did not have more biochemical recurrence during follow-up. Perineural invasion should not preclude Grade Group 1 patients from active surveillance but they may warrant more stringent monitoring.

Identifying Men Who Can Remain on Active Surveillance Despite Biopsy Reclassification to Grade Group 2 Prostate Cancer.

PURPOSE: Men on active surveillance with Grade Group 1 prostate cancer who reclassify to Grade Group 2 on surveillance biopsy often leave active surveillance. We aimed to identify subgroups of men who can safely remain on active surveillance despite preoperative reclassification to Grade Group 2. MATERIALS AND METHODS: We studied 249 active surveillance patients with surveillance biopsies classified as Grade Group 1 or Grade Group 2 who underwent radical prostatectomy. Perineural invasion, cancer volume, linear length and maximum percentage of Gleason pattern 4, and prostate-specific antigen density were evaluated. Radical prostatectomy adverse pathology was defined by any of: pN1; ≥pT3; ≥Grade Group 2 with ≥20% Gleason pattern 4; intraductal carcinoma; large cribriform glands. RESULTS: A multivariable logistic regression model incorporating prostate-specific antigen density and perineural invasion stratified radical prostatectomy adverse pathology risk among Grade Group 1 and Grade Group 2 active surveillance patients. 57% (39/68) of Grade Group 1 men reclassified to Grade Group 2 while on active surveillance had favorable radical prostatectomy pathology. Those without biopsy perineural invasion and with low prostate-specific antigen density were more likely to have favorable radical prostatectomy pathology. CONCLUSIONS: Most Grade Group 1 men who enter active surveillance and subsequently reclassify to Grade Group 2 have favorable findings at radical prostatectomy and can remain on active surveillance. Among patients reclassified to Grade Group 2, those with low prostate-specific antigen density and without perineural invasion had the lowest risk of radical prostatectomy adverse pathology, comparable to (or below) that of Grade Group 1 patients who were not reclassified to Grade Group 2 preoperatively. Prostate-specific antigen density and perineural invasion stratify risk in active surveillance patients reclassified to Grade Group 2 and, if concordant with other clinicopathological and radiographic findings, can enable more patients to remain on active surveillance. Reclassification to Grade Group 2 alone should not disqualify men from remaining on active surveillance.

Association of prostate cancer polygenic risk score with number and laterality of tumor cores in active surveillance patients.

BACKGROUND: Prostate cancer (PCa) is characterized by its tendency to be multifocal. However, few studies have investigated the endogenous factors that explain the multifocal disease. The primary objective of the current study is to test whether inherited PCa risk is associated with multifocal tumors in PCa patients. METHODS: Subjects in this study were PCa patients of European ancestry undergoing active surveillance at Johns Hopkins Hospital (N = 805) and NorthShore University HealthSystem (N = 432). The inherited risk was measured by genetic risk score (GRS), an odds ratio-weighted and population-standardized polygenic risk score based on known risk-associated single nucleotide polymorphisms. PCa multifocality was indirectly measured by the number and laterality of positive tumor cores from a 12-core systematic biopsy. RESULTS: In the combined cohort, 35.7% and 66.3% of patients had ≥2 tumor cores at the initial diagnostic biopsy and on at least one subsequent surveillance biopsy, respectively. For tumor laterality, 7.8% and 47.8% of patients had bilateral tumor cores at diagnostic and surveillance biopsies, respectively. We found, for the first time, that patients with higher numbers of positive cores at diagnostic and surveillance biopsies, respectively, had significantly higher mean GRS values; p = .01 and p = 5.94E-04. Additionally, patients with bilateral tumors at diagnostic and surveillance biopsies, respectively, had significantly higher mean GRS values than those with unilateral tumors; p = .04 and p = .01. In contrast, no association was found between GRS and maximum core length of tumor or tumor grade at diagnostic/surveillance biopsies (all p > .05). Finally, we observed a modest trend that patients with higher GRS quartiles had a higher risk for tumor upgrading on surveillance biopsies. The trend, however, was not statistically significant (p > .05). CONCLUSIONS: The associations of GRS with two measurements of PCa multifocality (core numbers and laterality) provide novel and consistent evidence for the link between inherited PCa risk and multifocal tumors.

Transperineal Prostate Biopsy Improves the Detection of Clinically Significant Prostate Cancer among Men on Active Surveillance.

PURPOSE: Transperineal prostate biopsy offers improved sampling of the anterior prostate compared to the transrectal approach. The objective of this study was to determine if transperineal prostate biopsy is associated with an increased incidence of cancer upgrading among men on active surveillance for very low or low risk prostate cancer. MATERIALS AND METHODS: Our active surveillance registry was queried to identify patients who underwent a surveillance biopsy following the introduction of transperineal prostate biopsy at our institution. Patients were dichotomized by the type of biopsy performed. The baseline characteristics and rates of cancer upgrading were compared between groups. RESULTS: Between November 2017 and June 2020, 790 men with very low or low risk prostate cancer underwent a surveillance biopsy. In total, 59 of 279 men (21.2%) in the transperineal prostate biopsy group were upgraded to grade group ≥2 as compared to 75 of 511 (14.7%) in the transrectal biopsy group (p=0.01). Among patients who were upgraded to grade group ≥2, 26 of 59 (44%) had grade group ≥2 detected in the anterior/transition zone with transperineal prostate biopsy compared to 14 of 75 (18.7%) with transrectal biopsy (p=0.01). Additionally, 17 of 279 men (6.1%) who underwent transperineal prostate biopsy were upgraded to grade group ≥3 vs 17 of 511 (3.3%) who underwent transrectal biopsy (p=0.05). After adjusting for age, prostate specific antigen density, use of magnetic resonance imaging, and number of prior transrectal biopsies, transperineal prostate biopsy was significantly associated with upgrading to grade group ≥2 (OR 1.49, 95% CI 1.11-2.19, p=0.01). CONCLUSIONS: Among men on active surveillance for very low or low risk prostate cancer, transperineal prostate biopsy was associated with an increased likelihood of upgrading to clinically significant prostate cancer. This is likely due to improved sampling of the anterior prostate with the transperineal approach.

Utility of multiparametric magnetic resonance imaging in the risk stratification of men with Grade Group 1 prostate cancer on active surveillance.

OBJECTIVE: To assess if the adoption of multiparametric magnetic resonance imaging (mpMRI) in active surveillance (AS) has improved the identification of occult higher-grade prostate cancer (PCa). PATIENTS AND METHODS: We retrospectively identified men from the Johns Hopkins AS registry enrolled since 2013 (year of mpMRI adoption) with Grade Group (GG) 1 PCa and who underwent a single mpMRI. Men in this group were dichotomised by the presence (n = 207) or absence (negative mpMRI, n = 225) of one or more lesions with a Prostate Imaging-Reporting and Data System (PI-RADS) score of ≥ 3. Both groups were compared to a third cohort of men with GG1 PCa enrolled in AS prior to 2013 (pre-mpMRI era, n = 669). The risk of upgrading to GG ≥ 2 PCa on follow-up biopsies (performed with or without MRI targeting) was evaluated among the groups using survival analysis. RESULTS: Men in both mpMRI groups underwent a median (interquartile range [IQR]) of 2 (2-3) biopsies separated by a median (IQR) interval of 13 (12-16) months, whereas men in the pre-MRI era underwent a median (IQR) of 3 (2-5) biopsies, separated by a median (IQR) interval of 12 (12-14) months. The 2- and 4-year upgrade-free survival rates were 93% and 83%, 74% and 59%; and, 87% and 76% for the negative mpMRI, PI-RADS ≥ 3, and pre-mpMRI-era groups, respectively (P < 0.001). On multivariable analysis, both mpMRI groups had significantly different risk of upgrading compared to pre-mpMRI-era group (negative mpMRI group: hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.39-0.95, P = 0.03; PI-RADS ≥ 3 group: HR 1.96, 95% CI 1.36-2.82, P < 0.001). CONCLUSIONS: mpMRI improves the risk stratification of men on AS and should be used to aid enrolment and monitoring decisions.

Development and Validation of the False Disorder Score: The Focal Scale of the Inventory of Problems.

This article introduces the Inventory of Problems (IOP)-a new, computerized, 181-item tool designed to discriminate bona fide from feigned mental illness and cognitive impairment-and presents the development and validation of its focal, feigning scale, the False Disorder Score (IOP-FDS). The initial sample included (a) 211 patients and 64 offenders who took the IOP under standard conditions, and (b) 210 community volunteers and 64 offenders who feigned mental illness. We split this sample into three subsamples. The first (n = 301) was used to select the variables to generate the IOP-FDS; the second (n = 148) scaled the IOP-FDS into a probability score; and the third (n = 100) tested its validity with an independent data set. In this third subsample, the IOP-FDS had sensitivity = .90, specificity = .80, and a greater area under the curve (AUC = .95) than the IOP-29 (.91). For 40 participants, the Personality Assessment Inventory (PAI) was available, too. Within this subgroup, the IOP-FDS outperformed the selected PAI validity scales (AUC = .99 vs. AUC ≤ .85).

Comparison of Biochemical Recurrence-Free Survival after Radical Prostatectomy Triggered by Grade Reclassification during Active Surveillance and in Men Newly Diagnosed with Similar Grade Disease.

PURPOSE: We compared biochemical recurrence between men on active surveillance who underwent radical prostatectomy triggered by grade reclassification and men diagnosed with similar grade disease treated with immediate radical prostatectomy. MATERIALS AND METHODS: We retrospectively analyzed the records of men who underwent surgery from 1995 to 2015 at our institution. We identified 4 groups, including 94 and 56 men on active surveillance who underwent radical prostatectomy following reclassification to Gleason 7 (3 + 4) or greater (grade groups 2 or greater) and Gleason 7 (3 + 4) (grade group 2), and 3,504 and 1,979 in the immediate prostatectomy group diagnosed with grade group 2 or greater and 2, respectively. Biochemical recurrence was assessed by Kaplan-Meir analysis and a multivariable Cox model. RESULTS: Men on active surveillance had a lower incidence of biochemical recurrence than men in the immediate radical prostatectomy groups for biopsy grade groups 2 or greater and 2 (each p <0.05). One, 5 and 10-year biochemical recurrence-free survival for men in the active surveillance group vs the immediate radical prostatectomy group was 97.9% vs 85.5%, 76.6% vs 65.1% and 69.0% vs 54.2% in biopsy grade groups 2 or greater (p = 0.009) and 96.4% vs 91.2%, 89.6% vs 74.0% and 89.6% vs 63.9%, respectively, in biopsy grade group 2 (p = 0.071). For biopsy grade groups 2 or greater there was no significant difference in the risk of biochemical recurrence between the groups after adjusting for age, biopsy extent of cancer and prostate specific antigen density. CONCLUSIONS: Patients on active surveillance reclassified to grade groups 2 or greater are at no greater risk for treatment failure than men newly diagnosed with similar grades.

Risk prediction tool for grade re-classification in men with favourable-risk prostate cancer on active surveillance.

OBJECTIVE: To create a nomogram for men on active surveillance (AS) for prediction of grade re-classification (GR) above Gleason score 6 (Grade group >2) at surveillance biopsy. PATIENTS AND METHODS: From a cohort of men enrolled in an AS programme, a multivariable model was used to identify clinical and pathological parameters predictive of GR. Nomogram performance was assessed using receiver operating characteristic curves, calibration, and decision curve analysis. RESULTS: Of 1 374 men, 254 (18.50%) were re-classified to Gleason ≥7 on surveillance prostate biopsy. Variables predictive of GR were earlier year of diagnosis [≤2004 vs ≥2005; odds ratio (OR) 2.16, P < 0.001], older age (OR 1.05, P < 0.001), higher prostate-specific antigen density [OR 1.19 (per 0.1 unit increase), P = 0.04], bilateral disease (OR 2.86, P < 0.001), risk strata (low-risk vs very-low-risk, OR 1.79, P < 0.001), and total number of biopsies without GR (OR 0.68, P < 0.001). On internal validation, a nomogram created using the multivariable model had an area under the curve of 0.757 (95% confidence interval 0.730-0.797) for predicting GR at the time of next surveillance biopsy. CONCLUSION: The nomogram described is currently being used at each return visit to assess the need for a surveillance biopsy, and could increase retention in AS.

The Development of the Inventory of Problems-29: A Brief Self-Administered Measure for Discriminating Bona Fide From Feigned Psychiatric and Cognitive Complaints.

This article describes the development of the Inventory of Problems-29 (IOP-29), a new, short, paper-and-pencil, self-administered measure of feigned mental and cognitive disorders. Four clinical comparison simulation studies were conducted. Study 1 (n = 451) selected the items and produced an index of potential feigning. Study 2 (n = 331) scaled this index to produce a probability score, and examined its psychometric properties. Study 3 tested the generalizability of Study 2's findings with 2 additional samples (ns = 128 and 90). Results supported the utility of the IOP-29 for discriminating bona fide from feigned psychiatric and cognitive complaints. Validity was demonstrated in feigning mild traumatic brain injury, psychosis, posttraumatic stress disorder, and depression. Within the independent samples of Studies 2 and 3, the brief IOP-29 performed similarly to the MMPI-2 and Personality Assessment Inventory, and perhaps better than the Test of Memory Malingering. Classifications within these samples with base rates of .5 produced sensitivity, specificity, positive predictive power, and negative predictive power statistics of about .80. Further research is needed testing the IOP-29 in ecologically valid field studies.

Conditional probability of reclassification in an active surveillance program for prostate cancer.

PURPOSE: We evaluated the risk of prostate cancer reclassification by time on active surveillance. MATERIALS AND METHODS: From 1995 to 2014 we evaluated 557 and 251 men at very low and at low risk, respectively, who were on active surveillance and compliant with prostate biopsies. Our primary study outcome was reclassification to higher risk disease by grade or extent. Freedom from reclassification was estimated using the Kaplan-Meier approach with adjustment for covariates using the Cox proportional hazards model. RESULTS: Within the first 2 years of surveillance patient survival free of reclassification by grade (p = 0.20) and by any biopsy criteria (p = 0.25) was similar in men with very low and low risk disease. After 2 years men with low risk disease were 2.4 times more likely to be diagnosed with a Gleason score of greater than 6 than men with very low risk disease (p = 0.002, HR 2.4, 95% CI 1.9-3.5). Additionally, beyond 2 years on surveillance the risk of lifetime reclassification by grade and by any criteria decreased by 30% and 35% (each p <0.0001, HR 0.70, 95% CI 0.60-0.76 and HR 0.65, 95% CI 0.57-0.72, respectively) with each biopsy that showed no reclassification. CONCLUSIONS: The reclassification rate during surveillance is not equally distributed across time or risk groups. Due to misclassification at diagnosis the reclassification rate in very low and low risk groups is similar in the first 2 years but differs significantly beyond 2 years. The risk of reclassification decreases with time for each nonreclassifying biopsy beyond 2 years.

Fluoroquinolone resistance in the rectal carriage of men in an active surveillance cohort: longitudinal analysis.

PURPOSE: Rectal swabs can identify men with fluoroquinolone resistant bacteria and decrease the infection rate after transrectal ultrasound guided prostate biopsy by targeted antimicrobial prophylaxis. We evaluated the rate of fluoroquinolone resistance in an active surveillance cohort with attention to factors associated with resistance and changes in resistance with time. MATERIALS AND METHODS: We evaluated 416 men with prostate cancer on active surveillance who underwent rectal swabs to assess the rate of fluoroquinolone resistance compared to that in men undergoing diagnostic transrectal ultrasound guided prostate biopsy. The chi-square test and Student t-test were used to compare categorical and continuous variables, respectively. Poisson regression analysis was used for multivariate analysis. RESULTS: On the initial swab fluoroquinolone resistance was found in 95 of 416 men (22.8%) on active surveillance compared to 54 of 221 (24.4%) in the diagnostic biopsy cohort (p = 0.675). Diabetes was found in 4.0% of the fluoroquinolone sensitive group vs 14.7% of the resistant group (p <0.001). Biopsy history was not associated with resistance. Of those with a resistant first swab 62.9% had a resistant second swab and 88.9% of those with 2 resistant swabs showed resistance on the third swab. Of men with a sensitive first swab 10.6% showed resistance on the second swab and 10.6% of those with 2 sensitive swabs had resistant third swabs. CONCLUSIONS: One of 4 men who present for surveillance and diagnostic transrectal ultrasound guided prostate biopsy have rectal flora resistant to fluoroquinolone. Resistance is significantly associated with diabetes but the number of prior biopsies is not. Men with fluoroquinolone resistant flora tend to remain resistant with time.

Prostate specific antigen velocity risk count predicts biopsy reclassification for men with very low risk prostate cancer.

PURPOSE: Prostate specific antigen velocity is an unreliable predictor of adverse pathology findings in patients on active surveillance for low risk prostate cancer. However, to our knowledge a new concept called prostate specific antigen velocity risk count, recently validated in a screening cohort, has not been investigated in an active surveillance cohort. MATERIALS AND METHODS: We evaluated a cohort of men from 1995 to 2012 with prostate cancer on active surveillance. They had stage T1c disease, prostate specific antigen density less than 0.15 ng/ml, Gleason score 6 or less, 2 or fewer biopsy cores and 50% or less involvement of any core with cancer. The men were observed by semiannual prostate specific antigen measurements, digital rectal examinations and an annual surveillance biopsy. Treatment was recommended for biopsy reclassification. Patients with 30 months or greater of followup and 3 serial prostate specific antigen velocity measurements were used in primary analysis by logistic regression, Cox proportional hazards, Kaplan-Meier analysis and performance parameters, including the AUC of the ROC curve. RESULTS: Primary analysis included 275 of 668 men who met very low risk inclusion criteria, of whom 83 (30.2%) were reclassified at a median of 57.1 months. Reclassification risk increased with risk count, that is a risk count of 3 (HR 4.63, 95% CI 1.54-13.87) and 2 (HR 3.73, 95% CI 1.75-7.97) compared to zero. Results were similar for Gleason score reclassification (HR 7.45, 95% CI 1.60-34.71 and 3.96, 95% CI 1.35-11.62, respectively). On secondary analysis the negative predictive value (risk count 1 or less) was 91.5% for reclassification in the next year. Adding the prostate specific antigen velocity risk count improved the AUC in a model including baseline prostate specific antigen density (0.7423 vs 0.6818, p = 0.025) and it outperformed the addition of overall prostate specific antigen velocity (0.7423 vs 0.6960, p = 0.037). CONCLUSIONS: Prostate specific antigen velocity risk count may be useful for monitoring patients on active surveillance and decreasing the frequency of biopsies needed in the long term.

Serum prostate-specific antigen (PSA) concentration is positively associated with rate of disease reclassification on subsequent active surveillance prostate biopsy in men with low PSA density.

OBJECTIVE: To investigate the association between serum prostate-specific antigen (PSA) concentration at active surveillance (AS) entry and disease reclassification on subsequent AS biopsy ('biopsy reclassification') in men with low PSA density (PSAD). To investigate whether a clinically meaningful PSA threshold for AS eligibility/ineligibility for men with low PSAD can be identified based on risk of subsequent biopsy reclassification. PATIENTS AND METHODS: We included men enrolled in the Johns Hopkins AS Study (JHAS) who had a PSAD of <0.15 ng/mL/g (640 men). We estimated the incidence rates (IRs; per 100 person years) and hazard ratios (HR) of biopsy reclassification (Gleason score ≥ 7, any Gleason pattern 4 or 5, ≥3 positive cores, or ≥50% cancer involvement/biopsy core) for categories of serum PSA concentration at the time of entry into AS. We generated predicted IRs using Poisson regression to adjust for age and prostate volume, mean percentage free PSA (ratio of free to total PSA) and maximum percentage biopsy core involvement with cancer. RESULTS: The unadjusted IRs (per 100 person years) of biopsy reclassification across serum PSA concentration at entry into JHAS showed, in general, an increase; however, the pattern was not linear with higher IRs in the group ≥ 4 to <6 ng/mL (14.2, 95% confidence interval [CI] 11.8-17.2%) when compared with ≥6 to <8 ng/mL (8.4, 95% CI 5.7-12.3%) but almost similar IRs when compared with the group ≥ 8 to <10 ng/mL (14.8, 95% CI 8.4-26.1%). The adjusted predicted IRs of reclassification showed a similar non-linear increase in IRs, whereby the rates around 4 ng/mL were similar to the rates around 10 ng/mL. CONCLUSION: Risk for biopsy reclassification increased non-linearly across PSA concentration in men with low PSAD, whereby no obvious clinically meaningful threshold could be identified. This information could be incorporated into decision-making for AS. However, longer follow-up times are needed to warrant final conclusions.

Expanded criteria to identify men eligible for active surveillance of low risk prostate cancer at Johns Hopkins: a preliminary analysis.

PURPOSE: At our institution the eligibility criteria used to enroll patients in active surveillance are clinical stage T1, prostate specific antigen density less than 0.15 ng/ml, biopsy Gleason score 6 or less, 2 or fewer positive biopsy cores and 50% or less involvement of any biopsy core. We hypothesized that these criteria may be excessively strict, precluding many men from active surveillance. MATERIALS AND METHODS: We studied pathological outcomes in men treated with radical prostatectomy between 1995 and 2012 who met 4 or more of the 5 active surveillance criteria. Outcomes included a definition of significant tumor (pathological Gleason 7 or greater, or nonorgan confined). We compared adverse pathology rates between men who met all 5 vs 4 of 5 active surveillance criteria. RESULTS: Of 8,261 men 1,890 (22.9%) met all active surveillance eligibility criteria and 2,133 (25.8%) met 4. Men with values exceeding prostate specific antigen density and biopsy Gleason criteria were at increased risk for adverse pathological outcomes. Clinical stage greater than T1 was not associated with adverse pathological findings. The risk of significant tumors in men with clinical stage T2 lesions, 3 or fewer positive biopsy cores and less than 60% core involvement was comparable to that of men who met all active surveillance criteria. CONCLUSIONS: Prostate specific antigen density greater than 0.15 ng/ml and biopsy Gleason score 7 or greater are strongly associated with adverse pathological findings at radical prostatectomy. Our findings suggest that active surveillance criteria should be expanded to include men with clinical stage T2 lesions and a greater number of positive biopsy cores of low grade. Based on these preliminary findings, we are in the process of reassessing active surveillance eligibility criteria using more detailed pathological analysis.

Pathological outcomes in men with low risk and very low risk prostate cancer: implications on the practice of active surveillance.

PURPOSE: We assessed oncologic outcomes at surgery in men with low risk and very low risk prostate cancer who were candidates for active surveillance. MATERIALS AND METHODS: In a prospectively collected institutional database, we identified 7,486 subjects eligible for active surveillance who underwent radical retropubic prostatectomy. Candidates were designated as being at low risk (stage T1c/T2a, prostate specific antigen 10 ng/ml or less, and Gleason score 6 or less) or very low risk (stage T1c, prostate specific antigen density 0.15 or less, Gleason score 6 or less, 2 or fewer positive biopsy cores, 50% or less cancer involvement per core) based on preoperative data. Adverse findings were Gleason score upgrade (score 7 or greater) and nonorgan confined cancer on surgical pathology. The relative risk of adverse findings in men at low risk with very low risk disease was evaluated in a multivariate model using Poisson regression. RESULTS: A total of 7,333 subjects met the criteria for low risk disease and 153 had very low risk disease. The proportion of subjects at low risk found to have Gleason score upgrade or nonorgan confined cancer on final pathology was 21.8% and 23.1%, respectively. Corresponding values in those at very low risk were 13.1% and 8.5%, respectively. After adjusting for age, race, year of surgery, body mass index, and prostate specific antigen at diagnosis, the relative risk of Gleason score upgrade in men with low risk vs very low risk disease was 1.89 (95% CI 1.21-2.95). The relative risk of nonorgan confined cancer was 2.06 (95% CI 1.19-3.57). CONCLUSIONS: Men with very low risk prostate cancer were at significantly lower risk for adverse findings at surgery compared to those with low risk disease. These data support the stratification of low risk cancer when selecting and counseling men who may be appropriate for active surveillance.

Multiparametric magnetic resonance imaging findings in men with low-risk prostate cancer followed using active surveillance.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Up to 35% of men on active surveillance (AS) for clinically localized prostate cancer will experience biopsy reclassification during follow-up. Currently, annual prostate biopsy is recommended in AS programmes. Multiparametric MRI has shown promise in identifying men at risk for immediate reclassification at the time of entry into AS; however, the MRI characteristics of men already enrolled in AS who may be at low risk for disease reclassification have not been fully described. In the present study, we describe the MRI findings of a cohort of men enrolled within AS, with extended follow-up. Among these men, multiparametric MRI demonstrated excellent specificity (0.974) and negative predictive value (0.897) for the detection of pathological index lesions (determined on serial biopsies). These results suggest that men enrolled in AS with a non-suspicious MRI are unlikely to harbour an index cancerous lesion. OBJECTIVE: To assess the performance of multiparametric magnetic resonance imaging (MRI) in identifying pathological-index (path-index) lesions, defined as cancer present in the same prostate sextant in two separate surveillance biopsies, in men followed within an active surveillance (AS) programme for low-risk prostate cancer (CaP) with extended follow-up. MATERIALS AND METHODS: A total of 50 men, representing >215 person-years of follow-up in an AS programme, who were referred for prostate MRI were randomly chosen to have their images reviewed by a radiologist with expertise in prostate MRI, who was blinded to biopsy results. Index lesions on MRI were defined as a single suspicious lesion ≥10 mm or >2 lesions in a given prostate sextant. Lesions on MRI were considered suspicious if ≥2 abnormal parameters co-registered anatomically. Path-index lesions were defined as cancer present in a given prostate sextant on two separate biopsy sessions. Sensitivity and specificity were calculated to test the performance of MRI for identifying path-index lesions. Clinical and pathological features were compared between men with and without a MRI-index lesion. RESULTS: A total of 31 path-index and 13 MRI-index lesions were detected in 22 and 10 patients, respectively. Multiparametric MRI demonstrated excellent specificity and negative predictive value (0.974 and 0.897, respectively) for the detection of path-index lesions. Sensitivity (0.19) and positive predictive value (0.46) were considerably lower. Patients with an index lesion on MRI were younger and less likely to have met the 'Epstein' criteria for very low-risk CaP. Compared with men without an MRI lesion, a significant increase in biopsy reclassification was noted for men with a MRI lesion (40 vs 12.5%, P = 0.04). CONCLUSIONS: A non-suspicious MRI was highly correlated with a lack of path-index lesions in an AS population. Multiparametric MRI may be useful in both the selection and monitoring of patients undergoing AS.

Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) Magnetic Resonance Imaging Scoring to Predict Clinical Outcomes in Active Surveillance for Grade Group 1 Prostate Cancer.

OBJECTIVE: To determine whether radiological change on serial multiparametric magnetic resonance imaging scored using the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) Scoring system predicts grade reclassification (GR) at surveillance biopsy in men on active surveillance (AS) with Grade Group 1 (GG1) prostate cancer (PCa). METHODS: We retrospectively reviewed records of 255 men with low-risk PCa on AS with magnetic resonance imaging (MRI)-informed diagnostic and confirmatory biopsies and studied the subset who had surveillance biopsies (n = 163) within 6months of an interval MRI. RESULTS: We studied 309 PRECISE scores in 255 men. 14% demonstrated radiological progression (PRECISE 4-5) on interval MRI performed within 24months, compared to 34% of those whose interval MRI was performed at a >3-year interval (P = .002). 28% (46/163) of men undergoing surveillance biopsy experienced GR to ≥ GG2 PCa. There was no significant increase in the rate of GR with increasing PRECISE score (PRECISE 1-2: 24%, PRECISE 3: 23%, PRECISE 4-5: 38%; P = .11). There was a significant increase in the rate of GR with increasing PI-RADS score (P < .05). On multivariable analysis, a PI-RADS score of 4-5 was significantly associated with GR compared to men who had a highest PI-RADS ≤3 (OR=1.98 [95% CI: 1.45-3.09, P = .01]). CONCLUSION: In a low-risk AS cohort with limited follow-up, a patient's highest PI-RADS rather than their PRECISE score on interval MRI was predictive of GR on surveillance biopsy.

Baseline prostate health index risk category and risk category changes during active surveillance predict grade reclassification.

BACKGROUND: It is not known whether baseline prostate health index (PHI) at the initiation of active surveillance (AS) or repeated PHI testing during AS is of clinical value after confirmatory biopsy in AS men followed with multiparametric magnetic resonance imaging (mpMRI). METHODS: We identified 382 AS patients with no greater than Grade Group 1 (GG1) prostate cancer on diagnostic and confirmatory biopsy, at least one mpMRI and PHI test, of which 241 had at least 2 PHI tests. Grade reclassification (GR) was defined as ≥GG2 on surveillance biopsy. PHI risk categories 1 to 4 were as defined by the manufacturer. Associations between baseline PHI risk category or baseline PSA density (PSAD), change in PHI risk categories over time or PSAD changes over time and GR were evaluated with multivariable Cox proportional hazard regression models adjusted for age, Prostate Imaging-Reporting and Data System score and number of positive cores. RESULTS: Men with baseline PHI scores in the highest risk categories had lower rates of GR-free survival (log-rank P < 0.001), as did those who increased in PHI risk category or remained in a high PHI risk category during surveillance (log-rank P = 0.032). On multivariable regression, baseline PHI risk category was a predictor of GR (risk category 4 [vs. 1] hazard ratio [HR] 2.74, 95% confidence interval [CI] 1.32-5.66, P = 0.002, model C-index 0.764, Akaike Information Criterion [AIC] 797), as were PHI risk category changes over time (risk category 4 [vs. 1] HR 4.20, 95% CI 1.76-10.05, P = 0.002, C-index 0.759, AIC 489). Separate models with baseline PSAD and PSAD changes over time yielded C-indices of 0.709 (AIC 809) and 0.733 (AIC 495) respectively. CONCLUSIONS: Baseline PHI risk category and PHI changes over time were both independent predictors of GR after confirmatory biopsy, but the added benefit over PSAD seemed modest. However, baseline PHI and PHI risk category changes provided clinically useful risk stratification for time to GR, so further evaluation of PHI's ability to help reduce the frequency of mpMRI and/or surveillance biopsies with more PHI data points over time may be warranted.

Association of [-2]proPSA with biopsy reclassification during active surveillance for prostate cancer.

PURPOSE: Previous studies have suggested an association between [-2]proPSA expression and prostate cancer detection. Less is known about the usefulness of this marker in following patients with prostate cancer on active surveillance. Thus, we examined the relationship between [-2]proPSA and biopsy results in men enrolled in an active surveillance program. MATERIALS AND METHODS: In 167 men from our institutional active surveillance program we used Cox proportional hazards models to examine the relationship between [-2]proPSA and annual surveillance biopsy results. The outcome of interest was biopsy reclassification (Gleason score 7 or greater, more than 2 positive biopsy cores or more than 50% involvement of any core with cancer). We also examined the association of biopsy results with total prostate specific antigen, %fPSA, [-2]proPSA/%fPSA and the Beckman Coulter Prostate Health Index phi ([-2]proPSA/free prostate specific antigen) × (total prostate specific antigen)(½)). RESULTS: While on active surveillance (median time from diagnosis 4.3 years), 63 (37.7%) men demonstrated biopsy reclassification based on the previously mentioned criteria, including 28 (16.7%) of whom had reclassification based on Gleason score upgrading (Gleason score 7 or greater). Baseline and longitudinal %fPSA, %[-2]proPSA, [-2]proPSA/%fPSA and phi measurements were significantly associated with biopsy reclassification, and %[-2]proPSA and phi provided the greatest predictive accuracy for high grade cancer. CONCLUSIONS: In men on active surveillance, measures based on [-2]proPSA such as phi appear to provide improved prediction of biopsy reclassification during followup. Additional validation is warranted to determine whether clinically useful thresholds can be defined, and to better characterize the role of %[-2]proPSA and phi in conjunction with other markers in monitoring patients enrolled in active surveillance.

Effect of treatment with 5-α reductase inhibitors on progression in monitored men with favourable-risk prostate cancer.

UNLABELLED: What's known on the subject? and What does the study add? Finasteride (Proscar) and dutasteride (Avodart) are 5-α reductase inhibitors (5-ARIs) used to treat LUTS in men with benign prostatic enlargement. Because these drugs suppress androgens, the theory has been put forward that 5-ARIs might prevent the development of prostate cancer. Careful analysis of two randomized controlled trials, however, showed that, in the clinical setting, this was not the case, and that these drugs can increase the occurrence of more aggressive high-grade disease. Because of this, the U.S. Food and Drug Administration did not approve 5-ARIs for the primary prevention of prostate cancer and notified healthcare professionals about a change in the 'Warnings and Precautions' for these drugs. Interest remains among some for using 5-ARIs in men diagnosed with very low-risk prostate cancer to delay the progression from clinically indolent disease to clinically significant disease requiring treatment. The present study investigated whether 5-ARI use among men with very low-risk prostate cancer in an active surveillance (AS) programme would reduce the number of cancers reclassified to clinically significant disease on surveillance biopsy. Our results do not support the use of 5-ARIs for slowing or preventing cancer progression in men with low-risk prostate cancer, but do suggest that men with very low-risk prostate cancer who take 5-ARIs for LUTS are unlikely to be at increased risk for the development of high grade disease during AS. OBJECTIVE: To determine whether 5-α reductase inhibitor (5-ARI) use delays cancer reclassification in an active surveillance (AS) cohort. PATIENTS AND METHODS: We performed a retrospective study of 587 men enrolled in an AS programme, who had no history of 5-ARI use. Chi-squared and t-tests were used to compare characteristics of 5-ARI users and non-users. Univariable and multivariable proportional hazards models, treating 5-ARI use as a time-dependent covariate, were used to evaluate the influence of 5-ARIs on the risk of a subsequent biopsy no longer meeting criteria for continued AS (i.e. reclassification). RESULTS: 5-ARI use was initiated in 47 men while on AS. Men using 5-ARIs had larger prostates and higher PSA levels at diagnosis. During 5-ARI use, PSA levels and prostate volume deceased by mean values of 47% and 11%, respectively. Men using 5-ARIs had a mean of 2.5 surveillance biopsies while on the drug. Reclassification occurred in 17% of 5-ARI users compared with 31% of non-users (P = 0.04). Multivariable models (adjusting for age, α-blocker use, PSA level, %free PSA, PSA density, prostate volume and number/percent biopsy core involvement at diagnosis) showed nonsignificant risk reductions for reclassification in 5-ARI users as determined by either tumour extent (hazard ratio [HR] = 0.37 (95% confidence interval [CI] 0.12 to 1.13), P = 0.08) or grade (HR = 0.8 (95% CI 0.25-2.59), P = 0.7). CONCLUSION: Treatment with 5-ARIs did not significantly alter the outcome of biopsy reclassification by grade in men with very low-risk prostate cancer.